MXPA00009574A

MXPA00009574A - Pharmaceuticals for the imaging of angiogenic disorders

Info

Publication number: MXPA00009574A
Application number: MXPA/A/2000/009574A
Authority: MX
Inventors: Prahlad R Singh; Miland Rajopadhye; D Scott Edwards; Thomas D Harris; Stuart J Heminway; Shuang Liu
Original assignee: Dupont Pharmaceuticals Company
Priority date: 1998-03-31
Filing date: 2000-09-29
Publication date: 2001-07-31

Abstract

The present invention describes novel compounds of the formula:(Q)d-Ln-Ch, useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

Description

PHARMACEUTICAL SUBSTANCES FOR THE FORMATION OF IMAGES OF ANGIOGENIC DISORDERS FIELD OF THE INVENTION The present invention provides novel pharmaceutical substances useful for the diagnosis and treatment of cancer, methods for imaging tumors in a patient, and methods for treating cancer in a patient. The present invention also provides novel pharmaceutical substances useful for monitoring the treatment of therapeutic angiogenesis and the destruction of new angiogenic vasculature. The pharmaceutical substances are comprised of an objective moiety that binds to a receptor that is activated during angiogenesis, an optional binding group, and a therapeutically effective radioisotope or a diagnostically effective image forming portion. The therapeutically effective radioisotope emits a sufficient particle or electron to be cytotoxic. The image forming portion is a gamma or positron-emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast or an ultrasound contrast agent. Ref: 122675 BACKGROUND OF THE INVENTION Cancer is a public health concern in the United States and in the world. It is estimated that more than one million new cases of invasive cancer will be diagnosed in the United States in 1998. The most prevalent forms of the disease are solid tumors of the lung, prostate, colon and rectum. Cancer is typically diagnosed by a combination of in vitro tests and imaging procedures. Imaging procedures include X-ray computed tomography, magnetic resonance imaging, ultrasound imaging, and radionuclide scintigraphy. Frequently, a contrast agent is administered to the patient to improve the image obtained by X-rays, CT, RI and ultrasound and the administration of a radiopharmaceutical that is localized in the tumors is necessary for the scintigraphy of radionuclides. Cancer treatment typically involves the use of external beam radiation therapy and chemotherapy, either alone or in combination, depending on the type and degree of disease. Many chemotherapeutic agents are available, but generally all suffer from a lack of specificity for tumor versus normal tissues, resulting in considerable side effects.

The effectiveness of these treatment modalities is also limited, as evidenced by the high mortality rates of many types of cancer, especially the most prevalent solid tumor diseases. Still more effective and specific means of treatment are needed. Despite the variety of imaging procedures available for the diagnosis of cancer, the need for improved methods remains. In particular, methods that can better differentiate between cancer and other pathological conditions from benign physiological abnormalities are needed. One means of obtaining this desired improvement would be to administer to the patient a metal-phar- maceutical substance which is specifically localized in the tumor by binding to a receptor expressed only in tumors or expressed to a significantly greater degree in tumors than the other tissue. The location of the metapharmaceutical substance can then be detected externally either by emission of imaging in the case of certain radiopharmaceutical substances, or by its effect on the rate of water relaxation in the immediate vicinity, in the case of agents of Contrast magnetic resonance imaging. This tumor-specific metalworking substance solution can also be used for the treatment of cancer when the metal-pharmaceutical substance is constituted by a radioisotope that emits particles. He radioactive decay of the isotope at the site of tumor results in enough ionizing radiation to be toxic to the tumor cells. The specificity of this solution for tumors minimizes the amount of normal tissue that is exposed to the cytotoxic agent and therefore can provide more effective treatment with fewer side effects. Previous efforts to obtain these desired improvements in cancer imaging and treatment have focused on the use of monoclonal antibodies labeled with radionuclides, fragments of antibodies and other proteins or polypeptides (ie, molecular weight greater than 10,000 D) that bind to receptors on the surface of tumor cells. The specificity of these radiopharmaceuticals is often very high, but they suffer from several disadvantages. First, because of their high molecular weight, they are usually cleared from the bloodstream very slowly, resulting in a prolonged blood background in the images. In addition, because its molecular weight does not easily extravasate at the site of the tumor and then diffuse only slowly through the extravascular space to the surface of the tumor cell. This results in a very limited amount of the radiopharmaceutical reaching the receptors and therefore it has a very low signal intensity in imaging and an insufficient cytotoxic effect for treatment. Alternative solutions for imaging and cancer therapy have involved the use of small molecules, such as peptides, that bind to tumor cell receptors. A somatostatin receptor binding peptide labeled with 111In-DTPA-D-Phe1-octeotide is in clinical use in many countries for imaging of tumors expressing the somatostatin receptor (Baker, et al., Life Sci., 1991, 49, 1583-91 and Krenning, et al., Eur. J. Nucí, Med., 1993, 20, 716-31). Higher doses of this radiopharmaceutical have been investigated for potential treatment of this type of cancer (Krening, et al., Digestion, 1996, 57, 57-61). Several types are investigating the use of Tc-99m-labeled analogues of 111In-DTPA-D-Phe1-octeotide for imaging and analogs labeled with Re-186 for therapy (Flanagan et al., US Pat. No. 5,556,939; , et al., United States document 5,382,654 and Albert et al., United States document 5,650,134). Angiogenesis is a process by which new blood vessels are formed from preexisting capillaries or postcapillary cells; it is an important component of various physiological processes that include ovulation, embryo development, wound repair and generation vascular collateral in the myocardium. It is also essential for numerous pathological conditions such as the growth of tumors and metastases, diabetic retinopathy and macular degeneration. The process begins with the activation of existing endothelial cells in response to various cytokines and growth factors. Tumor-related cytokines and angiogenic factors stimulate vascular endothelial cells by interacting with cell-surface receptor-specific factors. Activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels. Then the endothelial cells proliferate and invade the tumor tissue. The endothelial cells differentiate to form lumens, forming deviations of new vessels from pre-existing vessels. The new blood vessels then provide nutrients to the tumor allowing for additional growth and a pathway for metastasis. Under normal conditions, the proliferation of endothelial cells is a very slow process, but it increases during a short period during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of numerous growth-promoting factors and growth-suppressing factors. In pathological angiogenesis, this normal balance is altered resulting in a proliferation of cells endothelial augmentation and continuous. Some of the proangiogenic factors that have been identified include the basic fibroblast growth factor angiogenin (bFGF), TGF-alpha, TGF-beta and vascular endothelial growth factor (VEGF), while interferon alpha, interferon beta and thrombospondin are examples of angiogenesis suppressors. The proliferation and migration of endothelial cells in the extracellular matrix is mediated by the interaction with various cell adhesion molecules (Folkman, J., Nature Medicine, 1995, 1, 27-31). Integrins are a very diverse family of heterodimeric cell surface receptors by which cells bind to the extracellular matrix, to each other and to other cells. The integrin α "β3 is a receptor for a wide variety of extracellular matrix proteins with an exposed tripeptide portion Arg-Gly-Asp and mediates cellular addition to its ligands: vitronectin, fibronectin and fibrinogen among others. The avß3 integrin is expressed minimally on normal blood vessels, but is significantly activated in vascular cells within various human tumors. The role of avß3 receptors is to mediate the interaction of endothelial cells and the extracellular matrix, as well as to facilitate the migration of cells in the direction of the angiogenic signal, to the population of tumor cells. The angiogenesis induced by bFGF or TNF-alpha depends on the integrin agency avß3, whereas the angiogenesis induced by VEGF depends on the integrin avß3 (Cheresh et al., Science, 1995, 270, 1500-2). The induction of integrin expression alr} . and -S1 on endothelial cell surfaces is another important mechanism by which VEGF promotes angiogenesis (Senger, et al., Proc Nati, Acad Sci USA, 1997, 94, 13612-7). Angiogenic factors interact with endothelial cell surface receptors such as the receptor for tyrosine kinases EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin and Axl. The Flk-l / KDR, neuropoline-1 and Flt-1 receptors recognize VEGF, and these interactions play key roles in VEGF-induced angiogenesis. The Tie subfamily of tyrosine kinase receptors are also prominently expressed during the formation of blood vessels. Due to the importance of angiogenesis in the growth of tumors and metastases, numerous chemotherapeutic solutions have been developed to interfere or to avoid this process. In one of these solutions, it involves the use of anti-angiogenic proteins such as angiostatin and endostatin. Angiostatin is a 38 kDa fragment of plasminogen that has been shown in animal models to be a potent inhibitor of endothelial cell proliferation (O'Reilly et al., Cell, 1994, 79, 315-328). Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that has been demonstrated that it is a potent inhibitor. (O'Relly et al., Cell, 1997, 88, 277-285). Systemic therapy with endostatin has been shown to result in strong antitumor activity in animal models. However, human clinical trials of these two chemotherapeutic agents of biological origin have been hampered by the lack of availability. Another solution for anti-angiogenic therapy is to use target portions that interact with the surface receptors of endothelial cells expressed in the angiogenic vasculature to which chemotherapeutic agents bind. Burrows and Thorpe (Proc. Nat. Acad. Sci. USA, 1993, 90, 8996-9000) describes the use of an immunotoxin antibody conjugate to eradicate tumors in a mouse model by destroying the tumor vasculature. Antibodies against the class II antigen of endothelial cells of the major histocompatibility complex are generated and then conjugated with the cytotoxic agent, deglycosylated ricin A chain. The same group (Clin.Can.Res., 1995, 1, 1623-1634) investigated the use of antibodies generated against endothelial cell surface receptors, endoglin, conjugated to deglycosylated ricin A chain. Both conjugates show potent antitumor activity in mouse models. However, both still suffer from drawbacks for systematic human use. As with most of antibodies and other foreign and large proteins, there is a considerable risk of immunological toxicity which limit or prevent its administration to humans. In addition, although it improve the target vasculature, the local concentration of the bound chemotherapeutic agents, these agents will still be separated from the carrier agent and transported or diffused into the cells to be cytotoxic. Therefore, it is desirable to provide antiangiogenic pharmaceutical substances and tumor imaging or new vasculature agents which do not suffer from poor diffusion or transport, possible immunological toxicity, limited availability, or a lack of specificity. There is also an increasing interest in therapeutic angiogenesis to improve blood use in regions of the body that have become hischemic or that are poorly irrigated. Several researchers are using locally administered growth factors to cause new vasculature to form either in the extremities or in the heart. The growth factors VFGF and bFGF are the most common for this application. Recent publications include: Takeshita, S., et. al., J. Clin. Invest., 1994, 93, 662-670; and Schaper,. and Schaper, J., Collateral Circulation: Heart, Brain, Kidney, Limbs, Kluwer Academic Publishers, Boston, 1993. The main applications that They are under investigation in many laboratories are to improve cardiac blood flow and improve blood flow to the peripheral vessels in the extremities. For example, Henry, T. et. to the. (J. Amer. College Cardiology, 1998, 31, 65A) describes the use of recombinant human VEGF in patients to improve myocardial perfusion by therapeutic angiogenesis. Patients receive infusions of rhVEGF and are monitored by nuclear perfusion imaging at 30 and 60 days after treatment to determine improvement in myocardial perfusion. Approximately 50% of patients show improvement by imaging by nuclear perfusion, while 5/7 show new colortization by angiography. Therefore, it is desirable to discover a method for monitoring improved cardiac blood flow which targets collateral vessels new to themselves and not, such as nuclear perfusion imaging, a regional consequence of new collateral vessels.

BRIEF DESCRIPTION OF THE INVENTION An objective of the present invention is to provide anti-angiogenic pharmaceutical substances, consisting of a target portion that binds to a receptor that is expressed in the tumor neovasculature, an optional binding group, and a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons. Compounds that bind to the receptor direct the radioisotope to the tumor neovasculature. The radioisotope emitting beta or alpha particles emits a cytotoxic amount of ionizing radiation which results in cell death. The ability to penetrate radiation eliminates the requirement that the cytotoxic agent be diffused or transported into the cell to be cytotoxic. Another objective of the present invention is to provide pharmaceutical substances for treating rheumatoid arthritis. These pharmaceutical substances comprise an objective moiety that binds to a receptor that is activated during angiogenesis, an optional binding group, and a radioisotope that emits cytotoxic radiation (ie, beta particles, alpha particles and Auger or Coster-Kronig electrons). In rheumatoid arthritis, the inward growth of a highly vascularized cloth is caused by the excessive production of angiogenic factors by infiltrating macrophages, immune cells or inflammatory cells. Therefore, the radiopharmaceuticals of the present invention that emit cytotoxic radiation can be used to destroy the resulting novel angiogenic vasculature and thereby treat the disease. Another objective of the present invention is to provide tumor imaging agents. constituted by an objective moiety that binds to a receptor that is activated during angiogenesis, an optional linker group and an image forming portion such as a gamma or positron emitting radioisotope, a magnetic resonance imaging contrast agent, a contrast agent for X-rays or an ultrasound contrast agent. Another objective of the present invention is to provide imaging agents for monitoring the progress and results of the therapeutic treatment of angiogenesis. These agents are comprised of an objective moiety that binds to a receptor that is activated during angiogenesis, an optional binding group, and an image forming portion. The imaging agents of the present invention can be administered periodically intravenously after the administration of growth factors and imaging can be performed using standard techniques of the affected areas, heart or limbs, to monitor progress and the result of treatment of therapeutic angiogenesis (ie, imaging of the formation of new blood vessels). Another objective of the present invention is to provide compounds useful for preparing pharmaceutical substances of the present invention. These compounds are composed of a peptide or a target portion peptidomimetics that bind to a receptor that is activated during angiogenesis, Q, an optional linker group, Ln, and a metal burner or chelator or binding portion, Ch. The compounds may have one or more protecting groups attached to the metal chelator or the union portion. The protecting groups provide improved stability to the reagents for long-term storage and are removed either immediately before or countercurrent with the synthesis of the radiopharmaceuticals. Alternatively, the compounds of the present invention are comprised of a peptide or peptidomimetic target moiety that binds to a receptor that is activated during angiogenesis, Q, an optional linking group, L n and a surfactant S f. The pharmaceutical substances of the present invention may be used for diagnostic, therapeutic or both purposes. The diagnostic radiopharmaceuticals of the present invention are radiopharmaceuticals consisting of a diagnostically useful radionuclide (ie, a radioactive metal ion having gamma rays or positron emission imaging). The therapeutic radiopharmaceuticals of the present invention are pharmaceutical substances consisting of a therapeutically useful radionuclide, a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons.

The pharmaceutical substances comprise gamma rays or positron-emitting radioactive metal ion that are useful for tumor imaging of gamma scintigraphy or positron emission tomography. Pharmaceutical substances comprising a radioactive metal ion emitting gamma rays or positrons are also useful for imaging of therapeutic angiogenesis by gamma scintigraphy or by positron emission tomography. Pharmaceutical substances comprising a radioactive metal ion emitting particles are useful for treating cancer by supplying a cytotoxic dose of radiation to the tumors. Pharmaceutical substances comprising a radioactive metal ion emitting particles are also useful for treating rheumatoid arthritis by destroying the angiogenic vasculature formation. Pharmaceutical substances comprising a paramagnetic metal ion are useful as contrast agents for magnetic resonance imaging. Pharmaceutical substances comprising one or more atoms that absorb X-rays or "heavy" atoms of atomic number 20 or greater are useful as X-ray contrast agents. The pharmaceutical substances comprise a microbubble of a biocompatible gas, a liquid carrier and a surfactant microsphere, and are useful as an ultrasound contrast agent.

DETAILED DESCRIPTION OF THE INVENTION [1] Therefore, in a first embodiment, the present invention provides a novel compound comprising: a target portion and a chelator, wherein the target portion that binds to a chelator is a peptide or peptidomimetic, and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linkers between the target portion and the chelator. [2] In a preferred embodiment, the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1 endoglin, endosialin, Axl, avß3, ocvß5 > a-ß? > "ß-ißßi, and < -2ß2 And the linking group is present between the target portion and the chelator. [3] In a more preferred embodiment, the receptor is the avß3 integrin and the compound is of the formula: (Q) d-Ln-Ch or (Q) d-Ln- (Ch) d, wherein Q is a peptide that is independently selected from the group: • \ M VJ K is an L-amino acid that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethyl-il-cysteine, dN-2-imidazolinylornithine, dN-benzylcarbamoylornithine, and acid β-2-benzylimidazolylacet-1, 2-diaminopropionic acid; K1 is a D-amino acid that is independently selected, each time it occurs, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoetc-cysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and σ i do ß - 2 - be n c i m i da z o l i 1 a c e t i 1 - 1, 2 - diaminopropionic; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M 'is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, α-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, phenylglycine, cyclohexylalanine, homofenilalanine, 1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, acid 2- aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, acid 1 , 2-diaminopropionic acid, cysteine, penicillamine, methionine and 2-aminothiazole-4-acetic acid; R3 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-f eni lgl ic ina, D-c ic 1 ohexi la l aniña, D-homophenylalanine, D-1 -naphthylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-diaminobutyric acid, D-1, 2 -diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2- acid aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homofenilalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-di-aminobutyric acid, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homofenilalanine, L-naphthylalanine, L-lysine, L-serine , L-ornithine, L-1, 2-di-ami nobu tic acid, Ll, 2-diaminopropionic acid, L-cysteine, L-penicillamine, L-methionine and 2-aminothiazole-4-acetic acid; with the proviso that one of R1, R2, R3, R4 and R5 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N- methylarginine, and with the additional proviso that when R "is 2-aminothiazole-4- acid acetic, K and K1 are N-methylarginine, and with the additional proviso that when R5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Ln is a linking group that has the formula: (CR6R7) g- (W) h- (CR6aR7 ») g '- (Z) k (W) h, - (CRßR?) G.- (W) h.- (Cr8» R9a) g .. with the proviso that g + h + g1 + k + h '+ g "+ h" + g "' are deferent of 0; it is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, OC (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (OCH2CH2) s, (CH2CH20), ', (OCH2CH2CH2) s. , (CH2CH2CH20) t and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, C3.10 cycloalkyl substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R10; R6, R6a, R7, R7a, R9, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, Cj-Cs alkyl substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10, alkoxy of x.-r substituted with 0-3 of R10, NHC (= 0) R11, CÍ- ^ OJNHR11, NHC (= 0) NHR11, NHR11, R11 and a bond to Ch; R10 is independently selected, each time it is presented from the group: a bond to Ch, COOR11, OH, NHR11, S03H, P03H, aryl substituted with 0-3 of R11, alkyl of Ci.s substituted with 0-1 of R12, C 1 alkoxy substituted with 0-1 of R 12, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O, and substituted with 0-3 of R 11; R11 is independently selected, each time it is presented, from group H, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that is independently selected from N, S and 0, and substituted with 0-1 of R12, cycloalkyl of C3_10 substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, polycarboxyalkyl substituted with 0-1 of R12, polyazaalkyl substituted with 0-1 of R12, peptide substituted with 0-1 of R12, wherein the peptide is constituted of 2-10 and a union to Ch; R12 is a link to Ch; k is selected from 0, 1 and 2, -h is selected from 0, 1 and 2; h 'is selected from 0, 1, 2, 3, 4 and 5; h "is selected from 0, 1, 2, 3, 4 and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g 'is selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10 g "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g" 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 s1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 s "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t is selected of O, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Ch is a unit that joins metal that has a formula that is selected from the group: A1, A2, A3, A4, A5, A6, A7 and A8 are independently selected, each time they occur, from the group: N, NR13, NR13R14, S, SH, S (Pg), O, OH, PR13, PR13R14 , P (0) R15R16 and a link to L "; E is a link, CH or a separating group that is independently selected, each time it is presented, from the group: C ^ C ^ alkyl substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C3.10 substituted with 0-3 of R17, heterocycloalkyl of C ^, substituted with 0-3 of R17, wherein the heterocycle group is a heterocyclic ring system of -10 members containing 1-4 heteroatoms which are independently selected from N, S and O, aryl (C6_10) C1.10 alkyl, substituted with 0-3 of R17, alkyl (Ci-; C6_10, substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O, and substituted with 0-3 of R17; each is independently selected from the group: a bond to Ln, hydrogen, C ^ Cj alkyl, substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C? _10 substituted with 0-3 of R17, C ^ K heterocycloalkyl, substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocycle ring system containing 1-4 heteroatoms that are independently selected from N, S, and O, aryl (C6.10) -alkyl of C1.l0 substituted with 0-3 of R17, alkyl (Ci ...) -aryl of C6.10, substituted with 0-3 of R17, a heterocyclic ring system of 5- members containing 1-4 heteroatoms that are independently selected from N, S and O, and substituted with 0-3 of R17 and one electron, with the proviso that when one of R13 or R14 is an electron, the other is also an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R15 and R16 are each independently selected from the group: a bond to Ln, -OH, Cj-C ^ alkyl substituted with 0-3 of R17, C ^ C ^ alkyl substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C3.10 substituted with 0-3 of R17, heterocycloalkyl of C ^ or substituted with 0-3 of R17, wherein the heterocycle group is a heterocyclic ring system of 5-10 members containing 1-4 heteroatoms that are independently selected from N, S and O, aryl (C6.10) -alkyl of C._10 substituted with 0-3 of R17, alkyl (CLU) -aryl of C6.10, substituted with 0- 3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R17; R17 is independently selected, each time it is presented, from the group: a link for Ln, = 0, F, Cl, Br, I, -CF3, -CN, -C02Rlβ, -C (= 0) R18, -C (= 0) N (R18) 2, -CHO, -CH20R18, -0C (= 0) R18, -OC (= 0) 0R18a, -OR18, -OC (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0 ) 0R18a, NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a, -S03H, -S02R18a, -SR18, -S (= 0) R18a, -S02N (R18) 2, -N (R18) 2, - NHC (= S) NHR18, = N0R18, N02, - C (= 0) NHOR18, -C (= 0) NHNR18R18a, -0CH2C02H, 2, 1- (morpholino) ethoxy, C ^ alkyl C ^ alkenyl of C-C, cycloalkyl of C3-C6, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, aryl substituted with 0-2 of R18 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and OR; R18, R18a and R19 are independently selected, each time they are presented from the group: a bond for Ln, H, C-C6 alkyl, phenyl, benzyl, Ci-C- alkoxy, halide, nitro, cyano and trifluoromethyl; Pg is a thiol protective group; R20 and R21 are independently selected from the group: H, C ^ C ^ alkyl, -CN, -C02R25, -C (= 0) R25, C (= 0) N (R25) 2, 1-alkene of C2-C10 substituted with 0-3 of R23, 1-alkyne of C2-C10 substituted with 0-3 of R23, aryl substituted with 0-3 of R23, a 5-10 unsaturated heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R23, and an unsaturated C3_10 carbocycle, substituted with 0-3 of R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H, R24, C1-Cl0 alkyl substituted with 0-3 of R24, C2-C10 alkenyl substituted with 0-3 of R24, C2-C10 alkynyl substituted with 0-3 of R24, aryl substituted with 0-3 of R24, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O substituted with 0-3 of R24, and a carbocycle of C3_10 substituted with 0-3 of R24; alternatively, R22, R23, taken together form a fused aromatic part of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0; a and b indicate the positions of the optional double bonds and n is 0 or 1; R24 is independently selected, each time it is presented from the group: = 0, F, Cl, Br, I, -CF3, -CN, -C02R25, -C (= 0) R25, -C (= 0) N (R25 ) 2, -N (R25) 3+, -CH2OR25, - OC (= 0) R25, -OC (= 0) OR25a, -OR25, -OC (= 0) N (R25) 2, NR26C (= 0) R25, -NR26C (= 0) OR25a, -NR26C (= 0) N (R25) 2, -NR26S02N (R25) 2, -NR26S02R25a, -S03H, -S02R25a, -SR25, -S (= 0) R25a, - S02N (R25) 2, -N (R25) 2, = NOR25, -C (= 0) NHOR25, -OCH2C02H, and 2- (1-morpholino) ethoxy; Y, R25, R25a and R26 each are independently selected, each time they occur, from the group: hydrogen and C ^ alkyl; and a pharmaceutically acceptable salt thereof. [4] In an even more preferred embodiment, the present invention provides a compound, wherein: L is glycine; R1 is an amino acid optionally substituted with a bond to L ", which is independently selected, each time it occurs, from the group: L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, tyrosine, phenylalanine, phenylglycine, cyclohexylalanine, homophenylalanine, lysine, ornithine, 1,2-diaminobutyric acid and 1,2-diaminopropionic acid; R2 is an amino acid optionally substituted with a bond to L ", which is independently selected, each time it occurs, from the group: valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, tyrosine, L-phenylalanine, D- phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-naphthylalanine, Dl-naphthylalanine, lysine, ornithine, 1-diaminobutyric acid, 1,2-diaminopropionic acid and 2-aminothiazole-4-acetic acid; R3 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-acid 2-aminobutyric acid, D-tyrosine, D-phenylalanine, D-f enylglucine, D-cyclohexyl 1 to aniña, D-homophenylalanine, D-lysine, D-serine, D-ornithine, D-1 acid, 2 -diaminobutyric acid, D-1, 2- diaminopropionic acid; R4 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-acid 2- aminobutyric acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, Dl-naphthylalanine, D-lysine, D-ornithine, D-1, 2-diaminobutyric acid, acid D-1, 2- diaminopropionic acid and 2-aminothiazole-4-acetic acid; R5 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time presented, from the group: L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine, L-naphthylalanine, L-lysine, L-ornithine, L, 2-diaminobutyric acid, L-l, 2-diaminopropionic acid and 2-aminothiazole-4-acetic acid; d is selected from l, 2 and 3, - W is independently selected, each time it is presented, from the group: O, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (0CH2CH2) s, (CH2CH20) s', (OCH2CH2CH2) s. and (CH2CH2CH20) t; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of C3.10 substituted with 0-1 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-1 of R10; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, substituted C ^^ alkyl with 0-1 of R10, aryl substituted with 0-1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of C ^ Cs substituted with 0-1 of R10, NHC UOR11, CÍ-NHR11, NHC (= 0) NHR11, NHR11, R11 and a bond to Ch; R10 is independently selected, each time it is presented from the group: COOR11, OH, NHR11, S03H, aryl substituted with 0-1 of R11, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected of N, S and O, and substituted with 0-1 of R11, Cl-C5 alkyl substituted with 0-1 of R12, alkoxy of C.-C5 substituted with 0-1 of R12, and a bond to Ch; R11 is independently selected, each time it is presented, from the group: H, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O, and substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, and a bond to Ch; k is O or 1; h is O or 1; h 'is O or 1; s is selected from 0, 1, 2, 3, 4 and 5 s' is selected from 0, 1, 2, 3, 4 and 5 s "is selected from 0, 1, 2, 3, 4 and 5 t is selected of 0, 1, 2, 3, 4 and 5 A1, A2, A3, A4, A5, A6, A7 and A8 are independently selected, each time they are presented, from the group: NR13, NR13R14, S, SH, S (Pg), OH and a bond to L "; E is a bond, CH or a spacer group that is independently selected, each time it is presented, from the group: CJ-CJ alkyl-substituted with 0-3 of R17, aryl substituted with 0-3 of R1 ', C3_10 cycloalkyl substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17; R13 and R14 are each independently selected from the group: a bond to Ln, hydrogen, CJ-CK alkyl, substituted with 0-3 of R17, aryl substituted with 0-3 of R17, a 5-10 membered heterocycle ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17, and one electron, with the proviso that when one of R13 or R14 is an electron, the other is also an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R17 is independently selected, each time it is presented, from the group: a bond for Ln, = 0, F, Cl, Br, I, -CF3, -CN, -C02R18, -C (= 0) R18, -C ( = 0) N (R18) 2, -CH2OR18, -0C (= 0) R18, -OC (= 0) OR18a, -OR18, -OC (= 0) N (R18) 2, -NR19C (= 0) R18 , -NR19C (= 0) OR18a, -NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a, -S03H, -S02R18a, -S02N (R18) 2, -N (R18) 2, -NHC (= S) NHR18, = N0R18, -C (= 0) NHNR18R18a, -OCH2C02H and 2, 1- (morpholino) ethoxy; R18, R18 and R19 are independently selected, each time they are presented from the group: a bond for Ln, H and Cl-Cß alkyl R20 and R21 are independently selected from the group: H, C ^ -C alkyl, C02R25, C2-C5 1-alkene substituted with 0-3 of R23, C2-C5 1-alkyne substituted with 0-3 of R23, aryl substituted with 0-3 of R23 and a heterocyclic ring system of 5-10 unsaturated members containing 1-4 heteroatoms which are independently selected from N, S and O and substituted with 0-3 from R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H and R24; alternatively, R22, R23, taken together form a fused aromatic part of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0; R24 is independently selected, each time it is presented from the group: -C02R25, -C (= 0) N (R25) -, -CH20R25, -0C (= 0) R25, -OR25, -S03H, -N (R25) 2 and -OCH2C02H; Y R25 is independently selected, each time it is presented, from the group: H and CJ-CJ alkyl. [5] In an even more preferred embodiment, the present invention provides a compound, wherein: Q is a peptide selected from the group: R1 is L-valine, D. valine, D-lysine optionally substituted with the e-amino group with a linkage to L "or L-lysine optionally substituted with the e-amino group with a linkage to Ln; R2 is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid, L-lysine optionally substituted in the amino group with a link to Ln or tyrosine, tyrosine is optionally substituted in the hydroxy group with a link to L "; R3 is D-valine, D-phenylalanine or L-lysine optionally substituted in the amino group with a bond to I "; R 4 is D-phenylalanine, D-tyrosine substituted on the hydroxy group with a bond to L n, or L-lysine optionally substituted on the amino group with a link to L n; with the proviso that one of R1 and R2 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1 or 2; is independently selected, each time it is presented from the group: NHC (= 0), C (= 0) NH, C (= 0), (CH2CH20) s, and (CH2CH2CH20) t; R? R6a, R7, R7a, RB, R8a, R9 and R9a are independently selected, each time they are presented from the group: H, NHC (= 0) R1L and a bond to Ch; k is 0; h "is selected from 0, 1, 2 and 3; g is selected from 0, 1, 2, 3, 4 and 5; g1 is selected from 0, 1, 2, 3, 4 and 5; g" is selected from 0, 1, 2, 3, 4 and 5; g "'is selected from 0, 1, 2, 3, 4 and 5, s' is 1 or 2, t is 1 or 2; A1 is selected from the group: OH, and a link to L "; A2, A4 and A6 are each N; A3, A5 and A8 are each OH; A7 is a link to Ln or link NH to Ln; E is a C2 alkyl substituted with 0-1 of R17; R17 ES = 0; alternatively, Ch is -? ^ A1 is NH2 or N = C (R20) (R21); E is a link; A2 NHR13; R13 is a heterocycle substituted with R17, the heterocycle is selected from pyridine and pyrimidine; R17 is selected from a bond to Ln, C (= I) NHRlβ; and C (= 0) R18; R18 is a link to L "; R24 is selected from the group: -C02R25, -OR25, -S03H and -N (R25) 2; R25 is independently selected, each time it is presented from the group: hydrogen and methyl; alternatively, Ch is A1, A2, A3 and A4 are each N; A5, A6 and A8 are each OH; A7 is a link to L "; E is a C2 alkyl substituted with 0-1 of R17; and R17 is = 0. [6] In another additional preferred embodiment, the present invention provides a compound selected from the group: (a) cycle. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic] -3-aminopropyl) -Val}; (b) cycle. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -18- amino-14-aza-4, 7, 10- oxy-15-oxo-octane-coyl) -3-aminopropyl) -Val}; (c) 2- [[[5- [Carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { D-Tyr (3-aminopropyl) -Val -Arg-Gly -Asp}) -cycle. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp}; (d) cycle. { Arg-Gly-Asp-D-Tyr-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (e) cycle. { Arg-Gly-Asp-D-Phe-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulonic acid] (f) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Phe.}.) - cycle. { Lys-Arg-Gly-Asp-D-Phe}; (g) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Phe-Glu (cyclo. {Lys-Arg-Gly-Asp-D-Phe.}. ) -cycle. { Lys-Arg-Gly-Asp-D-Phe}; (h) cycle. { Arg-Gly-Asp-D-Nal-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (i) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Nal.}.) - cycle. { Lys-Arg-Gly-Asp-D-Nal}; (j) cycle. { Arg-Gly-Asp-Lys ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -D-Val.}; (k) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-D-Val-Arg-Gly-Asp {) - cycle. { Lys -D-Val-Arg-Gly-Asp}; (1) cycle. { Arg-D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic] -3-aminopropyl) -D-Asp-Gly}; (m) cycle. { D-Lys ([2- [[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] encens sulfonic acid]) -D-Phe-D-Asp-Gly-Arg.}.; (n) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { D-Lys-D-Phe-D-Asp-Gly-Arg}) -cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg}; (o) cycle. { D-Phe-D-Lys- ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -D-Asp-Gly-Arg.}, - (p) cycle. { N-Me-Arg-Gly-Asn-ATA-D-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (q) cycle. { Cit-Gly-Asp-D-Phe-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (r) 2- (1,4, 7, 10-tetraaza-4, 7, 10 -tris (carboxymethyl) -1- cyclododecyl) acetyl-Glu (cyclo. {Lys -Arg-Gly-Asp-D-Phe .}.) - cycle. { Lys -Arg-Gly-Asp-D- Phe} ) (s) cycle. { Arg-Gly-Asp-D-Phe-Lys (DTPA)}; (t) cycle (Arg-Gly-Asp-D-Phe-Lys. {2 (DTPA); (u) cycle. { Arg-Gly-Asp-D-Tyr (N-DTPA-3-aminopropyl) -Val}; (v) cycle. { ? rn (dN-2-imidazolinyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic] -3-aminopropyl) - Val}; (w) cycle. { Lys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -3-aminopropyl) -Val}; (x) cycle. { Cys (2-aminoethyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val}; (and) cycle. { HomoLys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val}; (z) cycle. { ? rn (d-N-benzylcarbonyl) -Gly-Asp-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val}; (aa) cycle. { Dap (b- (2-benzimidazolylacetyl))) -Gly-Asp-D-Tyr (N- [2- [[[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid] -3- aminopropyl) - Val}; (bb) cycle. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid])}; (cc) cycle. { rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] -benzenesulfonic acid])}; _ ^ | ^^^ _ ^^ faith (dd) cycle. { Lys-D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp-Gly}; (ee) cycle. { ? rn (dN-benzylcarbonyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -D- Asp-Gly}; Y (ff) cycle. { ? rn (dN-2-imidazolinyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) - D-Asp-Gly}; or a pharmaceutically acceptable salt form thereof. [7] In a further preferred embodiment, the present invention provides a kit comprising a compound of the present invention. [8] In a further preferred embodiment, the kit further comprises one or more auxiliary ligands and a reducing agent; [9] In a further preferred embodiment, the auxiliary ligands are tricine and TPPTS.

[10] Another additional prjiferida modality, the reducing agent is tin (II).

[11] In a second embodiment, the present invention provides a novel diagnostic or therapeutic metal-pharmaceutical composition comprising: a metal, a chelator capable of chelating the metal a target portion, wherein the target portion is attached to the chelator, a peptide or peptidomimetic and binds to a receptor that is activated during angiogenesis, and the compound has 0-1 linkers between the target portion and the chelator.

[12] In another preferred embodiment, the substance me t al of the armacautica i ca is a diagnostic radiopharmaceutical, the metal is a radioisotope that is selected from the group: "Te, 95Tc, "-" In, 6Cu, 6Cu, S7Ga and 68Ga, the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, avß3, avß5, avß1 (a.ß !, a ^ Y a2ß2 and the linking group is present between the target portion and the chelator.

[13] In another more preferred embodiment, the target portion is a cyclic pentapeptide at avß3 receptors,

[14] In another even more preferred embodiment, the radioisotope is 99mTc or 95Tc, the radiopharmaceutical further comprises a first auxiliary ligand and a second auxiliary ligand capable of stabilizing the radiopharmaceutical.

[15] In another additional preferred embodiment, the radioisotope is 99"Tc.

[16] In another additional preferred embodiment, the radiopharmaceutical is selected from the group: "Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridyl] diazenido] -3-aminopropyl) -Val)); 99mTc (tricine) (TPPMS) (cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly)); 99p, Tc (tricine) (TPPDS) (Cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly) ); "Te (tricine) (TPPTS) (Cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly)); "" Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Phe-Lys (N- [[5- [carbonyl] -2-pyridinyl] diazenido]))); "Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido]]))); "" Te (tricine) (TPPTS) ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Phe-Glu (cyclohexane. {Lys-Arg-Gly-Asp} -D-Phe.}.) -cycle { Lys-Arg-Gly- Asp-D-Phe.}.); 99mTc (tricine) (TPPTS) (Cyclo { Arg-Gly-Asp-D-Nal-Lys ([Acid 2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic]). .); "Te (tricine) (TPPTS) ([2- [[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclohexane. {Lys-Arg-Gly-Asp-D} -Nal.}.) -cycle { Lys-Arg-Gly-Asp-D-Nal.}.); "Te (tricine) (TPPTS) (Cyclo { Arg-Gly-Asp-D-Tyr ((N- [[5- [carbonyl] -2-pyridinyl] diazenido] -18-amino-14-aza- 4, 7, 10-oxy-15-oxo-octadecoyl) -3-aminopropyl) -Val)); "Te (tricine) (TPPTS) (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -Glu (0-cyclo (Lys-Arg-Gly-Asp-D-Phe)) -0-cyclo ( Lys-Arg-Gly-Asp-D-Phe)); "Te (tricine) (TPPTS) (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -Glu (0-cyclo (D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp)) - 0-Cyclo (D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp)); "Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-Lys (N- [[5- [carbonyl] -2-pyridinyl] diazenido]) -D-Val; "Te (tricine) (TPPTS) (cycle {D-Lys ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid]) D-Phe-D- Asp-Gly -Arg.}.); 9Tc (tricine) (TPPTS) (2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] met il] -benzenesulfonic acid] - Glu (cyclo {D-Lys-D-Phe-D-Asp -Gly-Arg.}.) -cycle {D-Lys-D- Phe-D-Asp-Gly-Arg.}.); 'Te (tricine) (TPPTS) cycle. { D-Phe-Lys ([2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid]) -D-Asp-Gly-Arg} ); "" Te (tricine) (TPPTS) (cyclo (N-Me-Arg-Gly-Asp-ATA-D-Lys (N- [[5- [carbonyl] -2-pyridinyl] diazenido]))); "Te (tricine) (TPPTS) (Cyclo { Cit-Gly-Asp-D-Phe-Lys ([Acid 2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic]]} ); Y "Te (tricine) (1, 2, 4-triazole) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) - Val )).

[17] In another even more preferred embodiment, the radioisotope is X11ln.

[18] In another additional preferred embodiment, the radiopharmaceutical is selected from the group: (D0TA-113Tn) -Glu (cyclo (Lys-Arg-Gly-Asp-D-Phe) -cyclo. {Lys-Arg-Gly-Asp-D-Phe.}; Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA-111In)); Y Cycle (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-111In)

[19] In another preferred embodiment, the metapharmaceutical substance is a therapeutic radiopharmaceutical, the metal is a radioisotope selected from the group: 18dRe, 188Re, 153Sm, 166Ho, 177Lu, 149Pm, 90Y, 21Bi, 103Pd, 109Pd, 159Gd, 140La, 198Au, 199Au, 169Yb, 175Yb, 165Dy, 67Cu, 105Rh, lxlAg and Irr, the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, «vß3, avß5, avß ?, a4ß ?, ce1ß1 and a2ß2 and the linking group is present between the target portion and the chelator.

[20] In another more preferred embodiment, the target portion is a cyclic pentapeptide at avß3 receptors,

[21] In another additional preferred embodiment, the radioisotope is 153Sm.

[22] In another additional preferred embodiment, the radiopharmaceutical is selected from the group: Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA-153Sm); Cyclo (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-ls3Sm); Y Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (153Sm) -3-aminopropyl) -Val).

[23] In another additional preferred embodiment, the radioisotope is 177Lu.

[24] In another additional preferred embodiment, the radiopharmaceutical is selected from the group: Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA-177Lu)); (DOTA-177Lu) -Glutciclo. { Lys-Arg-Gly-Asp-D-Phe} ) -cycle. { Lys-Arg-Gly-Asp-D-Phe}; Cyclo (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-177Lu); Y Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (177Lu) -3-aminopropyl) -Val).

[25] In another additional preferred embodiment, the radioisotope is 90Y.

[26] In another additional preferred embodiment, the radiopharmaceutical is: (DOTA-90Y) -Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.).) -cycle. { Lys-Arg-Gly- Asp-D-Phe}; [7] In another preferred embodiment, the metapharmaceutical substance is an MRI contrast agent, the metal is a paramagnetic metal ion selected from the group: Gd (III), Dy (III), Fe (III) and Mn (II ), the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, ovß3, avß5, avß., A4ß1; a ^ Y a2ß2 and the linking group is present between the target portion and the chelator. [8] In another more preferred embodiment, the target portion is a cyclic pentapeptide at avß3 receptors, [9] In another even more preferred embodiment, the metal ion is Gd (III).

[30] In another yet more preferred embodiment, the contrast agent is: Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (Gd (III)) -3-aminopropyl) -Val).

[31] In another preferred embodiment, the metapharmaceutical substance is a contrast agent of X rays, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag and Ir, the target portion is a cyclic pentapeptide, the receptor is «vß3, and the linking group is present between the target portion and the chelator.

[32] In another even more preferred embodiment, the present invention provides a novel method for treating rheumatoid arthritis in a patient, comprising: administering a therapeutic radiopharmaceutical of the present invention capable of localizing in a new angiogenic vasculature to a patient by injection or infusion.

[33] In another even more preferred embodiment, the present invention provides a novel method for treating cancer in a patient, comprising: administering to the patient in need thereof a therapeutic radiopharmaceutical substance of the present invention, by injection or infusion.

[34] In another even more preferred embodiment, the present invention provides a novel method for imaging new blood vessels in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, an MRI contrast agent or an X-ray contrast agent of the present invention to a patient, by injection or infusion; (2) forming images of the patient's area where the desired formation of new blood vessels is located.

[35] In another even more preferred embodiment, the present invention provides a novel method for imaging cancer for a patient comprising: (1) administering a diagnostic radiopharmaceutical of the present invention to a patient by injection or infusion, ( 2) Patient imaging using flat scintigraphy or gamma SPECT, or positron emission tomography.

[36] In another even more preferred embodiment, the present invention provides a novel method for cancer imaging in a patient, comprising: (1) administering an MRI contrast agent of the present invention; and (2) imaging of the patient using magnetic resonance imaging.

[37] In another even more preferred embodiment, the present invention provides a novel method for cancer imaging in a patient, comprising: (1) administering an X-ray contrast agent of the present invention; and (2) forming images of the patient using X-ray computed tomography.

[38] In a third embodiment, the present invention provides a novel compound capable of being used in an ultrasound contrast composition, comprising: a target portion and a surfactant, wherein the target portion is attached to the surfactant, which is a peptide or peptidomimetic, and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linkers between the target portion and the surfactant.

[39] In a preferred embodiment, the target portion is a peptide or a mimetic thereof, and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropiline- 1, endoglin, endosialin, Axl, avß3, avß5, a5ßl; a4ßx, a ^ ß. And a2ß2 and the linking group is present between the objective portion and the surfactant.

[40] In a more preferred embodiment, the receptor is the avß3 integrin and the compound is of the formula: (Q) d-Ln-S £ wherein Q is a cyclic pentapeptide which is independently selected from the group: K is an L-amino acid that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, * ^ tó ^^ homolysine, 2-aminoethoxysine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and β-2-benzyl imidazolyl-1-yl-1,2-diaminopropionic acid; K 'is a D-amino acid that is independently selected, each time it occurs, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, dN-2-imidazolinylornithine, dN-benzylcarbamoylornithine, and acid β-2-benzylimidazole ilacet i 1 -1,2-diaminopropionic; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M 'is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, phenylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-1-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine, methionine and 2-aminothiazole-4-acetic acid, - R3 is an amino acid, substituted with 0-1 bonds to L ", which is independently selected, each time it is presented, from the group: glycine, D-valine , D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-phenylalanine, D-thienylalanine, D-phenylglycine, D- cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-diaminobutane, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-di-amino-nobu tic acid, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine, L- naphthylalanine, L-lysine, L-serine, L-ornithine, L-1, 2-di-aminobutyrate, L-2, diaminopropionic acid, L-cysteine, L-penicillamine, L-methionine and -aminothiazole-4-acetic; with the proviso that one of R1, R2, R3, R4 and R5 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N- methylarginine, and with the additional proviso that when R 4 is 2-aminothiazole-4-acetic acid, K and K 'are N-methylarginine, and with the additional proviso that when R 5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; S £ is a surfactant which is a lipid or a compound of the formula: s, P-A; A A9 is selected from the group: OH and OR27; A10 is OR27; R27 is C (= 0) alkyl of Cj .--; E1 is C? .10 alkylene substituted with 1-3 of R28; R2ß is independently selected, each time it is presented, from the group: R30, -P03H-R30; = 0, -C02R29, -C (= 0) R29, and C2-C4 alkenyl; R29 is independently selected, each time the group is presented: R30, H, C ^ Cs alkyl, phenyl, benzyl and trifluoromethyl; R30 is a link to L_; Ln is a linking group that has the formula: W is independently selected, each time it is presented, from the group: 0, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0) ), NHC (= S) NH, NHC (= 0) NH, S02, (0CH2CH2) 2o-oo »(CH2CH20) 200-200 '> (OCH2CH2CH2) 2o-2oo / (CH2CH2CH20) t and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of C3_10 substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R10; R6, R6a, R7, R7a, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, alkyl substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and Cs alkoxy substituted with 0-3 of R10, NHC (-OÍR11, C (= 0) NHR11, NHC (= 0) NHR11, NHR11, R11 and a link to S £; R10 is independently selected, each time it is presented from the group: a bond for S £, COOR11, OH, NHR11, S03H, P03H, aryl substituted with 0-3 of R11, C1_s alkyl substituted with 0-1 of R12, alkoxy of Ci.s substituted with 0-1 of R12, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-3 of R11; independently selects, each time it occurs, from group H, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O, and substituted with 0-1 of R12, cycloalkyl of C3.10 substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, and a bond to S £; R12 is a link to S £; k is selected from 0, 1 and 2; h is selected from 0, 1 and 2; h1 is selected from 0, 1, 2, 3, 4 and 5; h "is selected from 0, 1, 2, 3, 4 and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g 'is selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10 g "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g" 'is selected from O, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and a pharmaceutically acceptable salt thereof.

[41] In another even more preferred embodiment, the compound is of the formula: Q-L - S, wherein, Q is a cyclic pentapeptide that is independently selected from the group: K is an L-amino acid that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethylsciscine, dN-2-imidazolinylornithine, dN-benzylcarbamoylornithine, and acid β-benzylimidazolylacetyl-1,2-diaminopropionic acid; K 'is a D-amino acid that is independently selected, each time it is presented, from group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and β-2-benzyl imidazolylacet-1, 2-diaminopropionic acid; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M1 is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, f-enylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine, methionine and 2-aminothiazole-4-acetic acid; R3 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-d i am i nobu t i r i c o, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-l-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-d i ami nobu t i r i c o, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine, Ll-naphthylalanine, L-lysine, L-serine, L-ornithine, acid L-1, 2-d i am i nobu t i r i c o, L-1, 2-diaminopropionic acid, L-cysteine, L-penicillamine, L-methionine and 2-aminothiazole-4-acetic acid; with the proviso that one of R1, R2, R3, R4 and R5 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N- methylarginine, and with the additional proviso that when R 4 is 2-aminothiazole-4-acetic acid, K and K 'are N-methylarginine, and with the additional proviso that when R 5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; S £ is a surfactant which is a lipid or a compound of the "1 .10 formula: / -A; A A9 is OR27; A10 is OR27; R27 is C (= 0) alkyl of C ^^; E1 is alkylene of C ^ substituted with 1-3 of R28; R28 is independently selected, each time it is presented, from the group: R30, -P03H-R30; = 0, -C02R29, -C (= 0) R29, -CH2OR29, -OR29, and Ci-C alkyl;, - R29 is independently selected, each time the group is presented: R30, H, Cj-C alkyl, phenyl, and benzyl; R30 is a link to Ln; Ln is a linking group having the formula: (CR6R7) - (W) "- (CR6aR7a) g '- (Z) k (W) h, - (CR8R9) g.- (W) h" - (Cr8aR9a) g " is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0) , NHC (= S) NH, NHC (= 0) NH, S02, (OCH2CH2) s0_200, (CH2CH20) 20.200, (OCH2CH2CH2) 20.200, (CH2CH2CH2O) 20.200 and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of C3.10 substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R10; R6, R6a, R7, R7a, R8, R a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, Ca-C5 alkyl substituted with 0-3 of R10 and C _ alkoxy. substituted with 0-3 of R10 and a link to S £; R10 is independently selected, each time it is presented from the group: a bond for St, COOR11, OH, NHR11, C1_5alkyl substituted with 0-1 of R12, and C- ... s alkoxy substituted with 0-1 of R12; R11 is independently selected, each time it is presented, from group H, aryl substituted with 0-1 of R12, cycloalkyl of C3.10 substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, and a bond to S £; R12 is a link to S £; k is selected from 0, 1 and 2; h is selected from 0, 1 and 2; h 'is selected from 0, 1, 2, 3, 4 and 5; h "is selected from 0, 1, 2, 3, 4 and 5; g is selected from 0, 1, 2, 3, 4, 5; g 'is selected from 0, 1, 2, 3, 4, 5; g "is selected from 0, 1, 2, 3, 4, 5 g" 'is selected from 0, 1, 2, 3, 4, 5 s is selected from 0, 1, 2, 3, 4, 5 s1 is select from 0, 1, 2, 3, 4, 5 s "is selected from 0, 1, 2, 3, 4, 5 t is selected from 0, 1, 2, 3, 4, 5 t 'is selected from O , 1, 2, 3, 4, 5 and a pharmaceutically acceptable salt thereof.

[42] In still another preferred embodiment, the present invention provides a compound selected from the group: 1- (1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- (cyclo (Arg-Gly-Asp-D-Phe-Lys) -dodecane-1,2-dione; 1- (1, -dipalmitoyl-sn-glycero-3-phosphoethanolamino) -1 - ((? -amino-PEG3400-a-carbonyl) -cyclo (Arg-Gly-Asp-D-Phe-Lys)) -dodecane- 1, 12-dione; Y 1- (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400-a-carbonyl) -Glu (cyclo (Arg-Gly-Asp-D-Phe-Lys)) 2) -dodecano-1, 12 -diona.

[43] In yet another preferred embodiment, the present invention provides a novel ultrasound contrast agent composition comprising: (a) a compound comprising: a cyclic pentapeptide that binds to the avß3 integrin, a surfactant and a linking group between the cyclic pentapeptide and the surfactant; (b) a parenterally acceptable carrier; and (c) an ecogenic gas.

[44] In another additional preferred embodiment, the ultrasound contrast agent further comprises: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and N- ( methoxypolyethylene glycol 5000 carbamoyl) -1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.

[45] In yet another preferred embodiment, the ecogenic gas is a C2.5 perfluorocarbon.

[46] In yet another preferred embodiment, the present invention provides a method for imaging cancer, in a patient comprising: (1) administering, by injection or infusion, an ultrasound contrast agent composition of the present invention to a patient; and (2) forming images of the patient using sonography.

[47] In another additional preferred embodiment, the present invention provides a novel method for imaging new blood vessels in a patient, comprising: (1) administering, by injection or infusion, an ultrasound contrast agent composition of the present invention to a patient; (2) forming images of the patient's area where the desired formation of the new blood vessels is located.

[48] In yet another preferred embodiment, the present invention provides a novel therapeutic radiopharmaceutical composition comprising: (a) a therapeutic radiopharmaceutical composition of the present invention; and (b) a parenterally acceptable carrier.

[49] In still another preferred embodiment, the present invention provides a novel diagnostic radiopharmaceutical composition, comprising: (a) a diagnostic radiopharmaceutical, an MRI contrast agent, or an X-ray contrast agent of the present invention invention; and (b) parenterally acceptable carrier.

[50] In another additional preferred embodiment, the present invention provides a novel therapeutic radiopharmaceutical composition comprising: a radiolabeled target portion, wherein the target portion is a compound Q and the radioactive label is a therapeutic isotope that is selected from the group of: 35S, 32P, 125I, 131I and 211At.

[51] In still another preferred embodiment, the present invention provides a novel radiopharmaceutical composition comprising: a radiolabeled target portion, wherein the target portion is a compound Q and the radioactive label is a therapeutic isotope which is 131I.

Another embodiment of the present invention is diagnostic equipment for the preparation of radiopharmaceuticals useful as imaging agents for cancer or as imaging agents for the formation of new blood vessels. The diagnostic kits of the present invention comprise one or more bottles containing the non-pyrogenic and sterile formulation constituted of a predetermined amount of a reagent of the present invention and optionally other components such as one or two auxiliary ligands, reducing agents, ligands of 'transfer, shock absorbers, lyophilization auxiliaries, stabilization aids, auxiliary solubilization and bacteriostats. The inclusion of one or more optional components in the formulation will often improve the ease of synthesis of the radiopharmaceutical by the end user's processing, the ease of manufacturing the equipment, the shelf life of the equipment or the stability and shelf life of the equipment. the radiopharmaceutical substance. The inclusion of one or two auxiliary ligands is necessary for diagnostic kits comprising reagents that are comprised of a hydrazine or hydrazone binding moiety. One or more bottles containing all or part of the formulation can be independently in the form of a sterile solution or a lyophilized solid.

DEFINITIONS The compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds and the like can also be present in the compounds described herein and all such stable isomers are contemplated in the present invention. It will be appreciated that the compounds of the present invention contain asymmetrically substituted carbon atoms, and they can isolate in optically active or racemic forms. It is well known in the art how to prepare optically active forms, for example by resolution of racemic forms or by synthesis from optically active starting materials. It is known that two distinct isomers (cis and trans) of the peptide bond are produced; both may also be present in the compounds described herein, and all stable isomers are contemplated in the present invention. The D and L isomers of a particular amino acid are designated herein using the conventional 3-letter abbreviation of the amino acids, as indicated by the following examples: D-Leu or L-Leu. When any variable occurs more than once in any substituent or in any formula, its definition each time it is presented is independent of its definition in another time it is presented. Thus, for example, if a group is shown to be substituted with 0-2 of R52, then such a group can optionally be substituted with up to two of R52, and R52, each time they are presented, is independently selected from the defined list of possibilities for R52. Further, by way of example, for the group .N (R53) 2, each of the two R53 substituents on N is independently selected from the defined list of possible R53. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When demonstrates that a bond to a substituent crosses the connecting junction of two atoms in a ring, then such a substituent may be attached to any atom in the ring. By "reactive" is meant a compound of this invention capable of directing the transformation into a metapharmaceutical substance of this invention. The reagents can be used directly for the preparation of the metapharmaceutical substances of this invention or can be a component in an equipment of this invention. The term "binding agent" means a metapharmaceutical substance of this invention that has affinity for, and is capable of binding to, the vitronectin receptor. The binding agents of this invention preferably have Ki < 1000 nM.

The metal-pharmaceutical substances, as used herein, are designed to refer to a pharmaceutically acceptable compound containing a metal, wherein the compound is useful for imaging, magnetic resonance imaging, contrast imaging or imaging. in X-rays. Metal is the cause of the signal that can be formed in an image in diagnostic applications and the source of cytotoxic radiation in radiotherapeutic applications. Radiopharmaceuticals are metalworking substances in which the metal is a radioisotope.

By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and its formulation into an effective pharmaceutical agent. The term "substituted" as used herein, means that one or more hydrogens in the designated atom or group are substituted with a selection of the indicated group, with the proviso that the normal valency of the atoms or atoms is not exceeded. designated groups and that the substitution results in a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens on the atom are substituted. The term "link" as used herein means a single or double bond. The term "salt" as used herein is used as defined in the CRC Handbook of Chemistry and Physics, 65th Edition, CRC Press, Boca Raton, Fia, 1984, as any substance which generates ions, other than those hydrogen or hydroxyl ions. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described modified compounds when making acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines; organic alkaline salts of acidic residues such as carboxylic acids; and similar. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions or dosage forms which are, within the scope of correct medical judgment, suitable for use in contact in the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by producing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic alkaline salts of organic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example from non-toxic inorganic or organic acids, for example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic , oxalic, isethionic and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound of which it contains a basic or acid portion, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. As used herein, "alkyl" is intended to include straight and branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. It is intended that C1.10 alkyl include C1 # C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. Examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl and s-pentyl. The term "haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogen atoms (eg -CCF "where v = 3). yw = la (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. The term "Cl-C10 alkoxy" is intended to include C1- to C2, C3, C4, C5, C6, C7, C8, C8 and C10 alkoxy groups. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and s-pentoxy. It is intended that "cycloalkyl" include saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. It is intended that cycloalkyl of C3_- include cycloalkyl groups of alkyl groups of C3, C4, C5, C6 and C,. The term "alkenyl" is intended to include hydrocarbon chains of straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethenyl and propenyl. The alkenyl of C__10 is intended to include the alkenyl groups C2, C3, C4, C5, C6, C7, C8, C9 and C10 It is intended that "alkynyl" include hydrocarbon chains of either linear or branched configuration and one or more triple carbon-carbon bonds which may occur at any stable point along the chain, such as ethynyl and propynyl. It is intended that C2_10 alkynyl include the alkynyl groups of C2, C3, C4, C5, C6, C7, Cs, C9 and C10. As used herein, the terms "carbocycle" or "carbocyclic residue" are intended to mean any stable monocyclic or bicyclic 3, 4, 5, 6 or 7 members, or a bicyclic or tricyclic 7, 8, 9, 10, 11, 12 or 13 members, any of which may be saturated, partially saturated or aromatic. Examples of such carbocycles include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2. .2 [bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. As used herein, the term "alkaryl" means an aryl group having an alkyl group of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the term "aralkyl" means an aralkyl group of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms having an aryl group; the term "arylalkaryl" means an aryl group having an alkyl group of 1-10 carbon atoms that have an aryl group; and the term "heterocycloalkyl" means an alkyl group of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of carbon atoms having a heterocycle. As used herein, the term "heterocycle" or "heterocyclic system" is designed to mean a stable 5, 6 or 7 membered monocyclic or bicyclic ring or a 7, 9, 9 or 10 membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms which are independently selected from the group consisting of N, NH, 0 and S and which include any bicyclic group in which any of the rings Heterocyclics defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are adjacent to each other. It is preferred that the total number of S atoms and 0 in the heterocycle is not greater than 1. As used herein, the term "aromatic heterocycle system" or "heteroaryl" is intended to mean a stable 5-, 6- or 7-membered monocyclic or bicyclic ring or a bicyclic heterocyclic aromatic ring of 7, 8. , 9 or 10 members which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms which are independently selected from the group consisting of N, NH, 0 and S. It should be noted that the total number of S atoms and O in the aromatic heterocycle is not more than 1. examples of heterocycles include, but are not limited to acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, thiazole benz yl, benztriazolyl, tet benz razolilo, benzisoxazolyl, benzisothiazolyl , benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, i midazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naftoridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, fteridinilo, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-qumolizinilo, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1, 2, 5-tiadizinilo, 1, 2, 3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2-triazolyl -¡ , 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthenyl. Preferred heterocycles include, but are not limited to pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Fused ring and spiro compounds containing, for example, the above heterocycles are also included. A "polyalkylene glycol" is a polyethylene glycol, polyethylene glycol or polybutylene glycol having a molecular weight less than about 5000, ending either in a hydroxy or alkyl ether portion. A "carbohydrate" is a polyhydroxyaldehyde, ketone, alcohol or acid, or derivatives thereof, which includes polymers thereof having polymeric bonds of the acetal type. A "cyclodextrin" is a cyclic oligosaccharide. Examples of cyclodextrins include, but are not limited to a-cyclodextrin, hydroxyethyl-a-cyclodextrin, hydroxypropyl-a-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6-di-O-methyl-β-cyclodextrin, sulphated β-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin and α-cyclodextrin sulphated As used herein, the term "polycarboxyalkyl" means an alkyl group having between 2 and about 100 carbon atoms and a plurality of carboxyl substituents; and the term "polyazaalkyl" means a linear or branched alkyl group having between two and about 100 carbon atoms, interrupted by, or substituted with a plurality of amine groups. A "reducing agent" is a compound that reacts with a radionuclide, which is typically obtained as a compound in a high oxidation state, relatively not reactive, to decrease its oxidation state by transfer of electron or electrons to the radionuclide, so it becomes more reactive. Reducing agents useful in the preparation of radiopharmaceuticals and diagnostic equipment useful for the preparation of such radiopharmaceuticals include, but are not limited to, stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and copper or ferrous salts. . Other reducing agents are described in Brodack et al. , PCT Application 94/22496, which is incorporated herein by reference. A "transfer ligand" is a ligand that forms an intermediate complex with a metal ion that is stable enough to avoid unwanted side reactions but labile enough to convert to a meta-phar- maceutical substance. The formation of the intermediate complex is kinetically favored, while the formation of the metapharmaceutical substance is favored thermodynamically. Transfer ligands useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of diagnostic radiopharmaceuticals include, but are not limited to, gluconate, glucoheptonate, mannitol, glucarate, N, N, N ', N acid. '-ethylenediaminetetraacetic acid, pyrophosphate and methylenediphosphonate. In general, the transfer ligands are constituted by oxygen or nitrogen donors. The term "donor atom" refers to the atom attached directly to a metal by a chemical bond. The "auxiliaries" or "associates" are ligands that are incorporated into a radiopharmaceutical during its synthesis. They serve to complete the coordination sphere of the radionuclide together with the chelator or the radionuclide binding unit of the reagent. For radiopharmaceuticals made up of a binary ligand system, the coordination sphere of the radionuclide consists of one or more chelators or binding units of one or more reagents and one or more auxiliaries or associates, provided that there is a total of two types of ligands, chelators or union units. For example, a radiopharmaceutical consisting of a chelator or a binding unit of a reagent and two of the same auxiliaries or co-ligands and a radiopharmaceutical consisting of two chelators or binding units of one or two reagents and an auxiliary or a co-ligand, are considered both constituted of binary ligand systems. For radiopharmaceuticals consisting of a ternary ligand system, the radionuclide coordination sphere is composed of one or more chelators or binding units of one or more reagents and one or more of two different types of auxiliaries or associates, with the condition that there is a total of three types of ligands, chelators or union units. For example, a radiopharmaceutical consisting of a chelator or binding unit of a reagent and two different auxiliaries or associates is considered to be constituted by a ternary ligand system. The auxiliaries or associates useful in the preparation of radiopharmaceuticals in the diagnostic equipment useful for the preparation of such radiopharmaceutical substances are constituted by one or more donor atoms of oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium and tellurium. A ligand can be a transfer ligand in the synthesis of a radiopharmaceutical and also serve as an adjuvant or as a co-ligand in another radiopharmaceutical. Whenever a ligand is called a transfer or auxiliary or binding, it depends on whether the ligand remains in the coordination sphere of the radionuclide in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator or the binding unit of the reagent or reagents. A "chelator" or "binding unit" is the portion or group in a reagent that binds to a metal ion through the formation of chemical bonds with one or more donor atoms.

The term "binding site" means the site in vivo or in vitro that binds to a biologically active molecule. A "diagnostic equipment" or "equipment" comprises a collection of components, called the formulation, in one or more features which are used for the practice of the end user in a chemical or pharmacy facility for synthesizing diagnostic radiopharmaceuticals. The equipment provides all components required to synthesize and use diagnostic radiopharmaceuticals except those that are commonly available to the practitioner or end user, such as water or saline for injection, a solution of the radionuclide equipment to heat the equipment during the synthesis of the radiopharmaceutical, if required, and the equipment necessary to administer the radiopharmaceutical to the patient, such as syringes and protections, and imaging equipment.

The therapeutic radiopharmaceuticals, the pharmaceutical agents of X-ray contrast agent, the pharmaceutical substances of ultrasound contrast agent and the metal-pharmaceutical substances for magnetic resonance imaging contrast are provided to the final user in its final form in a formulation typically contained in a bottle, either as a lyophilized solid or as an aqueous solution. The end user reconstitutes the substance lyophilized with water or saline and extracts the dose from the patient or only extracts the dose of the aqueous solution formulation to be provided. A "lyophilization adjuvant" is a component that has favorable physical properties for infiltration, such as vitreous transition temperature, and is added to the formulation to improve the physical properties of the combination of all components of the lyophilization formulation. A "stabilization aid" is a component that is added to the metapharmaceutical substance or diagnostic equipment either to stabilize the meta-phar maceutical substance or to prolong the shelf life of the equipment before it should be used. Stabilization aids can be antioxidants, reducing agents or radical scavengers and can provide improved stability by reacting preferentially with species that degrade other components or metapharmaceuticals. A "solubilization aid" is a component that improves the solubility of one or more additional components in the medium necessary for the formulation. A "bacteriostatic" is a component that inhibits the growth of bacteria in a formulation either during storage before use or after the diagnostic equipment to synthesize a radiopharmaceutical substance. The term "amino acid" as used herein, means an organic compound that contains a basic amino group and an acid carboxyl group. Included within this term are natural amino acids (eg L-amino acids), modified or rare amino acids (eg D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but that usually do not occur in protein. Included within this term are the modified and unusual amino acids, such as those described, for example, in Roberts and Vellaccio (1983) The Peptides. 5: 342-429, whose teachings are incorporated herein by reference. Amino acids that occur in natural proteins include, but are not limited to alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine , tyrosine, tryptophan, proline and valine. Natural non-protein amino acids include, but are not limited to, arginosuccinic acid, citrulline, cysteine, sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserin, ornithine, 3-monoiodotyrosine, 3,5-diiodotyrosine, 3, 5, 5 ' -triyodotironin and 3, 3 ', 5, 5' -tetrayodotironin. Modified amino acids or uncommon which can be used to carry out the invention include, but are not limited to D-amino acids, hydroxylysine, 3-hydroxyproline, an amino acid protected with N-Cbz, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, ß-f-enylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N, N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine- 4-carboxylic acid, 6-aminocaproic acid, trans-4- (aminomethyl) -cyclohexanecarboxylic acid, 2-, 3- and 4- (aminomethyl) benzoic acid, 1-aminociclopentanecarboxylic acid, 1-aminociclopropanecarboxylic acid and 2-benzyl-5 acid -aminopentanoic acid The term "peptide" as used herein means a linear compound consisting of two or more amino acids (as defined herein) that are linked via a peptide bond. A "peptide" as used in the invention claimed herein, is understood to refer to a portion with a molecular weight of less than 10,000 Daltons, preferably less than 5,000 Daltons, and more preferably less than 2,500 Daltons. The term "peptide" also includes compounds that contain peptide and non-peptide components, such as pseudopeptide residues or peptidomimetics and other components other than amino acids. Such a compound that contains Peptide and non-peptide components can also be referred to as a "peptide analog". A "pseudopeptide" or "peptidomimetic" is a compound which mimics the structure of an amino acid residue or a peptide, for example, by the use of linkers other than amide bonds between the peptidomimetic and the amino acid residue (pseudopeptide bonds) and / or by the use of different amino acid substituents and / or a modified amino acid residue. A "pseudopeptide residue" means that portion of a pseudopeptide or peptidomimetic that is present in a peptide. The term "peptide bond" means a covalent amide bond formed by the loss of a water molecule between the carboxyl group of an amino acid and the amino group of a second amino acid. The term "pseudopeptide linkages" include isosteri of peptide bonds which may be used in place of, or as substitutes for, the normal amide bond. These substitute or "equivalent" amide bonds are formed from combinations of atoms that are not normally found in peptides or proteins which mimic the spatial requirements of the amide bond and which must stabilize the molecule for enzymatic degradation. The following abbreviations are used here: Acm acetamidomethyl b-Ala, beta-Ala or bAla 3-aminopropionic acid ATA 2-aminothiazole-5-acetic acid or 2-aminothiazole-5-acetyl group Boc t-butoxycarbonyl CBZ, Cbz or Z Carbobenzyloxy Cit citrulline Dap acid 2, 3 -diaminopropionic DCC dicyclohexylcarbodiimide DIEA diisopropylethylamine DMAP 4 -dimethylaminopyridine EOE ethoxyethyl HBTU 2- (lH-benzotriazol-1-yl) .1, 1, 3, 3 -tetramethyluronium hynic group boc-hydrazinonicotinyl or 2- [[5- carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic NMeArg or MeArg aN-methylarginine NMeAsp aN-methylaspartic acid NMM N-methylmorpholine OcHex O-cyclohexyl OBzl O-benzyl oSu O-succinimidyl TBTU 2- (lH-benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium tetrafluoroborate THF tetrahydrofuranyl THP tetrahydropyranyl Tosyl tr Trityl The following three-letter, conventional amino acid abbreviations are used herein; the abbreviations of amino acids of a conventional letter are NOT used in the present: Ala = alanine Arg = arginine Asn = asparagine Asp = aspartic acid Cys = cysteine Gln = glutamine Glu = glutamic acid Gly = glycine His = histidine He = isoleucine Leu = leucine Lys = lysine Met = methionine NIe = norleucine Orn = ornithine Phe = phenylalanine Phg = phenylglycine Pro = proline Sar = sarcosine Ser = serine Thr = threonine Trp = tryptophan Tyr = tyrosine Val = valine The pharmaceutical substances of the present invention are comprised of a target portion for a receptor that is expressed or activated in angiogenic tumor vasculature. To target the VEGF, Flk-1 / KDR, Flt-1 and neuropilin-1 receptors, the target portions are made up of peptides or peptidomimetics that bind with high affinity to the receptors. For example, peptides consisting of a 23 amino acid portion of the C-terminal domain of VEGF have been synthesized which are competitively inhibited by binding of VEGF or VFGFR (Soker, et al., J. Biol. Chem., 1997, 272, 31582-8). Linear peptides of 11 to 23 amino acid residues that bind to the basic FGF receptor (bFGFR) are described by Cosic et. al., Mol. and Cell. Biochem., 1994, 130, 1-9. A Preferred linear peptide antagonist of bFGFR is the 16 amino acid peptide, Mel-Trp-Tyr-Arg-Pro-Asp-Leu-Asp-Glu-Arg-Lys-Gln-Gln-Lys-Arg-Glu. Gho et. al., (Cancer Research, 1997, 57, 3733-40) describe the identification of small peptides that bind with high affinity to the angiogenin receptor on the surface of endothelial cells. A preferred peptide is Ala-Gln-Leu-Ala-Gly-Glu-Cys-Arg-Glu-Asn-Val-Cys-Met-Gly-Ile-Glu-Gly-Arg, in which the two Cys residues form a bond intramolecular disulfide. Yayon et. al., (Proc. Nati. Acad. Sci. USA, 1993, 90, 10643-7) describes other antagonists of linear FGFR peptides, identified from a peptide library exhibited from random phage. The two linear Ala-Pro octapeptides. Ser-Gly-His-Tyr-Lys-Gly and Lys-Arg-Thr-Gly-Gln-Tyr-Lis-Leu are preferred to inhibit the binding of bFGF to its receptor. Target portions for integrin expressed in tumor vasculature include peptides and peptidomimetics that bind to avß3, av5, beta5β, aβ, a -β1 and "2β2-Pierschbahter and Rouslahti (J. Biol. Chem., 1987, 262, 17294 -8) describe peptides that bind selectively to ace. and avß3. US 5,536,814 discloses peptides that bind with high affinity to a5P1 integrins. Burgess and Lim (J. Med. Chem., 1996, 39, 4520-6) describes the synthesis of three peptides that bind with high affinity to avß3: cycle [Arg-Gly-Asp-Arg-Gly-Asp], cycle [Arg-Gly-Asp-Arg-Gly-D-Asp] and the linear peptide Arg- Gly. -Asp-Arg-Gly-Asp. US Patents 5,770, 565 and 5,766,591 describe peptides that bind with high affinity to avß3. U.S. Patents 5,767,071 and 5,780,426 disclose cyclic peptides having an exocyclic Arg amino acid having high affinity for avß3. Srivatsa et. to the., (Cardiovascular Res., 1997, 36, 408-28) describe a cyclic peptide antagonist for avß3, cycle [Ala-Arg-Gly-Asp-Mamb]. Tran et. al., (Bioorg, Med. Chem. Lett., 1997, 7, 997-1002) describes the cyclic peptide that binds with high affinity to avß3. Arap et. al., (Science, 1998, 279, 377-80) describes cyclic peptides that bind avß3 and avß5, Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys and cyclo [Cys-Asn-Gly -Asp-Cys] Corbett et. to the. (Biorg. Med. Chem. Lett., 1997, 7, 1371-6) describes a series of avß3 selective peptidomimetics. And Haubner et. al., (Angew. Chem. Int. Ed. Engl., 1997, 36, 1374-89) describes avß3 antagonist peptides and peptidomimetics obtained from peptide libraries. The subject portions of the present invention preferably have a binding affinity for the otvß3 integrin of less than 1000 nM. More preferably, the target portions of the present invention preferably have a binding affinity for the ocvß3 integrin of less than 100 nM. Even more preferably, the subject portions of the present invention preferably have a binding affinity for the avß3 integrin of less than 10 nM.

The ultrasound contrast agents of the present invention comprise a plurality of target portions of angiogenic tumor vasculature attached to or incorporated in a microbubble of a biocompatible gas, a liquid carrier and a tensoactive microsphere, further comprising an optional linker portion, Ln, between the target portions and the microbubble. In this context, the term "liquid carrier" means an aqueous solution, and the term "surfactant" means any amphiphilic material which produces a reduction in interfacial tension in a solution. A list of suitable surfactants to form surfactant microspheres is described in EP0727225A2 incorporated herein by reference. The term tensoactive microsphere includes nanospheres, liposomes, vesicles and the like. The biocompatible gas can be air or a fluorocarbon, such as a C3-C5 perfluoroalkane, for example perfluoropropane, perfluorobutane or perfluoropentane which provides the difference in echogenicity and therefore the contrast in ultrasound imaging. The gas is encapsulated or contained in the microsphere in which the biodirector group is attached, optionally via a linking group. The union can be covalent, ionic or by van der Waals forces. Specific examples of such contacting agents include lipid encapsulated perflurocarbons with a plurality of peptides or peptidomimetics of tumor neovasculature receptor binding. As used herein, S £ is a surfactant which is lipid or a compound of formula A1-E-A2, defined above. The surfactant is intended to form a vesicle (for example a microsphere) capable of containing an echogenic gas. The ultrasound contrast agent compositions of the present invention are designed to be capable, upon agitation (eg with agitation, etc.) of encapsulating an echogenic gas in a vesicle in a manner that allows the resulting product to be useful as a contrast agent for ultrasound. The term "vesicle" refers to a spherical entity which is characterized by the presence of an internal hollow. Preferred vesicles are formulated from lipids, which include the various lipids described herein. In any given vesicle, the lipids may be in the form of a monolayer or a bilayer, and the lipid monolayer or bilayer may be used to form one or more monolayers or bilayers. In the case of more than one monolayer or bilayer, the monolayer or bilayer are generally concentric. The lipid vesicles described herein include such entities commonly referred to as liposomes, micelles, bubbles, microbubbles, microspheres, and the like. Therefore, lipids can be used to form a unilamellar vesicle (consisting of a monolayer or of a bilayer), an oligolamellar vesicle (constituted of approximately two or approximately three monolayers or bilayers), or a multilamellar vesicle (constituted of more than approximately three monolayers or bilayers). The internal void of the vesicles, an aqueous liquid, a gas, a gaseous precursor and / or a solid or a dissolute material include, for example, a bioactive agent, as desired. The term "vesicular composition" refers to a composition which is formulated from lipids and which comprises vesicles. The term "vesicle formulation" refers to a composition which comprises vesicles and a bioactive agent. A microsphere, as used herein, is preferably a sphere less than or equal to 10 microns. A liposome, as used herein, may include a single lipid layer (a lipid monolayer), two lipid layers (one lipid bilayer) or more than two lipid layers (one lipid multiple layer). The term "liposomes" refers to a generally spherical assembly or an aggregate of amphipathic compounds that includes lipid compounds, typically in the form of one or more concentric layers, for example bilayers. It can also be referred to herein as lipid vesicles.

The term "bubbles", as used herein, refers to vesicles which are generally characterized by the presence of one or more membranes or walls surrounding an internal void that is filled with a gas or a precursor thereof. Exemplary bubbles include, for example, liposomes, micelles and the like. The term "lipid" refers to a synthetic or naturally occurring amphipathic compound which comprises a hydrophilic component and a hydrophobic component. The lipids include, for example, fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alcohols and waxes, terpenes and steroids. The term "lipid composition" refers to a composition which comprises a lipid compound. Exemplary lipid compositions include suspensions, emulsions and vesicle compositions. The term "lipid formulation" refers to a composition which comprises a lipid compound and a bioactive agent. Examples of suitable lipid classes and specific lipids suitable include: phosphatidylcholines, such as dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC) and diesteraroylphosphatidylcholine; phosphatidylethanolamines, such as dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidyl- ethanolamine and N-succinyl-dioleoylphosphatidylethanolamine; phosphatidylserines; phosphatidylglycerols; espingolipids; glycolipids, such as the GMl ganglioside; glycolipids; sulfatides; glycosphingolipids; phosphatidic acids such as dipalmatoylphosphatidic acid (DPPA); palmitic fatty acids; stearic fatty acids; arachidonic fatty acids; lauric fatty acids; myristic fatty acids; lauroleic fatty acids; fatty acids fisetéricos; myristoleic fatty acids; palmitoleic fatty acids; petroselinic fatty acids; oleic fatty acids; isoláuric fatty acids; isomiristic fatty acids; isopalmitic fatty acids; isostearic fatty acids; cholesterol and cholesterol derivatives, such as cholesterol hemisuccinate, cholesterol sulfate and cholesteryl- (4'-trimethylammonium) butanoate; esters of polyoxyethylene fatty acid; polyoxyethylene fatty acid alcohols; ethers of polyoxyethylene fatty acid alcohol; esters of polyoxyethylated sorbitan fatty acid; glycerol oxystearate and polyethylene glycol; glycerol ricinooleate and polyethylene glycol; soybean sterols ethoxylates; ethoxylated castor oil; polyoxyethylene-polyoxypropylene fatty acid polymers; polyoxyethylene fatty acid stearates; 12 - (((7'-dietoxyaminocoumarin-3-yl) -carbonyl) -methylamino) -octadecanoic acid; N- [12 - (((7'-diethylamino-coumarin-3-yl) -carbonyl) -methyl-amino) octadecanoyl] -2-amino- acid palmitic; 1,2-dioleyl-sn-glycerol; 1,2-dipalmitol-sn-3-sucucinylglycerol; 1,3-dipalmitoyl-2-succinyl-glycerol; and 1-hexadecyl-2-palmitoyl-glycerophosphoethanolamine and palmitoylhomocysteine; lauryltrimethylammonium bromide; cetyltrimethylammonium bromide; myristyltrimethylammonium bromide; chlorides are alkyldimethylbenzylammonium, for example wherein the alkyl is a C12 alkyl, Cl4 to C16; benzyldimethyldodecylammonium bromide; benzyl dimethyldodecyl ammonium chloride; benzyldimethylhexadecylammonium bromide; benzyldimethylhexadecylammonium chloride; benzyldimethyl-tetradecylammonium bromide; benzyldimethyltetradecylammonium chloride; Cetyl dimethyl ethyl ammonium bromide; cetyldimethylethylammonium chloride; cetylpyridinium bromide; cetylpyridinium chloride; N- [1,2,3-dioleoyloxy) -propyl] -N, N, N-trimethylammonium chloride (DOMTA); 1, 2-dioleoyloxy-3- (trimethylammonio) propane (DOTAP); and 1,2-dioleoyl-c- (4'-trimethylammonium) -butanoyl-sn-glycerol (DOTB). The ecogenic gas may be a gas or mixture of gases such as CF4, C2F6, C3F8, cyclo-C4Fβ, C4F10, C5F12, cycloC5F10, cyclo-C4F, (1-trifluoromethyl), propane (2-trifluoromethyl) -1, 1, 1, 33,, 3-hexafluoro and butane (2-trifluoromethyl) -1,1,1,3,3,3,4,4,4 nonafluoro. Also preferred are the corresponding unsaturated versions of the above compounds, for example C2F4, C3F6, the C4Fβ isomers. Also, mixtures of these gases, especially mixtures of perfluorocarbon with other perfluorocarbons and mixtures of perfluorocarbons with other inert gases, such as air, N2, 02, He, may be useful. Examples of these can be found in Quay, U.S. Patent No. 5,595,723, the content of which is incorporated herein by reference. The X-ray contrast agents of the present invention are comprised of one or more target portions of angiogenic tumor vasculature attached to one or more "heavy" X-ray absorbing atoms of atomic number 20 or greater, which further comprise a binding moiety optionally, Ln, between the target portions and the atoms that absorb x-rays. The heavy atom frequently used in X-ray contrast agents is iodine. Recently, X-ray contrast agents consisting of metal chelates (Wallace, R., US Pat. No. 5,417,959) and polychelates composed of a plurality of metal ions have been described (Love, D., US Pat. No. 5,679,810). . More recently, complexes of multinuclear groups have been described as X-ray contrast agents (U.S. Patent 5,804,161, PCT WO91 / 14460 and PCT W092 / 17215). Examples of X-ray agents include non-reductive or naturally occurring analogs of the radionuclides included above (eg Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag and Go).

Contrast agents MRI of the present invention consist of one or more target portions of angiogenic tumor vasculature attached to one or more paramagnetic metal ions, further comprising an optional linking portion, Ln, between the target portions and the paramagnetic metal ions . Paramagnetic metal ions are present in the form of metal complexes or metal oxide particles. US 5,412,148 and 5,760,191 describe examples of chelators for paramagnetic metal ions for use in MRI contrast agents. US 5,801,228, 5,567,411 and 5,281,704 describe examples of polychelants useful for forming complexes with more than one paramagnetic metal ion for use in MRI contrast agents. US 5,520,904 discloses particulate compositions comprised of paramagnetic metal ions, for use as MRI contrast agents. The pharmaceutical substances of the present invention have the formulas (Q) dL "- (C" -X), (Q) d-Ln- (0, -X1) d ', (Q) d- _- (X2) d .. and (Q) d-L- (X3), wherein Q represents a peptide or a peptidomimetic that binds to a receptor expressed in angiogenic tumor vasculature, d is 1-10, Ln represents an optional linking group, Ch represents a metal chelator or a binding portion, X represents a radioisotope, X1 represents a paramagnetic metal ion, X2 represents an ion paramagnetic metal or a heavy atom containing solid and soluble particles, d "is 1-100, and X3 represents a microsphere of surfactant or an echogenic gas.The preferred pharmaceutical substances of the present invention are constituted of target portions, Q, which are peptides and peptidomimetics which bind to vitronectin receptors avß3 and avß5. pharmaceutical substances most preferred of the present invention consist of target portions, Q, that are peptides and peptidomimetics that join avß3. pharmaceutical substances most preferred of present invention consist of avß3 target portions Q, which are composed of 1 to 10 cyclic pentapeptides or peptidomimetics, independently attached to a therapeutic radioisotope or forming image portion, further comprising an optional linker portion, L ", between portions target and therapeutic radioisotopes or portions f Imaging machines The cyclic peptides are constituted by a tripeptide sequence that binds to the avß3 receptor and two amino acids, any of which can be linked to Ln, Ch, X2 or X3. The interaction of the tripeptide recognition sequences of the cyclic peptide or peptidomimetic portion of the pharmaceuticals with avß3 receptor results in localization of the pharmaceuticals in angiogenic tumor vasculature, which express the receptor avß3.

The pharmaceutical substances of the present invention can be synthesized by various approaches. One approach involves the synthesis of the target peptide or the peptidomimetic portion, Q, and the direct attachment of one or more portions, Q, to one or more metal chelators or binding portions, Ch, or to a paramagnetic metal ion or a heavy atom that contains a solid particle, or a microbubble of ecogenic gas. Another solution involves the joining of one or more portions, Q, to the linking group, Ln, which then binds to one or more metal chelators or binding portions, Ch, or to a paramagnetic metal ion or a heavy atom containing solid particles , or a microbubble of ecogenic gas. Another solution, useful in the synthesis of pharmaceutical substances where d is 1, involves the synthesis of the Q-L "portion, together with incorporating an amino acid or an amino acid mimetic residue having L" in the peptide or peptidomimetic synthesis. The resulting portion, Q-L ", is then attached to one or more metal chelators or binding portions, Ch, or to a paramagnetic metal ion or a heavy atom containing solid particles or a microbubble of echogenic gas. Another solution involves the synthesis of a peptide or peptidomimetic, Q, which has a fragment of the linking group, Ln, one or more of which are then joined to the rest of the linking group and then to one or more metal chelators or binding portions. , or a paramagnetic metal ion or a heavy atom that contains a solid particle, or a microbubble of ecogenic gas. The peptides or peptidomimetics, Q, optionally have a linker group, L ", or a fragment of the linker group, and can be synthesized using standard synthesis methods known to those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Generally, the peptides and peptidomimetics are elongated by deprotection of the alpha-amine of the C-terminal residue and coupled with the following appropriately protected amino acid via a peptide bond using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be carried out with the constitutive amino acids in a gradual manner, or by condensation of fragments (two to several amino acids), or by a combination of both processes, or by synthesis of solid phase peptides according to the method described. originally by Merrifield, J. Am. Chem. Soc., 85, 2149-2154 (1963), the disclosure of which is incorporated herein by reference. Peptides and peptidomimetics can also be synthesized using automated synthesizing equipment. In addition to the above, the procedures for the synthesis of peptides and peptidomimetics are described in Stewar and Young, "Solid Phase Peptide Synthesis", 2nd ed, Pierce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Undenfriend, Eds., "The Peptides: Analysis, Synthesis, Biology, Vol. 1, 2, 3, 5 and 9, Academic Press, New York, (1980-1987); Bodanszky," Peptide Chemistry: A Practical Textbook ", Springer-Verlag, New York (1988), and Bodanszky et al." The Practice of Peptide Synthesis "Springer-Verlag, New York (1984), whose descriptions are incorporated herein by reference. amino acid derivatives, an amino acid and a peptide or peptidomimetic, two peptide fragments or peptidomimetics, or the cyclization of a peptide or a peptidomimetic can be carried out using standard coupling methods such as the azide method, the acid anhydride method mixed carbon (isobutyl chloroformate), the carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimides), the active ester method (p-nitrophenylester, N-hydroxysuccinic imido ester), the reactive method Kward of Woodward, the carbonildiimiazole method, phosphorus reagents such as BOP-C1 or the oxidation-reduction method. Some of these methods (especially carbodiimide) can be improved by the addition of 1-hydroxybenzotriazole. These coupling reactions can be carried out either in solution (liquid phase) or in solid phase.

The functional groups of the constitutive amino acids or the amino acid mimetics must be protected during the coupling reactions to prevent the formation of unwanted bonds. Protective groups that can be used are included in Greene, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is incorporated herein by reference.The alpha-carboxyl group of the C terminal residue it is usually protected by an ester that can be separated to provide the carboxylic acid These protecting groups include: 1) alkyl esters such as methyl and t-butyl, 2) aryl esters such as benzyl and substituted benzyl, or 3) esters which can be separated by treatment with moderate base or a moderate reducing medium such as trichloroethyl and phenacyl esters.In the case of solid phase, the C-terminal amino acid is bound to an insoluble carrier (usually polystyrene) .These insoluble carriers contain an group which will react with the carboxyl group to form a bond which is stable to the elongation conditions, but which can be easily separated afterwards, examples of which are: ma (DeGrado and Kaiser (1980) J. Org. Chem. 45, 1295-1300), chlorine or bromomethyl resin, hydroxymethyl resin and aminomethyl resin.

Many of these resins are commercially available with the desired C-terminal amino acid incorporated in advance. The alpha-amino group of each amino acid must be protected. Any protecting group known in the art can be used. Examples of these are: 1) acyl types such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (p-biphenyl) -1-methyleneoxycarbonyl and 9-fluorenylmethoxycarbonyl (Fmoc), - 3) aliphatic carbamate types such as tertiary oxycarbonyl (Boc) , ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl. The protected alpha-amino protecting group is Boc or Fmoc. Many amino acids or mimetic derivatives of amino acids suitably protected for peptide synthesis are commercially available.

The alpha-amino protecting group is separated before coupling the next amino acid. When the Boc group is used, the methods of choice are trifluoroacetic acid, pure or in dichloromethane, or HCl in dioxane. The resulting ammonium salt is then neutralized either before coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or dichloromethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or piperidines substituted in dimethylformamide, but any secondary amine or aqueous basic solutions can be used. The deprotection is carried out at a temperature between 0 ° C and room temperature. Any of the amino acids or amino acid mimetics having side chain functionalities must be protected during the preparation of the peptide using any of the groups identified above. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities will depend on the amino acid or amino acid mimetic and the presence of other protecting groups on the peptide or peptidomimetic. The selection of such a protective group is important insofar as it should not be removed during the deprotection and coupling of the alpha-amino group. For example, when Boc is chosen for the alpha-amine protection, they are acceptable in the following protecting groups: p-toluenesulfonyl (tosyl) and nitro for arginine; benzyloxycarbonyl, substituted benzyloxycarbonyls, tosyl or trifluoroacetyl for lysine; benzyl esters or alkyl such as cyclopentyl for glutamic and aspartic acids; benzyl ethers for serine and threonine; benzyl ethers, substituted benzyl ethers or 2-bromobenzyloxycarbonyl for tyrosine; p-methylbenzyl, p-methoxybenzyl, acetamidomethyl, benzyl or t-butylsulfonyl for cysteine; and the indole or tryptophan can be left unprotected or protected with a formyl group. When Fmoc is chosen for alpha-amine protection, tert-butyl-based protecting groups are usually acceptable. For example, Boc can be used for lysine, terbutyl ether for serine, threonine and tyrosine and terbutyl ester for glutamic and aspartic acids. Once the elongation of the peptide or peptidomimetic, or the elongation and cyclization of a cyclic peptide or peptidomimetic is complete, all of the protecting groups are removed. For the synthesis in liquid phase, the groups are removed in any way as established by the choice of protecting groups. These procedures are well known to those skilled in the art. When solid phase synthesis is used to synthesize a cyclic or peptidomimetic peptide, the peptide or peptidomimetic must be removed from the resin without simultaneously removing protective groups of functional groups that must interfere with the cyclization process. Thus, if the peptide or peptidomimetic is to be cyclized in solution, the separation conditions should be chosen so as to generate a free a-carboxylate and a free a-amino group without simultaneously removing other protecting groups. Alternatively, the peptide or peptidomimetic can be removed from the resin by hydrazinolysis, and then can be coupled by the azide method. Another very convenient method involves peptide or peptidomimetic synthesis on an oxime resin, followed by intramolecular nucleophilic displacement of the resin, which generates a cyclic or peptidomimetic peptide (Osapay, Profit, and Taylor (1990) Tetrahedron Letters 43, 6121- 6124). When the oxime resin is used, the Boc protection scheme is generally chosen. Next, the preferred method for removing the side chain protecting groups generally involves treatment with anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole or p-cresol at 0 ° C. Peptide or peptidomimetic separation can also be carried out by other acid reagents such as mixtures of trifluoromethanesulfonic acid / trifluoroacetic acid. The uncommon amino acids used in this invention can be synthesized by standard methods familiar to those skilled in the art ("The Peptides: Analysis, Synthesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981) The N-alkylamino acids can be prepared using previously described procedures (Cheung et al., (1997) Can. J. Chem. 55, 906; Freidinger et al., (1982) J. Org. Chem. 48, 77 (1982)), which are incorporated in the present as a reference. Additional synthetic methods that can be used by a person skilled in the art to synthesize the peptides and peptidomimetics of the target portions are described in PCT WO94 / 22910, the content of which is incorporated herein by reference. The binding of linking groups, Ln, to peptides and peptidomimetics, Q; chelators or binding units, Ch, to the peptides and peptidomimetics, Q or to the linking groups, L "; and peptides and peptidomimetics that present a fragment of the linking group to the rest of the linking group, in combination form the portion (Q) d-L "and then to the portion Ch, all can be carried out by standard techniques. These include, but are not limited to amidation, esterification, alkylation and the formation of ureas and thioureas. The procedures for carrying out these linkages can be found in Brinkley, M., Bioconjugate Chemistry 1992, 3 (1), which is incorporated herein by reference. Many methods can be used to bind the peptides and peptidomimetics, Q, to a paramagnetic metal ion or a heavy atom containing solid particles, X2, by a person skilled in the art of surface modification. of solid particles. In general, the target Q portion or combination (Q) dLn is attached to a coupling group that reacts with a constituent of the surface of the solid particle. The coupling groups may be any of numerous silanes which react with hydroxyl groups on the solid particle surface, as described in U.S. Application No. 60 / 092,360, and which also includes polyphosphonates, polycarboxylates, polyphosphates or mixtures thereof which are coupled to the surface of the solid particles, as described in US 5,520,904. Many reaction schemes can be used to bind the peptides and peptidomimetics, Q, to the tensoactive microsphere, X3. These are illustrated in the following reaction schemes, where S £ represents a surfactant portion that forms the tensoactive microsphere.

Alkylation reaction: S £ -C (= 0) -Y + Q-NH2 or > S £ -C (= 0) -NH-Q Q-OH or S £ -C (= 0) -0-Q And it's an outgoing group or an active ester Disulfide coupling: S £ -SH + Q-SH > S £ -S-S-Q Coupling with sulfonamide: S £ -S (= 0) 2-Y + Q-NH 2 > S £ -S (= 0) 2-NH-Q Reductive amidation: Sf - CHO Q-NH2 Sf-NH-Q In these reaction schemes, the substituents S £ and Q can also be reversed. The linking group Ln can have several functions.

First, it provides a spacer group between the metallic chelator or the binding portion, Ch, the paramagnetic metal ion or the heavy atom containing a solid particle, X2, and the surfactant microsphere, X3, and one or more of the peptides or peptidomimetics, Q, so as to minimize the possibility that the Ch-X, C ^ X1, X2 and X3 portions interfere with the interaction of Q recognition sequences with angiogenic tumor vasculature receptors. The need to incorporate a linking group in a reagent depends on the identity of Q, Ch-X, 0, -X1, X2 and X3. if Ch-X, Ch-X1, X2 and X3 can not be bound to Q without substantially decreasing their affinity for the receptors, then a linking group is used. A linker group also provides a means to independently bind multiple peptides and peptidomimetics, Q, to a group that binds to Ch-X, C.-X1, X2 and X3. The linking group also provides a means for incorporating a pharmacokinetic modifier into the pharmaceutical substances of the present invention. The pharmacokinetic modifier serves to direct the biodistribution of the injected pharmaceutical substance different from the interaction of the target portions, Q with the receptors expressed in the tumoral neovasculature. A wide variety of functional groups can serve as pharmacokinetic modifiers and include, but are not limited to, carbohydrates, polyalkylene glycols, peptides or other polyamino acids and cyclodextrins. The modifiers can be used to improve or decrease the hydrophilicity and to improve or decrease the rate of blood clearance. Modifiers can also be used to direct the route of elimination of pharmaceutical substances. Preferred pharmacokinetic modifiers are those that result in moderate to rapid blood clearance and increased renal excretion.

The metal chelator or the binding portion, Ch, is selected to form stable complexes with the metal ion chosen for the particular application. Chelators or binding portions for diagnostic radiopharmaceuticals are selected to form stable complexes with radioisotopes having gamma-ray or positron-imaging emissions, such as 99pTc, 95Tc, llaTn, d2Cu, 60Cu, 64Cu, 67Ga, 68Ga, 86Y. The chemists for technetium, copper and gallium isotopes are selected from diaminodithiols, monoamine-monoamytdithiols, triamide-monothiols, monoamine-diamide-monothiols, diaminadioximes and hydrazines. Chelators are generally tetradentate (tetravalent) with donor atoms that are selected from nitrogen, oxygen and sulfur. Preferred reagents are made up of chelators having amine nitrogen and sulfur thiol donor atoms and hydrazine binding units. The thiol sulfur atoms and the hydrazines can have a protecting group which can be displaced either before using the reagent to synthesize a radiopharmaceutical, or preferably in situ during the synthesis of the radiopharmaceutical. Exemplary thiol protecting groups include those included in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley &; Sons, New York (1991), whose description is incorporated herein by reference.

Any thiol protecting group known in the art can be used. Examples of thiol protecting groups include, but are not limited to the following: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl and triphenylmethyl. Exemplary protecting groups for the hydrazine binding units are hydrazones which may be aldehyde or ketone hydrazones having substituents which are selected from hydrogen, alkyl, aryl and heterocycle. Particularly preferred hydrazones are described in copending US Serial No. 08/476, 296, the disclosure of which is incorporated herein by reference in its entirety. The hydrazine binding unit, when attached to a metal radionuclide, is referred to as a hydrazide or diazenide group and serves as a point of attachment of the radionuclide to the rest of the radiopharmaceutical. The diazenide group can be terminal (only one atom of the group is attached to radionuclide) or chelant. In order to have a diazenide chelating group, at least one other atom in the group must also bind to the radionuclide. The atoms attached to the metal are called donor atoms. Chelators for 11? In and 86Y are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2-benzyl-DOTA, alpha- (2-phenethyl) -1,4,7,10-tetraazazcyclododecane-1- acetic-4, 7, 10-tris (methylacetic), 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA and 6, 6"-bis [N, N, N", N "-tetra (carboxymethyl) aminomethyl) -4 '- (3-amino-4 -methoxyphenyl) -2,2 ': 6', 2"-terpyridine. The procedures for synthesizing these chelators are not commercially available and can be found in Brechbiel, M. and Gansow, O., J. Chem. Soc. Perkin Trans. 1992, 1, 1175; Brechbiel, M. and Gansow, 0., Bioconjugate Chem. 1991, 2, 187; Deshpande, S., et. al., J. Nucí. Med. 1990, 31, 473; Kruper, J., U.S. Patent 5,06, 956 and Toner J., U.S. Patent 4,859,777, the disclosures of which are incorporated herein by reference in their entirety. The coordination sphere of the metal ion includes all ligands or groups attached to the metal. For a transition metal radionuclide to be stable, it typically has a coordination number (number of donor atoms) comprised of an integer greater than or equal to 4 and less than or equal to 8; that is, there are 4 to 8 atoms attached to the metal and it is claimed that they have a complete coordination sphere. The coordination number required for a stable radionuclide complex is determined by the identity of the radionuclide, its oxidation state and the type of donor atoms. If the chelating or binding unit does not provide all the atoms necessary to stabilize the metallic radionuclide upon completion of its coordination sphere, the sphere of coordination is completed by donor atoms of other ligands, called auxiliaries or co-ligands, which are also terminal or chelating agents. Many of the ligands can serve as auxiliaries or co-ligands, the choice of which is determined by various considerations such as the ease of synthesis of the radiopharmaceutical, the chemical and physical properties of the auxiliary ligand, the rate of formation, the yield and the number of isomeric forms of the resulting radiopharmaceuticals, the ability to administer the auxiliary or binding to a patent without adverse physiological consequences to the patient, and the compatibility of the ligand in a formulation in lyophilized equipment. The loading and lipophilicity of the auxiliary ligand will alter the charge and lipophilicity of the radiopharmaceuticals. For example, the use of 4,5-dihydroxy-1,3-benzenedisulfonate results in radiopharmaceuticals with two additional anionic groups because the sulfonate groups will be anionic under physiological conditions. The use of 3, 4-hydroxypyridinones substituted with N-alkyl results in radiopharmaceuticals with varying degrees of lipophilicity depending on the size of the alkyl substituents. The preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazide or diazenide linking unit and an auxiliary ligand, AL1, or a unit of union and two types of auxiliaries AL1 and AL2, or a chelator tetradentado constituted of two atoms of nitrogen and two of sulfur. The auxiliary ligands AL1 are constituted by two or more hard donor atoms such as oxygen and amine nitrogen (with sp3 hybridization). The donor atoms occupy at least two of the sites in the coordination sphere of the radionuclide metal; the auxiliary ligand AL1 serves as one of the three ligands in the ternary ligand system. Examples of the auxiliary ligands AL1 include, but are not limited to, dioxygen ligands and functionalized aminocarboxylates. A large amount of such ligands are available from commercial sources. Auxiliary dioxygen ligands include ligands that coordinate with the metal ion through at least two oxygen donor atoms. Examples include, but are not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate, lactate, tartrate, mannitol, glucarate, maltol, Kojic acid, 2, 2-bis (hydroxymethyl) propionic acid, sulfonate, 4, 5-dihydroxy- 1, 3-benzene or 1,2 or 3,4-hydroxypyridinones substituted or unsubstituted. (The names for the ligands in these examples refer to their protonated or non-protonated forms of the ligands). Functionalized aminocarboxylates include ligands that have a combination of amine nitrogen and oxygen donor atoms. Examples include, but not I limited to: - iminodiacetic acid, 2, 3 -diaminopropiónico, nitrilotriacetic acid, N, N'-etilendiaminodiacético acid, N, N, '- eti one end i ami no triac icfoot, hydroxyethylethylenediaminetriacetic acid, and N, N' ethylenediamine bis-hydroxyphenylglycine. (The names for the ligands in these examples refer to either the protonated or non-protonated forms of the ligands). A series of functionalized aminocarboxylates are described in Bridger et. al., U.S. Patent No. 5,350,837, incorporated herein by reference, which results in improved rates of protein formation modified with hydrazino labels with technetium. We have determined that some of these aminocarboxylates result in improved yields of the radiopharmaceuticals of the present invention. Preferred auxiliary ligands AL1 of functionalized aminocarboxylates which are glycine derivatives; the most preferred one is tricine (tris (hydroxymethyl) methylglycine). The most preferred radiofarmacéticas substances of the present invention consist of technetium unit hydrazido or diazenido bonding and two types of ancillary designated ALl and AL2, or diaminedithiol chelator. The second type of auxiliary ligands AL2 are constituted by one or more soft donor atoms which are selected from the group: phosphine phosphorus, arsine arsenic, imine nitrogen (hybridized sp2), sulfur (hybridized sp2) and carbon (hybridized sp); atoms which have a p-acid character. Ligands AL2 may be monodentate, bidentate or tridentate, denticity is defined as the number of donor atoms in the ligand. One of the two donor atoms in a bidentate ligand and one of the three donor atoms in a tridentate ligand must be a soft donor atom. We have found in document US copending Serial No. 08 / 415.908 and document US serial number 60/013360 and 08 / 646.886, which are incorporated by reference in its entirety, that radiopharmaceuticals comprised of one or more AL2 auxiliaries or associates are more stable when compared to radiopharmaceuticals that are not constituted by one or more auxiliary ligands, Au; that is, they have a minimum number of isomeric forms, whose relative relationships of which do not change significantly with time, and which remain substantially intact when diluted. Ligands AL2 are comprised of phosphine or donor atoms are trisubstituted phosphines and arsine, trisubstituted arsines, tetrasubstituted diphosphines and tetrasubstituted diarsines. The AL2 ligands which are composed of imine nitrogen are unsaturated or are 5- or 6-membered heterocycles containing unsaturated or aromatic nitrogen. Ligands that are made up of donor atoms of Sulfur (sp2 hybridized) are thiocarbonyl, formed from the C = S portion. Ligands consisting of carbon donor atoms (sp hybridized) are isonitriles, constituted of the CNR portion, wherein R is an organic radical. A large amount of such ligands are available from commercial sources. The isonitriles can be synthesized as described in European Patent 0107734 and in U.S. Patent 4,988,827, incorporated herein by reference.

Preferred auxiliary ligands A? they are trisubstituted phosphines and 5 or 6 membered unsaturated or aromatic heterocycles. The most preferred auxiliary ligands AL2 are trisubstituted phosphines and unsaturated 5-membered heterocycles. The auxiliary ligands AL2 may be substituted with alkyl, aryl, alkoxy, heterocycle, alkyl, alkaryl and arylaryl groups, or may or may not have functional groups consisting of heteroatoms such as oxygen, nitrogen, phosphorus or sulfur. Examples of such functional groups include, but are not limited to: hydroxyl, carboxyl, carboxamide, nitro, ester, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate and phosphonoamide. The functional groups may be chosen to alter the lipophilicity and water solubility of the ligands which may affect the biological properties of the radiopharmaceuticals, such as alteration in the distribution in tissues that are not targets, cells or fluids, and the mechanism and speed of elimination of the body. Chelators or binding portions for therapeutic radiopharmaceuticals are selected to form stable complexes with radioisotopes having alpha particles, beta particles, Auger or Coster-Kroning electron emissions, such as 186Re, 188Re, 153Sm, 166Ho, 177Lu, 149Pm , 90Y, 21Bi, 103Pd, 109Pd, 159Gd, 140La, 198Au, 199Au, 169Yb, 175Yb, 165Dy, 166Dy, 67Cu, 1G5Rh, L11Ag and 1.2Ir. Chelators for isotopes of rhenium, copper, palladium, platinum, iridium, rhodium, silver and gold are selected from diaminodithiols, monoamine monoxamithiols, triamidemonotols, monoamine -diamidemonotols, diaminodioximes and hydrazines. Chelators for the isotopes of yttrium, bismuth and lanthanides are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2 -benzyl-DOTTA, alpha- (2-phenethyl) -1, 4, 7, 10- tetraazacyclododecane-1-acetic-4, 7, 10-tris (methylacetic), 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA and 6, 6"-bis (N, N, N", N " -tetra (carboxymethyl) aminomethyl) -4 '- (3-amino-4-methoxyphenyl) -2,2': 6 ', 2"-terpyridine. Chelators for magnetic resonance imaging contrast agents are selected to form stable complexes with paramagnetic metal ions such as Gd (III), Dy (III), Fe (III) and Mn (II) which are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2 -benzyl-DOTA, alpha- (2-phenethyl) -1,4,7,10-tetraazacyclododecane-1-acetic acid-4,7,1-tris (methylacetic acid ), 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA and 6,6-bis (, N, N ", N" -tetra (carboxymethyl) aminomethyl) -4 '- (3-amino) 4-methoxyphenyl) -2, 2 ': 6', 2"-terpyridine. The technetium and rhenium radiopharmaceuticals of the present invention are constituted by a hydrazide or diazenide linking unit which can be easily prepared by mixing a salt of a radionuclide, a reagent of the present invention, an auxiliary ligand AL1, an auxiliary ligand AL2 and a reducing agent, in an aqueous solution at temperatures of 0 to 100 ° C. The technetium and rhenium radiopharmaceuticals of the present invention are comprised of a tetradentate chelator having two nitrogen atoms and two sulfur atoms which can be easily prepared by mixing a salt of a radionuclide, a reagent of the present invention and an agent reducer, in an aqueous solution at temperatures of 0 to 100 ° C. When the binding unit in the reagent of the present invention is present as a hydrazone group, then it must first be converted to a hydrazine, which may or may not be protonated, prior to complex formation with the metal radionuclide. Conversion of the hydrazone group The hydrazine can be carried out either before the reaction with the radionuclide in which case the radionuclide and the auxiliary or binding agent or the ligands are combined not with the reagent but with a hydrolyzed form of the reagent which has the chelator or the chelating unit. binding, or in the presence of the radionuclide in which case the reagent itself is combined with the radionuclide and the auxiliary or by binding or ligands. In the latter case, the pH of the reaction mixture must be neutral or acidic. Alternatively, the radiopharmaceutical of the present invention are constituted by a hydrazide or diazenide linking unit which can be prepared by first mixing a salt of a radionuclide, an auxiliary ligand AL1 and a reducing agent in an aqueous solution at temperatures from 0 to 100 ° C to form an intermediate radionuclide complex with the auxiliary ligand AL1 and then add a reagent of the present invention and an auxiliary ligand A ^ and further react at temperatures of 0 to 100 ° C. Alternatively, the radiopharmaceutical of the present invention comprised of a hydrazide or diazenide linking unit can be prepared by first mixing a salt of a radionuclide, an auxiliary ligand AL1, a reagent of the present invention and a reducing agent in an aqueous solution of temperatures from 0 to 100 ° C to form an intermediate radionuclide complex, and then add an auxiliary ligand AL2 and further react at a temperature from 0 to 100 ° C. The technetium and rhenium radionuclides are preferably in the chemical form of pertechnetate or perrenate and a pharmaceutically acceptable cation. The pertechnetate salt form preferably sodium pertechnetate as obtained from commercial Tc-99m generators. The amount of pertechnetate used to prepare the radiopharmaceuticals in the present invention may vary from 0.1 mCi to 1 Ci, or more preferably from 1 to 200 mCi. The amount of the reagent of the present invention used to prepare the technetium and rhenium radiopharmaceuticals of the present invention can vary from 0.01 μg to 10 mg, or more preferably from 0.5 μg to 200 μg. The amount used will be determined by the amounts of the other reagents and the identity of the radiopharmaceuticals of the present invention to be prepared. The amounts of the auxiliary ligands AL1 used can vary from 0.1 mg to 1 g, or more preferably from 1 mg to 100 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the radiopharmaceuticals of the present invention to be prepared, the procedure used in the amounts and identities of the others reagents A too large amount of AL1 will result in the formation of byproducts consisting of AL1 labeled with technetium without a biologically active molecule or by-products consisting of biologically active molecules labeled with technetium with the auxiliary ligand AL1, but without the auxiliary ligand AL2. A too small amount of AL1 will result in other byproducts such as biologically active molecules labeled with technetium with the auxiliary ligand AL2, but they are the auxiliary ligand AL1, or a reduced hydrolyzed technetium or technetium colloid. The amounts of the AL2 auxiliary ligands used can vary from 0.001 mg to 1 g, or more preferably from 0.01 mg to 10 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the radiopharmaceuticals of the present invention to be prepared, the method used and the amounts and identities of the other reagents. A too large amount of AL2 will result in the formation of byproducts consisting of AL2-labeled technetium without a biologically active molecule or by-products consisting of biologically active molecules labeled with technetium with the auxiliary ligand AL2, but without the auxiliary ligand AL1. If the reagent has one or more substituents that are composed of a soft donor atom, as defined above, at least a molar excess of ten is required. times of the auxiliary ligand AL2 relative to the reagent of formula 2 to prevent the substituent from interfering with the coordination of the auxiliary ligand AL2 with the metal radionuclide. Suitable reducing agents for the synthesis of the radiopharmaceuticals of the present invention include stannous salts, salts of dithionite or bisulfite, borohydride salts and acids of formamidinsulfinic salts, wherein the salts are in any pharmaceutically acceptable form. The preferred reducing agent is a stannous salt. The amount of the reducing agent used can vary from 0.001 mg to 10 mg, more preferably from 0.005 mg to 1 mg. The specific structure of a radiopharmaceutical of the present invention constituted by a hydrazide or diazenide linking unit will depend on the identity of the reagent of the present invention used, the identity of any auxiliary ligand AL1, the identity of any auxiliary ligand AL2, and the identity of the radionuclide. Radiopharmaceuticals consisting of a hydrazide or diazenide linking unit synthesized using reagent concentrations of < 100 μg / ml, will consist of a hydrazido or diazenido group. Those synthesized using concentrations of > 1 mg / ml will consist of two hydrazide or diazenide groups from two reagent molecules. For most applications, you can only inject an amount limited of the biologically active molecule and does not result in unwanted side effects, such as chemical toxicity, interference with a biological process or altered biodistribution of the radiopharmaceutical. Therefore, radiopharmaceuticals which require higher concentrations of the reagents constituted in part of the biologically active molecule must be diluted or purified after the synthesis to avoid such side effects. The identities and quantities used of the auxiliary ligands AL1 and AL2 will determine the values of the variables y and z. The values of y and z can be independently an integer from 1 to 2. In combination, the values of y and z will result in a technetium coordination sphere that is made up of at least five and a maximum of seven donor atoms. For non-dentate auxiliary ligands AL2, z can be an integer from 1 to 2; for bidentate or tridentate auxiliary ligands, AL2, z is 1. The preferred combination of monodentate ligands is y equal to 1 or 2 and z equals 1. The preferred combination for bidentate or tridentate ligands is y equal to 1 and z equal to 1. The The indium, copper, gallium, silver, palladium, rhodium, gold, platinum, bismuth, yttrium and lanthanide radiopharmaceuticals of the present invention can be easily prepared by mixing a salt of a radionuclide and a reagent of the present invention, in an aqueous solution at temperatures of 0 to 100 ° C. These radionuclides are typically obtained as an aqueous solution diluted in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The radionuclides are combined with from one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. A buffer is typically used to maintain the pH of the reaction mixture between 3 and 10. The galodinium, dysprosium, iron and manganese metapharmaceutical substances of the present invention can be easily prepared by mixing a salt of the paramagnetic metal ion and a reagent the present invention, in an aqueous solution at temperatures from 0 to 100 ° C. These paramagnetic metal ions are typically obtained as an aqueous solution diluted in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The paramagnetic metal ions are combined with one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. Typically, a buffer is used to maintain the pH of the reaction mixture between 3 and 10. The total preparation time will vary depending on the identity of the metal ion, the identities and amounts of the reagents and the process used for the preparation. The preparations can be complete, which results in a performance of > 80% of the radiopharmaceutical in 1 minute or may require more time. If greater purity of the metapharmaceuticals is needed or desired, the products can be purified by any of numerous techniques well known to those skilled in the art such as liquid chromatography, solid phase extraction, solvent extraction, dialysis or ultrafiltration. Buffers useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of such radiopharmaceuticals include, but are not limited to, phosphate, citrate, sulfosalicylate and acetate. A more complete list can be found in the Pharmacopeia of the United States. Lyophilization adjuvants useful in the preparation of diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to mannitol, lactose, sorbitol, dextran, Ficoll and polyvinylpyrrolidine (PVP). Stabilization aids useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include but are not limited to ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentic acid and inositol.

Solubilization aids useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include, but are not limited to ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooleate, polysorbates, copol polyblock (oxyethylene) oli (oxypropylene) poly (oxyethylene), (Pluronics) and lecithin. The preferred solubilization aids are polyethylene glycol and Pluronics. Bacteriostats useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include, but are not limited to, benzyl alcohol, benzalkonium chloride, chlorbutanol and methyl, propyl or butylparaben. A component in a diagnostic equipment can also serve with more than one function. A reducing agent can also serve as a stabilization aid, a buffer can also serve as a transfer ligand, a lyophilization aid can also serve as a transfer aid or a co-ligand, and so on. Diagnostic radiopharmaceuticals are administered by intravenous injection, usually in saline, at a dose of 1 to 100 mCi per 70 kg of body weight, or preferably at a dose of 5 to 50 mCi. The imaging is performed using known procedures. The therapeutic radiopharmaceuticals are administered by intravenous injection, usually saline, at a dose of 0.1 to 100 mCi per 70 kg of body weight, or preferably at a dose of 0.5 to 5 mCi per 70 kg of body weight. The magnetic resonance imaging contrast agents of the present invention can be used in a manner similar to other MRI agents as described in U.S. Patent 5,155,215; U.S. Patent 5,087,440; Margerstadt et al., Magn. Reson. Med., 1986, 3, 808; Runge et al., Radiology, 1988, 166, 835; and Bousquet et al., Radiology, 1988, 166, 693. The generally sterile aqueous solutions of the contrast agents are administered to a patient intravenously in dosages ranging from 0.01 to 1.0 mmol per kg of body weight. For use as X-ray contrast agents, the compositions of the present invention generally should have a heavy atom concentration of 1 mM to 5 M, preferably 0.1 M to 2 M. Dosages, administered by intravenous injection, typically will vary from 0.5 mmoles / kg to 1.5 mmoles / kg, preferably from 0.8 mmole / kg to 1.2 mmole / kg. The imaging is performed using known techniques, preferably X-ray computed tomography. The ultrasound contrast agents of the present invention are administered by intravenous injection in an amount from 10 to 30 μl of the echogenic gas per kg of body weight or by infusion at a rate of approximately 3 μl / kg / min. The imaging is carried out using known sonography techniques. Other features of the invention will become apparent in the development of the following descriptions of exemplary embodiments which are provided for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES The representative materials and methods that can be used in the preparation of the compounds of the invention are described below in the following. Peptide synthesis in manual solid phase is carried out in 25 ml polypropylene filtration tubes purchased from BioRad Ine. , or in 60 ml glass-hour reaction vessels purchased from Peptides International. The oxime resin (substitution level = 0.96 mmol / g) is prepared according to the published procedure (DeGrado and Kaiser, J. Org. Chem. 1980, 45, 1295) or it is purchased from Novabiochem (substitution level = 0.62 mmol / g). All chemicals and solvents (reactive grade) that are used are supplied from the listed vendors without further purification. The t-butyloxycarbonyl (Boc) amino acids and other initial amino acids can be obtained commercially from Bachem Inc., Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTec (Louisville, KY), Peninsula Laboratories (Belmont, CA), or Sigma ( St. Louis, MO). 2- (lH-Benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and TBTU are purchased from Advanced ChemTech. N-methylmorpholine (NMM), m-cresol, D-2-aminobutyric acid (Abu), trimethylacetyl chloride, diisopropylethylamine (DIEA), 1,2,4-triazole, stannous chloride dihydrate and trisodium salt of tris (3 -sulfonatophenyl) phosphine (TPPTS) is purchased from Aldrich Chemical Company. The bis (3-sulfonatophenyl) phenylphosphine disodium salt (TPPDS) is prepared by the published method (Kuntz, E., US Pat. No. 4,248,802). The monosodium salt of (3-sulfonatophenyl) diphenylphosphine (TPPMS) is purchased from TCI America, Inc. Tricine is obtained from Research Organic, Inc. Technetium-99m pertechnetate (99Tc04 ~) is obtained from DuPont Pharma 99Mo / 99 ™ Tc Technelite "generator.In-111 chloride (Indichlor ™) is obtained from Amersham Medi-Physics, Inc. Sm-153 chloride and lutetium-177 chloride is obtained from the University of Missouri Research Reactor (MURR). Yttrium-90 chloride is obtained from Pacific Northwest Research Laboratories. Dimethylformamide (DMF), ethyl acetate, chloroform (CHC13), methanol (MeOH), pyridine and hydrochloric acid are obtained from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroacetic acid (TFA), ethyl ether, triethylamine, acetone and magnesium sulfate are commercially available. Absolute ethanol is obtained from Quant Chemical Corporation.

General procedure for the synthesis of solid phase peptides using Boc chemistry on oxime resin for the preparation of cyclic peptides Appropriately protected cyclic peptides, described in the examples, are prepared by manual solid phase peptide synthesis using the Boc-bag tea chemistry (Houghton, 1985) on a solid support of p-nitrobenzophenone oxime (DeGrado, 1982, Scarr et al. Findeis, 1990). The 5.0 cm x 5.0 cm tea bags are manufactured from 0.75 mm mesh polypropylene filters (Spectra Filters) and filled with 0.5 g (or 1 g) of oxime resin. The coupling and deprotection steps are carried out in a polypropylene reactor using a stirrer cabinet for agitation. The synthesis of the pentapeptide intermediate Protected-resin is obtained by first coupling Boc-Gly-OH to the oxime resin (substitution 0.69 mmoles / g or 0.95 mmoles / g). The binding of Boc-Gly-OH on the oxime resin is obtained by using five equivalents of each amino acid, HBTU and diisopropylethylamine (DIPEA) in DMF. The coupling of the first amino acid generally occurs after 2-3 days. After careful washing, replacement levels are determined using the picric acid assay (Stewart and Martin). The oxime groups which have not reacted in the resin are then topped with a solution of DIPEA and trimethylacetyl chloride in DMF. The boc group is deprotected using 50% TFA or 25% in DCM (30 min). The coupling of the other protected amino acids with boc is performed in a similar manner by stirring overnight (1-2 days), and the coupling yields for each of the newly added amino acids is determined using the picric acid assay.

General procedure for the synthesis of solid phase peptides using the Fmoc chemistry in HMPB-BHA resin for the preparation of cyclic peptides The linear peptide precursors appropriately protected for the cyclic peptides, described in the examples, are also prepared by automated solid phase peptide synthesis using the Fmoc chemistry in a Advanced ChemTech Model 90 synthesizer and using HMPB-BHA resin as the solid support. The synthesis of the protected pentapeptide-resin intermediates is obtained by coupling (for 3 h) Fmoc-amino acids sequentially to a commercially available Fmoc-Gly-HMPB-BHA resin (Novabiochem) (usually 2 g, substitution 0.47 to 0.60 mmol / g) by using three to five equivalents of each of the amino acids, HBTU, HOBT and diisopropylethylamine (DIPEA) in DMF. The Fmoc group is deprotected using piperidine 20% in DMF (30 min). The peptides are separated from the HMPB-BHA resin using a 1% solution of TFA / DCM and the peptide solutions are collected in a solution of pyridine in methanol (1:10). The linear protected peptides are isolated by removing the solvents and reagents in vacuo and by triturating the crude residue in diethyl ether. The synthesis of several amino acids that are not commercially available are described in the following procedures.

Synthesis of Tfa-amino acids Boc-HomoLys (Tfa) -OH and Boc-Cys (2-N-Tfa-aminoethyl) -OH are prepared via the reaction of Boc-HomoLys-OH and Boc-Cys (2-aminoethyl) -OH, respectively, with thiol trifluoroacetate from ethyl acetate in aqueous NaOH and purified by recrystallization from ethanol.

Synthesis of Boc-Orn (d-N-benzylcarbamoyl) To a solution of Boc-Orn (1 mmol) in 30 ml of DMF are added .2 mmoles of benzyl isocyanate and 3 mmoles of diisopropylamine. The reaction mixture is then stirred overnight at room temperature. The volatile fractions are removed in vacuo and the crude material is purified by column chromatography to obtain the desired product.

Synthesis of Boc-Orn (d-N-l-Tos-2-imidazolidinyl) A solution of Boc-Orn-OH (10 mmol), l-tosyl-2-methylthioimidazoline (12 mmol) (which in turn is prepared from the reaction of the available 2-methylthioimidazoline hydroiodide) commercial and p-toluenesulfonic anhydride in methylene chloride (0 ° C at room temperature) in the presence of triethylamine)) and diisopropylethylamine (12 mmol) is stirred at reflux overnight. The volatile fractions are removed and the desired product is isolated by chromatography.

Synthesis of Dap (b- (l-Tos-2-benzimidazolylacetyl)) To a solution of 1-Tos-2-benzimidazolylacetic acid (10 mmol, prepared using tosyl chloride and standard reported conditions) and 10 mmol of N-methylmorpholine in anhydrous DMF, 10 mmol of isobutyl chloroformate are added. After stirring at an ice bath temperature for 5-10 min., Add 10 mmoles of Boc-Orn-OH and 20 mmoles of N-methylmorpholine in anhydrous DMF., in one portion. The reaction mixture is stirred overnight at room temperature, the volatile fractions are removed in vacuo, and the product is isolated by chromatography. (Alternatively Boc-Orn-OMe is used and the isolated product is treated with aqueous LiOH to obtain the acid). The analytical CLAP methods used are described below: Method 1 of CLAP Instrument: HP1050 Column: Vydac C18 (4.6 x 250 mm) Detector: Diode array detector 220 nm / 500ref Flow rate: 1.0 ml / min. Column temperature: 50 ° C Sample size: 15 μl Mobile phase: A: 0.1% TFA in water B: 0.1% TFA in ACN / water (9: 1) Gradient A: Time (min)% A% B 0 80 20 20 0 100 30 0 100 31 80 20 Gradient B: Time (min)% A 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 98 2 Example 1 Synthesis of cycle. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic-3-aminopropyl) -Val} Part A: Cycle preparation. { Arg (Cough) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of the N-terminal part of the Boc-As (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-Arg (Tos) -Gly-Oxima resin peptide sequence is removed using standard deprotection ( TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min.). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The retina (1.7474 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 444.4 mg of the desired product. ESMS: Calculated for C51H63N9012S, 1025.43; Found, 1026.6 [M + H] + l. Analytical CLAP. Method IA, Rt = 14,366 min, Purity = 75%.

Part B: Preparation of the trifluoroacetic acid salt of citric acid. { Arg-Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

The cycle is dissolved. { Arg (Cough) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} (0.150 g, 0.146 mmoles) in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintained at a temperature of -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The crude product obtained is filtered, washed with diethyl ether, dried under high vacuum and purified by the preparative CLAP method, to provide 29.7 mg (23%) of the desired product as a lyophilized solid. ESMS: Calculated for C29H45N908, 647.34; Found: 648.5 [M + H] + 1. Analytical CLAP, Method IB, Rt = 10,432 min, Purity = 91%.

Method 1 of preparative CLAP Instrument: Programming elements Dynamax Rainin Rabbit; Column: Vydac C-18 (21.2 mm x 25 cm) Detector: Knauer VWM Flow rate: 15 ml / min Column temperature: Ambient temperature Mobile phase: A: 0.1% TFA in H20 B: 0.1% TFA in ACN / H20 (9: 1) Gradient: Time (min)% A% B 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 98 2 Part C: Cycle preparation. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} The trifluoroacetic acid salt of the cycle is dissolved. { Arg-Gly-Asp-D-Tyr (3-aminopropyl) -Val} (0.020 g, 0.0228 mmol) in 1 ml of DMF. Triethylamine (9.5 μl, 0.0648 mmol) is added and, after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] is added. -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid, (0.121 g, 0.0274 mmol). The reaction mixture is stirred for 7 days, and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP method 1 to provide 8.9 mg (37%) of the title product as a lyophilized solid (TFA salt). ESMS: Calculated for C42H54N12012S + H, 951.3783; Found: 951.3767. Analytical CLAP, Method IB, Rt = 14,317 min, Purity = 95%.

EXHIBITION 2 Synthesis of cycle. { Arg-Gly-Asp-D-Tyr ((N- [2 - [[[5- [carbonyl-2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -18 amino-14-aza-4, 7, 10- oxy-15-oxo-octadecoyl) -3-aminopropyl) • Val} Part A: Preparation of 3- (N- (3- (2- (2- (3- ((tert-butoxy) -carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) -propanoic acid N- (3 - (2 - (2 - (3-Aminopropoxy) ethoxy) ethoxy) propyl) (terbutoxy) formamide (1.5 g, 4.68 mmol) is added to 15 ml of DMF. To this solution is added 15 ml of pyridine, succinic anhydride (0.47 g, 4.68 mmol) followed by dimethylaminopyridine (62 ml, 0.468 μmol). The reaction mixture is stirred overnight at 100 ° C. The mixture is concentrated under high vacuum and the residue is extracted into water, acidified to pH 2.5 with 1N HCl and extracted with ethyl acetate. (3x) The combined organic extracts are dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to provide 1.24 g of an oily product (63%). The desired product is used without further purification. aHNMR (CDC13) 3.67-3.45 (m, 11H), 3.41-3.28 (m, 2H), 3.21-3.09 (m, 2H), 2.95-2.82 (m, 2H), 2.80-2.35 (m, 3H), 1.81 -1.68 (m, 4H), 1.50-1.35 (s, 9H); ESMS: Calculated for C19H36N208, 420.2471 Found: 419.3 [M-H] -l.

Part B: Preparation of the succinimidic ester of 3- (N- (3- (2 - (2 - (3 - ((t e r - b u t or x i) -carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoic acid To a solution of 3- (N- (3- (2- (2- (3- ((terbutoxy) -carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) -propanoic acid (1.12 g, 2.66 mmol), N -hydroxysuccinimide (0.40 g, 3.46 mmol) and 40 ml of N, N-dimethylformamide was added l- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.67 g, 3.46 mmol). The reaction mixture is stirred at room temperature for 48 h. The mixture is concentrated under high vacuum and the residue is extracted into 0.1 N HCl and extracted with ethyl acetate (3x). The combined organic extracts are washed with water (2?) And then with saturated sodium chloride, dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to provide 1.0 g of the product as an oil (73%). The desired product is used without further purification. ESMS: Calculated for C23H39N3010, 517.2635, Found: 518. [M + H] +1.

Part C. Cycle preparation. { Arg-Gly-Asp-D-Tyr (3- (3-N- (3- (2- (2- (3- ((tert-butoxy) -carbonylamino) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) - propanamide) propyl -Val} Dissolve the TFA salt cycle. { Arg-Gly-Asp-D-Tyr (3-aminopropyl) -Val} (0.040 g, 0.0457 mmoles) in 2 ml of DMF. Triethylamine (19.1 μl, 0.137 mmol) is added and after stirring for 5 minutes, the succinimide ester of 3 - (N- (3 - (2 - (2- (3 - ((tert-butoxy) -carbonylamino ) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propionic (0.0284 g, 0.548 mmol). The reaction mixture is stirred under N2 for 48 h and then concentrated to an oil under high vacuum. The oil is triturated with ethyl acetate and the product is filtered, washed with ethyl acetate and dried under high vacuum. The crude product is purified by preparative CLAP method 1 to provide 7.4 mg (14%) of the desired product as a lyophilized solid. ESMS: Calculated for CßH79 -.-? O-5, 1049.58; Found: 1050.5 [M + H] + 1. Analytical CLAP, Method IB, Rt = 20,417 min, Purity = 100%.

Part D. Cycle preparation. { Arg-Gly-Asp-D-Tyr (3- (3-N- (3- (2- (2- (3- (amino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) -propanamido) propyl) -Val} The cycle is dissolved. { Arg-Gly-Asp-D-Tyr (3- (3- (N- (3- (2- (2- (3- ((tert-butoxy) -carbonylamino) propoxy) ethoxy) ethoxy) propyl) -carbamoyl) -propanamide) propyl) -Val} (6.0 mg, 0.00515 mmoles) in 1 ml of methylene chloride and add 1 ml of trifluoroacetic acid. The solution is stirred for 2 h and then concentrated to an oil under high vacuum. The oil is triturated with diethyl ether, the product is filtered, washed with diethyl ether and dried under high vacuum to provide 6.0 mg (98%) of the desired product. ESMS: Calculated for C43H71N1: 1013, 949.52; Found: 950.6 [M + H] + 1. Analytical CLAP, Method IB, Rt = 14,821 min, Purity = 73%.

Part E: Cycle preparation. { Arg-Gly-Asp-D-Tyr ((N- [2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] - 18 -. 18-amino-14-aza-4, 7, 10-oxy-15-oxo-octadecoyl) -3-aminopropyl) -Val} The cycle is dissolved. { Arg-Gly-Asp-D-Tyr (3- (3-N- (3- (2- (2- (3- (amino) propoxy) ethoxy) ethoxy) propyl) -carbamoyl) -propanamido) propyl) -val } (5.0 mg, 0.00424 mmoles) in 1 ml of dimethylformamide. Triethylamine (1.8 μl, 0.01 7 mmol) is added and after stirring for 5 min, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] -carbonyl acid is added. ] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid (2.2 mg, 0.00509 mmol). The reaction mixture is stirred for 4 h and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP method 1 to provide 2.2 mg (38%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C56H80N14O17S, 1252.6; Found: 1253.7 (M + H *). Analytical CLAP, Method IB, Rt = 17.328 min, Purity = 100%.

Example 3 Synthesis of [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp}) -cycle. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} Part A. Preparation of Boc-Glu (Cyclo {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp.}.) -cyclo. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} The cycle is dissolved. { D-Tyr (3-aminopropyl) -Val-ARg-Gly-Asp} (0.040 g, 0.0457 mmoles) in 2 ml of dimethylformamide. Triethylamine (19.1 μl, 0.137 mmol) is added and the reaction mixture is stirred for 5 minutes. Boc-Glu (OSu) -OSu (0.0101 g, 0.0299 mmoles) is added and the reaction mixture is stirred under N2 for 18 h. The reaction mixture is then concentrated to an oil under high vacuum. The oil is triturated with ethyl acetate. The product is filtered, washed with ethyl acetate and dried under high vacuum to provide 38.0 mg (55%) of the desired product. ESMS: Calculated for C68H103N19O20, 1505.76; Found: 1504.9 [M-H] -l. Analytical CLAP, Method IB, Rt = 19,797 min, Purity = 73%.

Part B. Preparation of the Glu-TFA salt (cycle {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp.}.) -cyclo. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} .

Boc-Glu (cyclo {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp.}.) - cycle is dissolved. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} (0.035 g, 0.232 mmol) in 1 ml of methylene chloride. 1 ml of trifluoroacetic acid is added and the reaction mixture is stirred for 2 h, concentrated to an oil under high vacuum and triturated with ether. The obtained product is filtered, washed with diethyl ether and dried under high vacuum to provide 30.7 mg (76%) of the desired product. ESMS: Calculated for C63H95N19018, 1405.71; Found: 1404.7 [M-H] -l. Analytical CLAP, Method IB, Rt = 15,907 min, Purity = 77%.

Part C. Preparation of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { D-Tyr (3-aminopropyl) -Val-Arg-Gly -Asp.}.) -cycle. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} To a solution of Glu (cyclo {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp.}.) -cyclo. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp} (0.025 g, 0.0143 mmoles) in 2 ml of dimethylformamide is added triethylamine (6.0 μl, 0.0429 mmole) and the reaction mixture is stirred for 5 min. The monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid (0.0076 g, 0.0172 mmol) is added and The reaction mixture is stirred for 5 days, then concentrated to an oil under high vacuum. The oil is purified by method 1 of preparative CLAP to provide 12.0 mg (43%) of the desired product as a lyophilized solid. ESMS: Calculated for C76H10.N22O22S, 1708.7; Found: 1710.1 (M + H *). Analytical CLAP, Method IB, Rc = 17.218 min, Purity = 94%.

Example 4 Synthesis of cycle. { Arg-Gly-Asp-D-Tyr-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Part A. Cycle preparation. { Arg (Cough) -Gly-Asp (OBzl) -D-Tyr (Bzl) -Lys (Cbz)} The Boc-protected group in the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr) Bzl) -Lys (Z) -Arg (Tos) -Gly-resin oxime is removed using standard deprotection (TFA 25 % in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.8711 g, 0.44 mmol / g) is then suspended in 15 ml of DMF. Glacial acetic acid (47.1 μl, 0.823 mmol) is added and the reaction is heated at 60 ° C for 72 h. The resin is filtered, and washed with DMF (2 x 10 ml). Filtering Concentrate to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 653.7 mg of the desired product. ESMS: Calculated for C56H65N9012S, 1087.45; Found: 1088.7 [M + H] + l. Analytical CLAP, Method A, R. = 17.599 min, Purity = 82%.

Part B. Cycle preparation. { Arg-Gly-Asp-D-Tyr-Lys} The cycle is dissolved. { Arg (Cough) -Gly-Asp (OBzl) -D-Tyr (Bzl) - Lyz (Cbz)} (0.200 g, 0.184 mmol) in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction is cooled to -50 ° C and stirred for 1 h. The crude product is filtered, washed with diethyl ether and dried under high vacuum. The crude product is purified by method 1 of preparative CLAP to provide 15.2 mg (10%) of the desired product as a lyophilized solid. ESMS: Calculated for C2, H41N908 + H, 620.3156; Found: 620.3145. Analytical CLAP, Method IB, R_ = 8.179 min, Purity = 100%.

Part C. Preparation of the cycle. { Arg-Gly-Asp-D-Tyr-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Dissolve the TFA salt cycle. { Arg-Gly-Asp-D-Tyr-Lys} (0.010 g, 0.0118 mmoles) in 1 ml of DMF. Triethylamine (5.0 μl, 0.0354 mmol) is added, and after stirring for 5 min, the monosodium salt of 2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] is added. - 2-pyridinyl] hydrazono] -methyl] -benzenesulfonic acid (0.0062 g, 0.0142 mmol). The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by method 1 of preparative CLAP to provide 6.2 mg (46%) of the desired product as a lyophilized solid. ESMS: Calculated for .C40H50N12O12S + H, 923.3470; Found: 923.3486. Analytical CLAP, Method IB, Rt = 11,954 min, Purity = 100%.

Example 5 Synthesis of cycle. { Arg-Gly-Asp-D-Phe-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Part A. Cycle preparation. { Arg (Cough) -Gly-Asp (OBzl) -D-Phe-Lys (Cbz)} The Boc protecting group in the N-terminal part of the peptide sequence Boc-Asp (Obzl) -D-Phe-Lys (Z) -Arg (Tos) -Gly-oxime resin, is removed using standard deprotection (TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x5) and dried under high vacuum.

The resin (1.7053 g, 0.44 mmol / g) is then suspended in ml of dimethylformamide. Glacial acetic acid is added (43.0 μl, 0.750 mmol) and the reaction is heated at 60 ° C for 72 h. The resin is filtered and washed with DMF (2 x ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate.

The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 510.3 mg of the desired product. ESMS: Calculated for C ^ H ^ NjOnS, 981. 40; Found: 982.6 [M + H] + 1. Analytical CLAP, Method A, Rt = 15,574 min, Purity = 89%.

Part B. Cycle preparation. { Arg-Gly-Asp-D-Phe-Lys} The cycle is dissolved. { Arg- (Cough) -Gly-Asp (OBzl) -D-Phe-Lys (Cbz)} (0.200 g, 0.204 mmoles) in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction is cooled to -50 ° C and stirred for 1 h. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by method 1 of preparative CLAP, to provide 121 mg (71%) of the desired product as a lyophilized solid. ESMS: Calculated for C27H41N970 + H, 604.3207; Found: 604.3206. Analytical CLAP, Method IB, Rt = 11,197 min, Purity = 100%.

Part C. Cycle preparation. { Arg-Gly-Asp-D-Phe-Lys [2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Dissolve the TFA salt cycle. { Arg-Gly-Asp-D-Phe-Lys} (0.040 g, 0.0481 mmoles) in 2 ml of DMF. Triethylamine (20.1 μl, 0.144 mmol) is added and, after stirring for 5 minutes, the monosodium salt of 2- [[[5- [[(, 5-dioxo-l-pyrrolidinyl) oxy] carbonyl] - is added. 2-pyridinyl] hydrazone] -methyl] -benzenesulfon (0.0254 g, 0.0577 mmol). The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP method 1 to provide 38.2 mg (78%) of the desired product as a lyophilized solid. ESMS: Calculated for C ^ Hs-N ^ OnS + H, 907.3521; Found: 907.3534. Analytical CLAP, Method IB, Rt = 14,122 min, Purity = 91%.

Example 6 Synthesis of [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Phe.).) -cycle . { Lys-Arg-Gly-Asp-D-Phe} Part A. Preparation of Boc-Glu (OSu) -OSu To a solution of Boc-Glu-OH (8.0 g, 32.25 mmoles), N-hydroxysuccinimide (8.94 g, 77.64 mmoles) and 120 ml of DMF, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (14.88 g, 77.64 mmol) is added. The reaction mixture is stirred at room temperature for 48 h. The mixture is concentrated under high vacuum and the residue is extracted in 0.1 N HCl and extracted with ethyl acetate. _- * -__ -? __--; - £ - ,. ethyl (3 x). The combined organic extracts are washed with water, saturated sodium bicarbonate and then saturated sodium chloride, dried over MgSO4 and filtered. The filtrate is concentrated in vacuo and purified via reverse phase CLAP (Vydac C18 column, 18 to 90% acetonitrile gradient containing 0.1% TFA, Rt = 9,413 min) to provide 8.5 g (60%) of the desired product as a white powder. "? NMR (CDC13): 2.98-2.70 (m, 11H), 2.65-2.25 (m, 2H), 1.55-1.40 (s, 9H); ESMS: Calculated for C18H23N3O10, 441.1383 Found: 459.2 [M + NH +1 .

Part B. Preparation of Boc-Glu (Cyclo. {Lys-Arg-Gly-Asp-D-Phe.).) -cyclo. { Lys-Arg-Gly-Asp-D-Phe} To a solution of cycle (Lys-Arg-Gly-Asp-D-Phe) (0.050 g, 0.0601 mmoles) in 2 ml of dimethylformamide is added triethylamine (25.1 μl, 0.183 mmol). After shaking during minutes, Boc-Gl u (OSu) - OSu (0.0133 g, 0. 0301 mmoles). The reaction mixture is stirred under N2 for h, and then concentrated to an oil under high vacuum and triturated with ethyl acetate. The product obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 43.7 mg (44%) of the desired product. ESMS: Calculated for C64H95N19018, 1417.71; Found, 1418.8 [M + H] + l. Analytical CLAP, IB Method, Rt = 19,524 min, Purity = 73%.

Part C. Preparation of the Glu-TFA salt (cycle { Lys-Arg-Gly-Asp-D-Phe.}.) -cyclo. { Lys-Arg-Gly-Asp-D-Phe} To a solution of Boc-Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.).) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (0.040 g, 0.0243 mmoles) in 1 ml of methylene chloride is added 1 ml of trifluoroacetic acid. The reaction mixture is stirred for 2 h, concentrated to an oil under high vacuum and triturated with diethyl ether. The product is filtered, washed with diethyl ether and dried under high vacuum to provide 39.9 mg (100%) of the desired product. ESMS: Calculated for C59Hβ7N.9016, 1317.66; Found, 1318.9 [M + H] + l. CLAP Analytical, Method IB, Rt = 15.410 min. Purity = 73%.

Part D. Preparation of [2- [[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Phe.} .) -cycle. { Lys-Arg-Gly-Asp-D-Phe} To a solution of Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (0.030 g, 0.0183 mmol) in 3 ml of dimethylformamide is added triethylamine (7.6 μl, 0. 0549 microwells) and the reaction mixture is stirred for 5 min. The monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinylioxy] carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid (0.0096 g, 0.0220 mmol) is added, and the reaction mixture is stirred for 18 h, then concentrated to an oil under high vacuum The oil is purified by preparative CLAP method 1 to provide 11.0 mg (32%) of the desired product as a lyophilized solid ESMS: Calculated for C72H96N22O20S, 1620.7; Found, 1620.1 (MH *). CLAP Analytical, Method IB, Rc = 16.753 min, Purity = 91%.

Example 7 Synthesis of [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Phe-Glu (cyclo { Lys-Arg-Gly-Asp-D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} Part A. Preparation of Phe-Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} A solution of Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.).) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (23.4 mg, 0.014 mmol) and triethylamine (7.8 μl, 0.56 mmol) in 2 ml of DMF are stirred for 5 min. To this is added Boc-Phe-OSu (5.1 mg, 0.014 mmol) and the reaction mixture is stirred overnight at room temperature under nitrogen. DMF is removed in vacuo, and the resulting residue is dissolved in 1.5 ml of TFA and 1.5 ml of methylene chloride. The solution is stirred for 2 h and concentrated in vacuo to provide 31 mg of the desired product as the TFA salt. ESMS: Calculated for C68H96N20O17, 1464.7; Found, 1465.6 (M + H) + l. CLAP Analytical, Method IB, Rt = 15.48 min. Purity = 95%.

Part B. Preparation of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] ethyl] -benzenesulfonic acid] -Phe-Glu (cyclo. {Lys-Arg-Gly-Asp-D-Phe}) -cycle. { Lys-Arg-Gly-Asp-D-Phe} To a solution of Phe-Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.).) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (0.030 g, 0.016 mmol) in 2 ml of dimethylformamide is added triethylamine (9 μl, 0.064 mmol) and the reaction mixture is stirred for 5 min. The monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid (0.0099 g, 0.0220 mmol) is added and the reaction mixture is stirred for 18 h, and then concentrated under high vacuum. The residue is purified by RP-CLAP method 1 to provide 7 mg (22%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C8lH105N23021S, 1767.8; Found, 1768.8 (M-H) + l. Analytical CLAP, Method IB, Rt = = 17.68 min, Purity = 99%.

Example 8 Synthesis of cycle. { Arg-Gly-Asp-D-Nal-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Part A. Cycle preparation. { Arg (Mtr) -Gly-Asp (OtBu) -D-Nal -Lys (Boc)} The peptide Asp (OtBu) -D-Nal-Lys (Boc) -Gar (Mtr) -Gly is obtained by automated solid-phase peptide synthesis using Fmoc chemistry. A 100 ml round bottom flask is charged with HBTU (349 mg, 0.92 mmol) and 10 ml of DMF. The solution is stirred at 60 ° C for 5 min. To this solution of 0.84 g of Asp (OtBu) -D-Nal-Lys (Boc) Arg (Mtr) -Gly (0.684 g) and Hunig's base (0.34 ml, 1.97 mmoles) in 10 ml of DMF is added, and the solution is stirred at 60 ° C for 4 h under nitrogen. The solvent is then removed in vacuo and the residue triturated with ethyl acetate. The solids are filtered and washed with ethyl acetate (3 x 5 ml) and dried in vacuo to provide the desired product (520 mg, 86%). ESMS: Calculated for C50H71N9O12S, 1021.5; Found, 1022.5 [M + H] + l. CLAP Analytical, Method IA, Rt = 15.91 min, (purity = 99%).

Part B. Preparation of the TFA salt cycle. { Arg-Gly-Asp-D-Nal-Lys} Bis A solution of cycle. { Arg (Mtr) -Gly-Asp (OtBu) -D-Nal-Lys (Boc)} (500 mg, 0.49 mmol), 7 ml of TFA, 0.25 ml of triisopropylsilane and 0.25 ml of water are stirred at room temperature under nitrogen for 18 h. The solvents are removed in vacuo (over 3 h) and the residue is triturated with diethyl ether to provide the desired product as the TFA salt (426 mg, 98%). ESMS: Calculated for C3lH43N907, 653.3; Found, 654.3 [M + H] + l. Analytical CLAP, Method IB, Rt = 13.30 min, Purity = 97%.

Part C. Cycle preparation. { Arg-Gly-Asp-D-Nal-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} The TFA salt cycle. { Arg-Gly-Asp-D-Nal-Lys} (0.056 g, 0.064 mmol) is dissolved in 2 ml of DMF. Triethylamine (27 μl, 0.19 mmol) is added and after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-1-pyrrolidinyl) oxy] carbonyl] - is added. 2-pyridinyl] -hydrazono] -methyl] -benzenesulfonic acid (0.039 g, 0.089 mmol). The reaction mixture is stirred overnight, under nitrogen, and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP method 1 to provide 49.3 mg (72%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C44H52N12011S, 956.4; Found, 957.5 [M + H] + l. Analytical CLAP, Method IB, Rt 16.19 min, Purity = 99%.

Example 9 Synthesis of [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Nal.}.) -cycle . { Lys-Arg-Gly-Asp-D-Nal} Part A. Preparation of Boc-Glu (Cyclo {Lys-Arg-Gly-Asp-D-Nal.}.) -cyclo. { Lys-Arg-Gly-Asp-D-Nal} To a cycle solution. { Lys-Arg-Gly-Asp-D-Nal} (0.052 g, 0.059 mmol) in 2 ml of dimethylformamide are added μl of triethylamine. After stirring for 5 minutes, Boc-Glu (OSu) -OSu (0.013 g, 0.029 mmol) is added. The mixture of The reaction is stirred under N2 for 20 h and then concentrated to an oil under high vacuum and triturated with ethyl acetate. The product obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 35.2 mg of the desired product in crude form. ESMS: Calculated for C72H99N190lβ, 1517.7; Found, 760.1 [M + 2H] +2. Analytical CLAP, Method IB, Rt = 21.07 min, Purity = (65%).

Part B. Preparation of Glu (cycle { Lys-Arg-Gly-Asp-D-Nal.}.) -cyclo. { Lys-Arg-Gly-Asp-D-Nal} To a solution of 35.2 mg of Boc-Glu (cycle { Lys-Arg-Gly-Asp-D-Nal.}.) -cyclo. { Lys-Arg-Gly-Asp-D-Nal} Crude in 1.5 ml of methylene chloride add 1.5 ml of trifluoroacetic acid. The reaction mixture is stirred for 2 h, concentrated to an oil under high vacuum and triturated with diethyl ether. The product is filtered, washed with ether diethyl ether and dried under high vacuum to provide 34.9 mg of the desired crude product (TFA salt). ESMS: Calculated for C67H91N19016. 1417.69; Found, 1418.7 [M + H] + l. Analytical CLAP, Method IB, Rt = 19.1 min, Purity = 62%.

Part C. Preparation of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo. {Lys-Arg-Gly-Asp-D-Nal.}. ) -cycle. { Lys-Arg-Gly-Asp-D-Nal} To a solution of 34.9 mg of Glu (cycle { Lys-Arg-Gly-Asp-D-Nal.}.) - cycle. { Lys - Arg-Gly-Asp-D-Nal} in 2 ml of dimethylformamide, triethylamine (10 μl, 0.074 mmol) was added and the reaction mixture was stirred for 5 min. Add the monosodium salt of 2- [[[2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (15.2 mg, 0.0344 mmol) and the reaction mixture it is stirred for 18 h, and then concentrated to an oil under high vacuum. The oil is purified by Method 1 of preparative RP-CLAP to provide 3 mg of the desired product (TFA salt). ESMS: Calculated for C80H100N22O20S, 1720.7; Found, 1722.6 (M + H) + 1. Analytical CLAP, Method IB, Rt = = 19.78 min, Purity = 92%.

Example 10 Synthesis of cycle. { Arg-Gly-Asp-Lys ([2- [[[5- [carbonyl] • 2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid]) -D-Val} Part A. Cycle preparation. { Arg (Cough) -Gly-Asp (OBzl) -Lys (Cbz) -D-Val} The Boc protecting group in the N-terminal part of the peptide sequence Boc-Asp (OBzl) -Lys (Z) -D-Val-Arg (Tos) -Gly-oxime resin is removed using standard TFA deprotection (25% in CH2C12 ). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.3229 g, 0.44 mmol / g) is then suspended in 10 ml of dimethylformamide. Glacial acetic acid (33.3 μl, 0.582 mmol) is added and the reaction is heated at 65 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate, dried under high vacuum, and then purified by preparative CLAP method 2 to provide 93.0 mg of the desired product as a lyophilized solid. ESMS: Calculated for CÍÜHSJNJOÍJS, 933.41; Found, 934.5 [M + H] +1. Analytical CLAP, Method A, Rt = 14,078 min, Purity = 85%.

Method 2 of preparative CLAP Instrument: Programming elements Dynamax Rainin Rabbit; Column: Vydac C-18 (21.2 cm x 25 cm) Detector: Knauer VWM Flow rate: 15 ml / min Column temperature: Ambient temperature Mobile phase: A: 0.1% TFA in H20 B: 0.1% TFA in ACN / H20 (9: 1) Gradient: Time (min)% A% B 0 80 20 20 0 100 30 0. 100 31 80 20 Part B Preparation of cycle. { Arg-Gly-Asp-Lys-D-Val) The cycle is dissolved. { Arg (Cough) -Gly-Asp (OBzl) -Lys (Cbz) -D- Val} (0.080 g, 0.0856 mmoles) in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid is added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction mixture is cooled to -50 ° C and stirred for 30 min. The resulting crude product is filtered, washed with ether, dried under high vacuum and purified by preparative CLAP Method 1 to provide 44.2 mg (66%) of the desired product as a lyophilized solid. ESMS: Calculated for C23H41N907, 555.31; Found, 556.3 [M + H] + l. Analytical CLAP, Method IB, Rt = 8.959 min, Purity = 92%.

Part C. Cycle preparation. { Arg-Gly-Asp-Lys ([2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid]) -D-Val} To a solution of cycl ?. { Arg-Gly-Asp-Lys-D-Val} (0.036 g, 0.0459 mmoles) in 3 ml of dimethylformamide was added triethylamine (19.2 μl, 0.0138 mmoles) and stirred for 5 minutes. 0.7 ml of dimethyl sulfoxide is added followed by the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] -hydrazono] methyl] - benzenesulfonic (0.0243 g, 0.0551 mmol) and the reaction mixture is stirred for 20 h. The reaction mixture is concentrated to an oil under high vacuum and purified by Method 1 in preparative CLAP to provide 13.9 mg (31%) of the desired product as a lyophilized solid. ESMS: Calculated for C ^ ft ^ N ^ O ^ S + H, 859.3443; Found, 859.3503. CLAP Analytical, Method IB, Rt = 13.479 min, Purity = 92%.

Example 11 Synthesis of [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { Lys-D-Val-Arg-Gly-Asp.}.) -cycle . { Lys-D-Val-Arg-Gly-Asp} Part A. Preparation of Boc-Glu (Cyclo {Lys-D-Val-Arg-Gly-Asp.}.) -cyclo. { Lys-D-Val-Arg-Gly-Asp} To a cycle solution. { Lys-D-Val-Arg-Gly-Asp} (0.400 g, 0.51 mmol) in 7 ml of dimethylformamide is added triethylamine (0.21 ml, 1.53 mmol). After stirring for 5 minutes, Boc-Glu (OSu) -OSu (115 mg, 0.26 mmol) is added. The reaction mixture is stirred under N2 for 20 h, and then concentrated to an oil. The product obtained in this manner is partially purified by preparative RP-CLAP to provide 124 mg of product. ESMS: Calculated for C56H95N.-018, 1321.71; Found, 1322.6 [M + H] +1.

Part B. Preparation of Glu (cycle { Lys-D-Val-Arg-Gly-Asp.}.) -cyclo. { Lys-D-Val-Arg-Gly-Asp} To a solution of 0.124 g of Boc-Glu (cycle { Lys-D-Val-Arg-Gly-Asp.}.) -cyclo. { Lys-D-Val-Arg-Gly-Asp} impure in 5 ml of methylene chloride, add 5 ml of trifluoroacetic acid. The reaction mixture is stirred for 2 h, concentrated to an oil using high vacuum and triturated with diethyl ether. The product is filtered, washed with diethyl ether and dried under high vacuum to provide 16.2 mg of the desired product after RP-CLAP (TFA salt). ESMS: Calculated for C51H87N19016, 1221.66; Found, 1222.6 [M + H] + l. Analytical CLAP, Method IB, Rt = 11.43 min, Purity = 93%.

Part C. Preparation of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo. {Lys-D-Val -Arg-Gly-Asp.}. ) -cycle. { Lys-D-Val -Arg-Gly-Asp} To a solution of Glu (cycle { Lys-D-Val-Arg-Gly-Asp.}.) -cycle. { Lys-D-Val -Arg-Gly-Asp} (0.016 g, 0.01 mmol) in 2 ml of dimethylformamide and 4.2 μl of triethylamine are added and the reaction mixture is stirred for 5 min. Add the monosodium salt of [2- [[[5- [[(2,5-dioxo-1-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.0063 g, 0.014 moles ) and the reaction mixture is stirred for 18 h, and then concentrated to an oil under high vacuum. The residue is purified by preparative RP-CLAP Method 1 to provide the desired product (TFA salt). ESMS: Calculated for Cβ4H96N22O20S, 1524.7; Found, 1525.7 (M + H) + l. Analytical CLAP, Method IB, Rc = 13.20 min, Purity = 99%.

Example 12 Synthesis of . { Cyclo (Arg-D-Val-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp-Gly} Part A: Cycle preparation. { Arg (Cough) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} The Boc protecting group in the N-terminal part of the peptide sequence Boc -Arg (Tos) -D-Val-D-Tyr (N-Cbz-aminopropyl) -D-Asp (OBzl) -Gly-oxime resin is removed using standard deprotection (50% TFA in CH2C12). After washing with DCM (8x), the resin is neutralized with 10% DIEA / DCM (2 x 10 min). The resin is washed with DCM (5x) and dried under high vacuum overnight. The resin (1.08 g, 0.36 mmol / g) is then suspended in 1 ml of N, N-dimethylformamide. Glacial acetic acid (67 ml, 1.16 mmol) is added and the reaction mixture is heated at 55 ° C for 7 h. The resin is filtered and washed with DMF (3 x 10 ml). The filtrate is concentrated under high vacuum to provide an oil. The resulting oil is triturated with ethyl acetate. The obtained solid is purified by reverse phase CLAP (Vydac C18 column, gradient of acetonitrile from 18 to 90% containing 0.1% TFA, Rt = 15.243 min) to provide 101 mg of a white spray product (30%). : Calculated for C44H57N9012S, 935.3847 Found, 936.5 [M + H] + l.

Part B. Cycle preparation. { Arg-D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} Cyclic peptide protected cycle. { Arg (Cough) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} (90 mg, 0.961 mmol) is dissolved in 0.95 ml of trifluoroacetic acid and cooled to -10 ° C in a dry ice / acetone bath. To this solution is added trifluoromethanesulfonic acid (0.1.16 mmoles), followed by 190 ml of anisole. The reaction mixture is stirred at -16 ° C for 3 h. The dry ice / acetone bath is then cooled to -35 ° and 40 ml of cold ether are added to the solution. The mixture is stirred for 30 min at -35 ° C, and then cooled to -50 ° C and stirred for another 30 min. The crude product is filtered, redissolved in water / acetonitrile (1/1), lyophilized and purified by reverse phase CLAP (Vydac C18 column, gradient of acetonitrile from 1.8 to 90% containing 0.1% TFA, Rt. = 13.383 min) to generate 17 mg of the title product (27%). : Calculated for C29H45N908, 647.3391 Found, 648.2 [M + H] + l.

Part C: Preparation of. { Cyclo (Arg-D-Va-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp-Gly} A solution of cycle. { Arg-D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} (14 mg, 0.0216 mmol) in 2 ml of N, N-dimethylformamide was added triethylamine (15 ml, 0.108 mmol) and stirred at room temperature for 10 min. The monosodium salt of [2- [[[5- [[(, 5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (11 mg, 0.060 mmol) is added ), and the mixture is stirred for 18 h. The mixture is concentrated under high vacuum and the residue is purified by reverse phase CLAP (Vydac C18 column, 1.8 to 90% acetonitrile gradient containing 0.1% TFA, Rt = 16264 min) to provide 10 mg of a white powdered product. (49%) : Calculated for C42H54N12012S, 950.3705 Found, 951.3 [M + H] + l.

Example 13 Synthesis of cycle. { D-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -D-Phe-D-Asp-Gly-Arg.}.

Part A: Cycle preparation. { D-Lys (Cbz) -D-Phe-D-Asp (OBzl) -Gly-Arg (Cough)} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Arg (Cough) -D-Lys (Cbz) -D-Phe-D-As (OBzl) -Gly-oxime resin is removed using standard deprotection (TFA) 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x5) and dried under high vacuum. The resin (1.93 g, 0.44 moles / g) is then suspended in 15 ml of dimethylformamide. 77 μl of glacial acetic acid are added, and the reaction is heated at 60 ° C for 72 h. The resin is filtered, and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide the desired product which is then purify by RP-CLAP (yield = 252 mg). ESMS: Calculated for C ^ H ^ NjOnS, 981.40; Found, 982.3 [M + H] + l. Analytical CLAP, Method A, Rt = 14,577 min.

Part B: Preparation of TFA salt cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg} The cycle is dissolved. { D-Lys (Cbz) -D-Phe-D-Asp (OBzl) -Gly-Arg (Cough)} (0.152 g, 0.155 mmol) in 1.55 ml of trifluoroacetic acid and cooled to -16 ° C. 1.86 ml of trifluoromethanesulfonic acid is added dropwise, maintaining the temperature at -16 ° C. 0.31 ml of anisole are added and the reaction is stirred at -16 ° C for 3 h. Diethyl ether is added, the reaction is cooled to -35 ° C and stirred for 20 min. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP Method 1, provide 69 mg (~ 53%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C27H41N907 + H, 604.3 07; Found, 604.4. Analytical CLAP, Method IB, Rt = 10.35 min. Purity = 93%.

Part C: Preparation of the TFA salt cycle. { D-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -D-Phe-D-Asp-Gly-Arg.}.

Dissolve the TFA salt cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg} (0.056 g, 0.0673 mmoles) in 2 ml of DMF. Triethylamine (28 μL, 0.20 mmol) is added and, after 5 min of stirring, the monosodium salt of [2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl is added. ] - 2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.029 g, 0.0673 mmol). The reaction mixture is stirred for 70 h and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP Method 1 to provide 14 mg (78%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C ^ H ^ N ^ O ^ S + H, 907.3521; Found, 907.3. Analytical CLAP, Method IB, Rt = 14.17 min, Purity = 99%.

Example 14 Synthesis of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo { D-Lys-D-Phe-D-Asp-Gly-Arg.} .) -cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg} Part A. Preparation of Boc-Glu (Cyclo {D-Lys-D-Phe-D-Asp-Gly-Arg.}.) -cyclo. { D-Lys-D-Phe-D-Asp-Gly-Arg} To a solution of cycle (D-Lys-D-Phe-D-Asp-Gly-Arg) (0.190 g, 0.228 mmoles) in 5 ml of dimethylformamide is added triethylamine (95 μl, 0.684 mmol). After stirring for 5 minutes, Boc-Glu (OSu) -OSu (0.050 g, 0.114 mmol) is added. The reaction mixture is stirred under N2 for 20 h, and then concentrated to an oil under high vacuum and triturated with ethyl acetate. The product obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide 172 mg of the desired product in crude form. ESMS: Calculated for C64H95N19018, 1417.71; Found, 1418.7 [M + H] + l. Analytical CLAP, Method IB, Rc = 16. 8 min.

Part B Preparation of Glu (Cyclo {D-Lys-D-Phe-D-Asp-Gly-Arg.}.) -cyclo. { D-Lys-D-Phe-D-Asp-Gly-Arg} To a solution of 0.17 g of Boc-Glu (cycle { D-Lys-D-Phe-D-Asp-Gly-Arg.}.) -cyclo. { D-Lys-D-Phe-D-Asp-Gly-Arg} Crude in 4.5 ml of methylene chloride is added 4.5 ml of trifluoroacetic acid. The reaction mixture is stirred for 2 h, concentrated to an oil under high vacuum and triturated with diethyl ether. The product is filtered, washed with diethyl ether and dried under high vacuum to provide 38 mg of the desired product after RP-CLAP as a lyophilized solid (TFA salt). ESMS: Calculated for C59H87N19016, 1317.66; Found, 1318.9 [M + H] + l. Analytical CLAP, Method IB, Rt = 13.06 min, Purity = 93%.

Part C. Preparation of [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclo {D.-Lys-D-Phe-D-Asp-Gly- Arg.}.) -cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg} To a solution of Glu (cycle {D-Lys-D-Phe-D-Asp-Gly-Arg.}.) -cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg} (0.025 g, 0.015 mmol) in 2 ml of dimethylformamide was added triethylamine (6.3 μl, 0.045 mmol) and the reaction mixture was stirred for 5 min. The monosodium salt of [2- [[[5- [(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.0092 g, 0.0210 mmol) is added and the reaction mixture is stirred for 18 h, and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP Method 1 to provide 12.5 mg of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C27H96N22O20S, 1620.7; Found, 1622.5 (M + H) +1. Analytical CLAP, Method IB, Rt = 14.62 min, Purity = 96%.

Example 15 Synthesis of (Cyclo {D-Phe-D-Lys- ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -D-Asp-Gly-Arg.} .

Part A. Cycle preparation. { D-Phe-D-Lys (Cbz) -D-Asp (OBzl) -Gly-Arg (Cough)} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Arg- (Cough) -D-Phe-D-Lys (Cbz) -D-Asp (OBzl) -Gly-oxime resin is removed using standard deprotection ( TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with DIEA 10% / DCM (2 x 10 min). The resin is subsequently washed with DCM (x5) and dried under high vacuum. The resin (1.5 g, 0.44 mmol / g) is then suspended in 12 ml of dimethylformamide. 61 μl of glacial acetic acid are added, and the reaction is heated at 60 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to provide the desired product (yield = 370 mg). E? MS: Calculated for C ^ H ^ NjOnS, 981.40; Found, 982.4 [M + H] + l. Analytical CLAP, Method IA, Rt = 14.32 min, (purity = 60%).

Part B. Preparation of the TFA salt cycle. { D-Phe-D-Lys-D-Asp-Gly-Arg} Bis Dissolve 0.146 g of cycle. { D-Phe-D-Lys (Cbz) -D-Asp (OBz 1) -Gly-Arg (Cough)} crude in 1.5 ml of trifluoroacetic acid, and cooled to -16 ° C. 1.8 ml of trifluoromethanesulfonic acid is added dropwise, maintaining the temperature at -16 ° C. 0.3 ml of anisole are added and the reaction is stirred at -16 ° C for 3 h. Diethyl ether is added, the reaction is cooled to -35 ° C and stirred for 20 min. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP Method 1, to provide 100 mg of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C27H41N907 + H, 604.3; Found, 604.3. Analytical CLAP, Method IB, Rt = 10.25 min, Purity = 90%.

Part C. Cycle preparation. { D-Phe-D-Lys ([2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -D-Asp-Gly-Arg.}.

Dissolve the TFA salt cycle. { D-Phe-D-Lys-D-Asp-Gly-Arg} (0.090 g, 0.108 mmol) in 2 ml of DMF. Triethylamine (45 μl, 0.324 mol) is added and after 5 minutes of stirring, the monosodium salt of [2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] is added] - 2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.048 g, 0.108 mmol). The reaction mixture is stirred for 70 h and then concentrated to an oil under high vacuum. The oil is purified by the preparative CLAP method to provide 10 mg of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C ^ HÜ-N ^ OUS + H, 907.4; Found, 907.3. Analytical CLAP, Method IB, Rt = 13.47 min, Purity = 89%.

Example 16 Synthesis of cycle. { N-Me-Arg-Gly-Asp-ATA-D-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Part A: Cycle preparation. { N-Me-Arg (Cough) -Gly-Asp (OBzl) -ATA-D-Lys (Cbz)} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -ATA-D-Lys (Z) -N-Me-Arg (Tos) -Gly-oxime ream is removed using the standard deprotection (TFA 50% in CH2C12). After washing with DCM (8x), the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is washed with DCM (5x) and dried under high vacuum overnight. The resin (1.4 g, 0.39 mmol / g) is then suspended in 12 ml of DMF. Glacial acetic acid (67 ml, 1.16 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (3 x 10 ml). The filtrate is concentrated under high vacuum to provide an oil. The oil is triturated with ethyl acetate. The solid obtained is purified by reverse phase CLAP (Vydac C18 column, 18 to 90% acetonitrile gradient containing 0.1% TFA Rt = 14129 min) to provide 42 mg (9%) of the desired product as a lyophilized solid. ESMS: Calculated for C ^ H ^ NÍ-OUSJ, 988.3571 Found, 989.4 [M + H] +1.

Part B: Cycle preparation. { N-Me-Arg-Gly-Asp-ATA-D-Lys} The cycle is dissolved. { N-Me-Arg (Cough) -Gly-Asp (OBzl) -ATA-D-Lys (Cbz)} (36 mg, 0.0364 mmole) in 0.364 ml of trifluoroacetic acid and cooled to -10 ° C in a dry ice / acetone bath. To this solution is added 0.437 mmoles of trifluoromethanesulfonic acid followed by 70 ml of anisole. The reaction mixture is stirred at -10 ° C for 3 h. The dry ice / acetone bath is then cooled to -35 ° C and 40 ml of cold ether are added to the solution. The mixture is stirred for 30 min at -35 ° C, and then further cooled to -50 ° C and stirred for another 30 min. The crude product is filtered, redissolved in water / acetonitrile (1/1) and lyophilized to generate 35 mg of the title product (100%). ESMS: Calculated for C24H38N1007S, 610.2646 Found, 611.4 [M + H] + l.

Part C: Cycle preparation. { N-Me-Arg-Gly-Asp-ATA-D-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] To a cycle solution. { N-Me-Arg-Gly-Asp-ATA-D-Lys} (31 mg, 0.051 mmol) in 2 ml of DMF is added triethylamine (28 ml, 0.204 mmol) and the reaction mixture is stirred at room temperature for 10 min. The monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) -oxy] carbonyl-2-pyridinyl] hydrazono] methyl-benzenesulfonic acid (27 mg, 0.0612 mmol) is added. The mixture is stirred for 18 h and then concentrated under high vacuum. The residue obtained is purified by reverse phase CLAP (Shandon HS-BDS column, 3 to 10% acetonitrile, Rt = 13,735 min) to provide 4 mg (8.8%) of the desired product as a lyophilized solid. ESMS: Calculated for C37H47N13011S2, 913.2959 Found, 914.5 [M + H] + l.

Example 17 Synthesis of cycle. { Cit-Gly-Asp-D-Phe-Lys ([2 - [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Part A. Cycle preparation. { Cit-Gly-As (OtBu) -D-Phe-Lys (Boc) The peptide Asp (OtBu) -D-Phe-Lys (Boc) -Cit-Gly is obtained by automated solid phase peptide synthesis using the Fmoc chemistry (see general procedure). A 100 ml round bottom flask is charged with HBTU (271 mg, 0.71 mmol) and 10 ml of DMF. The solution is stirred at 60 ° C for 5 min. To this solution is added 0.456 g of As (OtBu) -D-Phe-Lys (Boc) -Cit-Gly (0.456 g) and Hunig's base (0.7 ml, 1.53 mmoles) in 10 ml of DMF, and The solution is stirred at 60 ° C for 4 h under nitrogen. The solvent is then removed in vacuo and the residue triturated with ethyl acetate. The solids are filtered and washed with ethyl acetate (3 x 6 ml) and dried in vacuo to provide the desired product (305 mg, 78%).

ESMS: Calculated for C36H56N8O10, 760.4; Found, 761.4 [M + H] + l. Analytical CLAP, Method IA, Rt = 11.8 min, (purity = 99)%.

Part B. Cycle preparation. { Cit-Gly-Asp (OtBu) -D-Phe-Lys (Boc)} A solution of cycle. { Cit-Gly-Asp (OtBu) -D-Phe-Lys (Boc)} (287 mg, 0.38 mmol), 6 ml of TFA, 0.25 ml of triisopropylsilane and 0.25 ml of water are stirred at room temperature under nitrogen for 4 h. The solvents are removed in vacuo (for 3 h) and the residue is triturated with diethyl ether, filtered and washed with ether to provide 315 mg of the desired product (TFA salt). ESMS: Calculated for C27H40N8Oß, 604.3; Found, 605.4 [M + H] + l. Analytical CLAP, Method IB, Rt = 9.6 min, Purity = 97%.

Part C. Cycle preparation. { Cit-Gly-Asp-D-Phe-Lys [2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} 0.44 g of the cyclic TFA salt are dissolved. { Cit-Gly-Asp-D-Phe-Lys} in 2 ml of DMF. Triethylamine is added (22 μl, 0.156 mmol) and, after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] -2- is added. pyridinyl] hydrazono] -methyl] -benzenesulfonic acid (0.032 g, 0.073 mmol). The reaction mixture is stirred overnight, under nitrogen, and then concentrated under high vacuum. The residue is purified by the Method 1 preparative RP-CLAP to provide 37 mg (70%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C40H49N11O12S, 907.3; Found, 908.4 [M + H] +1. Analytical CLAP, Method IB, Rt = 14.15 min, Purity = 99%.

Example 18A Synthesis of tris (t-butyl) -1,4,7,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid Part A. Preparation of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) -phenylmethyl acetate A solution of (1, 4, 7, 10-tetraaza-4, 7-bis (((tert-butyl) oxycarbonyl) methyl) cyclodedecyl) tert-butyl acetate (0.922 g, 1.79 mmol), 1.8 ml of TEA and benzyl bromoacetate (0.86 ml, 5.37 mmol) in 24 ml of anhydrous DMF is stirred at room temperature under a nitrogen atmosphere for 4 h. The DMF is removed under vacuum and the resulting oil is dissolved in 300 ml of EtOAc. This solution is washed consecutively with water (2 x 50 ml) and 50 ml of saturated NaCl, dried (MgSO.) and concentrated to give 1.26 g of the title compound as an amorphous solid. MS: m / e 663.5 [M + H].

Part B. Preparation of 2 - (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclodedecyl) acetic acid The product of part A above (165 mg, 0.25 mmol) is subjected to hydrogenolysis on 50 mg of 10% Pd on carbon in 15 ml of EtOH at 414 kPa (60 psi) for 24 h. The catalyst is removed by filtration through a filter aid and washed with EtOH. The filtrates are concentrated to provide the title compound as an amorphous solid (134 mg, 94%). MS: m / e 573.5 [M + H].

Example 18 Synthesis of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) 1-cyclododecyl) acetyl-Glu (cyclo. {Lys-Arg-Gly-Asp-D-Phe.} .) - cicio. { Lys-Arg-Gly-Asp-D-Phe} Part A. Preparation of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (t-butoxycarbonylmethyl) -1-cyclodedecyl) acetyl-Glu (cyclo. {Lys -Arg -Gly-Asp -D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} To a solution of tris (t-butyl) -1,4,7,7-tetraazacyclododecan-1,4,7,10-tetraacetic acid (28 mg, 0.049 mmol) and 14 μl of Hunig's base in 2 ml of DMF is added HBTU (17 mg, 0.0456 mmol) and the mixture is stirred for 5 min. To this is added a solution of Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (54.1 mg, 0.0326 mmol) in 1 ml of DMF and the reaction mixture is allowed to stir under nitrogen at room temperature for 4 h. The solvent is removed in vacuo and the residue is purified by preparative RP-CLAP to give the product as 18.3 mg of a lyophilized solid (TFA salt). ESMS: Calculated for C87H137N23023, 1872.0; Found, 937. [M + 2H] +2. Analytical CLAP, Method IB, Rt = 19.98 min, Purity = 99%.

Part B. Preparation of 2 - (1, 4, 7, 10 - tetraaza -4, 7, l 0 -tris (carboxymethyl) -1-cyclododecyl) acetyl-Glu (cyclo. {Lys-Arg-Gly-Asp- D-Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (t-butoxycarbonylmethyl) -1-cyclododecyl) acetyl-Glu (Cyclo. {Lys-Arg-Gly-Asp-D -Phe.}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} (18.3 mg, 8.71 mmol) in 3 ml of TFA is stirred at room temperature under nitrogen for 5 h. The solution is concentrated in vacuo and the residue is purified by preparative RP-CLAP to provide 8 mg (45%) of the desired product as a lyophilized solid (TFA salt). ESMS: Calculated for C75H113N23023, 1703.8; Found, 853.0 [M + 2H] +2. CLAP Analytical, Method IB, Rt = 13.13 min, Purity = 99%.

Example 19 Synthesis of cycle. { Arg-Gly-Asp-D-Phe-Lys (DTPA) To a cycle solution. { Arg-Gly-Asp-D-Phe-Lys} (0.050 g, 0.0601 mmoles) in 2 ml of DMF triethylamine is added (41.9 μl, 0.301 mmol). This solution is added dropwise over 4 h to a solution of diethylenetriaminepentaacetic dianhydride (0.1074 g, 0.301 mmol) in 2 ml of DMF and 2 ml of methyl sulfoxide. The reaction mixture is then stirred for 16 h, concentrated to an oil under high vacuum and purified by preparative CLAP Method 1 to provide 29.9 mg (46%) of the desired product as a lyophilized solid. ESMS: Calculated for C41H62N12016, 978.4; Found, 977.5 (M-H *). CLAP Analytic, Method IB, Rt = 11,916 min, Purity = 100%.

Example 20 Synthesis of cycle. { Arg-Gly-Asp-D-Phe-Lys} 2 (DTPA) The oil obtained in Example 9, after purification by preparative CLAP Method 1, also provides 21.5 mg (21%) of the title product as a lyophilized solid. ESMS: Calculated for C68H101N21O22, 1563.7; Found, 1562.8 (M-H *). Analytical CLAP, Method IB, Rt = 15.135 min, Purity = 93%.

Example 21 Synthesis of cycle. { Arg-Gly-Asp-D-Tyr (N-DTPA-3-aminopropyl) - Val} To a cycle solution. { Arg-Gly-Asp-D-Tyr (3-aminopropyl) -Val} (0.050 g, 0.0571 mmol) in 2 ml of dimethylformamide is added triethylamine (39.8 μl, 0. 286 mmoles). This solution is added dropwise over 5 h to a solution of diethylenetriaminepentaacetic dianhydride (0.1020 g, 0.286 mmole) in 2 ml of methyl sulfoxide. The reaction mixture is stirred for an additional 18 h, then concentrated to an oil under high vacuum and purified by preparative CLAP Method 1 to provide 41.9 mg (65%) of the desired product as a lyophilized solid. ESMS: Calculated for C43H66N12017, 1022.5; Found, 1021.4 (M-H *). Analytical CLAP, Method IB, Rt = 15.690 min, Purity = 96%.

Example 22 Synthesis of . { Orn (d-N-2-imidazolinyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] - pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} Part A: Cycle preparation. { R n (d-N-l-Tos-2-imidazolinyl) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-0rn (dNl-Tos-2-imidazolinyl) -Gly-oxime resin is remove using standard deprotection (25% TFA in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added, and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered, and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

Dissolve 0.146 mmoles of cycle. { R n (d-N-l-Tos-2-imidazolinyl) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0. 6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid is added dropwise maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C. Cycle preparation. { ? rn (dN-2-imidazolinyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) - Val} 0.0228 mmol of the cycloalkyl trifluoroacetic acid salt is dissolved. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} in 1 ml of DMF. 0.0648 mmol of triethylamine are added and, after 5 min of stirring, 0.0274 mmol of the monosodium salt of 2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] - are added. 2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid. The reaction mixture is stirred for 1-2 days and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP to obtain the desired product.

Example 23 Synthesis of cycle. { Lys-Gly-Asp-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -Val} Part A: Cycle preparation. { Lys (Tf a) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-Lys (Tf a) - Glycosm of oxime is removed using standard deprotection (TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (0.2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 X 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { Lys (Tfa) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} Dissolve 0.146 mmoles of cycle. { Lys (Tfa) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C. for 3 h. Diethyl ether, the reaction mixture, is added. The mixture is cooled to -35 ° C and then stirred for 30 min.The reaction mixture is further cooled to -50 ° C and stirred for 30 min. filter, wash with diethyl ether, dry under high vacuum and purify by preparative CLAP to obtain the desired product.

Part C. Cycle preparation. { Lys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -Val} 0.0228 mmol of the cycloalkyl trifluoroacetic acid salt are dissolved. { ys (Tf a) -Gly- Asp-D- Tyr (3-aminopropyl) -Val} in 1 ml of DMF. 0.0648 mmol of triethylamine are added and after 5 min of stirring, 0.0274 mmol of the monosodium salt of 2- [[[5- [[(2, 5-dioxo-1-pyrrol idini I) oxy] carboni are added. ] - 2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid, the reaction mixture is stirred for 1-2 days, and then concentrated to an oil under high vacuum. The oil is treated with piperidine 20% in DMF and the crude material is purified by preparative CLAP to obtain the desired product.

Example 24 Synthesis of cycle. { Cis (2-aminoethyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} Part A: Cycle preparation. { Cys (2-N-Tfa-aminoethyl) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group in the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-Cys (2-N-Tfa-aminoethyl) -Gly-oxime resin is remove using standard deprotection (25% TFA in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated until an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of cycloalkyl trifluoroacetic acid salt. { Cys (2-N-Tfa-aminoethyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

Dissolve 0.146 mmoles of cycle. { Cys (2-N-Tfa-aminoethyl) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0. 6 ml of trifluoroacetic acid, and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The crude product obtained is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C: Cycle preparation. { Cys (2-aminoethyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} 0.0228 mmol of the cycloalkyl trifluoroacetic acid salt are dissolved. { Cys (2-N-Tfa-aminoethyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} in 1 ml of DMF. Triethylamine (9.5 μl, 0.0648 mmol) is added and after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl-oxy]] carbonyl] - 2 - is added. pyridinyl] hydrazono] methyl] -benzenesulfonic acid (0.0121 g, 0.074 mmol) The reaction mixture is stirred for l-days, and then concentrated to an oil under high vacuum.The oil is treated with piperidine 20% in DMF, and the crude material is purified by preparative CLAP to obtain the desired product.

Example 25 Synthesis of acid cycle. { HomoLys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} Part A: Cycle preparation. { HomoLys (Tfa) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-HomoLys (Tfa) -Gly-oxime resin is removed using standard deprotection (25). % of TFA in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM. { 2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of the salt of the trifluoroacetic acid cycle. { HomoLys (Tfa) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

Dissolve 0.146 mmoles of cycle. { HomoLys (Tfa) -Gly- Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0.6 mmole of trifluoroacetic acid and cooled to -10 ° C. It is added to drops 0. 5 ml of trifluoromethanesulfonic acid, maintaining the temperature at -10 ° C. 0.1 ml of anisole are added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, and the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The crude product obtained is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C. Cycle preparation. { HomoLys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -Val} 0.0228 mmol of the cycloalkyl trifluoroacetic acid salt are dissolved. { HomoLys (Tfa) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} in 1 ml of DMF. Triethylamine (9.5 μl, 0.0648 mmol) is added and after 5 minutes of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] carbonyl] - is added. 2-pyridinyl] hydrazone] methyl] -benzenesulfonic acid (0.0121 g, 0.074 mmol). The reaction mixture is stirred for 1-2 days and then concentrated toan oil under high vacuum. The oil is treated with 20% piperidine in DMF, and the crude material is purified by preparative CLAP to obtain the desired product.

Example 26 Synthesis of cycle. { rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} Part A: Cycle preparation. { ? rn (d-N-benzylcarbamoyl) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of part N ends the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val- Orn (d-N-benzylcarbamoyl) -Gly-oxime resin is removed using standard protection (25% TFA in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { 0rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

Dissolve 0.146 mmoles of cycle. { Orn (d-N-benzylcarbamoyl) -Gly-As (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid is added dropwise maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. It is added diethyl ether, the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The crude product obtained is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C. Preparation of acid cycle. { rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Tyr (N- [2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val} 0.0228 moles of the acid salt cycle are dissolved. { ? rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} trifluoroacetic acid in 1 ml of DMF. Triethylamine (9.5 μl, 0.0648 mmol) is added and, after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-l-pyrrolidinyl-oxy]] carbonyl] -2 is added. pyridinyl] hydrazono] methyl] -benzenesulfonic acid, (0.0121 g, 0.0274 mmol) The reaction mixture is stirred for l-2 days and then concentrated to an oil under high vacuum.The oil is purified by preparative CLAP to obtain the desired product.

Example 27 Synthesis of cycle. { Dap (b- (2-benzimidazolylacetyl)) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -Val} Part A: Cycle preparation. { Dap (b- (1-Tos-2-benzimidazolylacetyl)) -Gly-As (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Tyr (N-Cbz-aminopropyl) -Val-Dap (b- (l-Tos-2-benzimidazolylacetyl)) -Gly- Oxime resin is removed using standard deprotection (25% TFA in CH2C12). After eight washes with DCM, the resin is treated with DIEA at 10% / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmol / g) is then suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered, and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { Dap (b- (2-benzimidazolylacetyl)) -Gly-Asp-D-Tyr (3-aminopropyl) -Val} .

Dissolve 0.146 mmoles of cycle. { Dap (b- (1-Tos-2-benzimidazolylacetyl)) -Gly-Asp (OBzl) -D-Tyr (N-Cbz-3-aminopropyl) -Val} in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid is added dropwise maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction mixture is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction mixture is cooled to -35 ° C and then stirred for 30 min. The reaction mixture is further cooled to -50 ° C and stirred for 30 min. The raw product obtained is filter, wash with diethyl ether, dry under high vacuum and purify by preparative CLAP to obtain the desired product.

Part C: Cycle preparation. { Dap (b- (2-benzimidazolylacetyl)) -Gly-Asp-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -Val} 0.0228 mmoles of the trifluoroacetic acid salt of cycloFDap (b- (2-benzimidazolylacetyl)) -Gly-Asp-D-Tyr (3-aminopropyl) -Val are dissolved} in 1 ml of DMF. Triethylamine (9.5 μl, 0.0648 mmol) is added and, after 5 min of stirring, the monosodium salt of 2- [[[5- [[(2,5-dioxo-1-pyrrol idinyl) oxy] carboni is added. l] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid. The reaction mixture is stirred for 1-2 days and then concentrated to an oil under high vacuum. The oil is purified by the method described below to obtain the desired product.

Example 28 Synthesis of the cycle acid. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic])} Part A: Cycle preparation. { rn (d-N-l-Tos-2-imidazolinyl) -Gly-Asp (OBzl) -D-Phe-Lys (Cbz)} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Phe-Lys (Z) -Orn (dNl-Tos-2-ymidazolinyl) -Gly-oxime resin, is removed using deprotection standard (TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmole / g) after it is suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 turnols) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B: Cycle preparation. { rn (d-N-2-imidazolinyl) -Gly-Asp-D-Phe-Lys} Dissolve 0.204 mmoles of cycle. { 0rn (d-N-l-Tos-2-imidazolinyl) -Gly-Asp (OBzl) -D-Phe-Lys (Cbz)} in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added, and the reaction is stirred at -10 ° C for 3 h. Diethyl ether is added, and the reaction is cooled to -50 ° C and stirred for 1 h. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C: Cycle preparation. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Phe-Lys (N- [2-l [[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} Dissolve 0.0481 mmoles of cycle. { rn (d-N-2-imidazolinyl) -Gly-Asp-D-Phe-Lys in 2 ml of DMF. Triethylamine (20.1 μl, 0.144 mmol) is added and, after 5 minutes of stirring, the monosodium salt of [2 - [[[5- [[(2, 5-dioxo-l-pyrrolidinyl) oxy] carbonyl is added. ] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.054 g, 0.0577 mmol). The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP to obtain the desired product.

Example 29 Synthesis of cycle. { rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid])} Part A: Cycle preparation. { ? rn (d-N-benzylcarbamoyl) -Gly-As (OBzl) -D-Phe-Lys (Cbz)} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Asp (OBzl) -D-Phe-Lys (Z) -Orn (dN-benzylcarbamoyl) -Gly-oxime resin is removed using standard deprotection (TFA 25% in CH2C12). After eight washes with DCM, the resin is treated with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum. The resin (1.75 g, 0.55 mmole / g) after it is suspended in 15 ml of dimethylformamide. Glacial acetic acid (55.0 μl, 0.961 mmol) is added and the reaction mixture is heated at 50 ° C for 72 h. The resin is filtered, and washed with DMF (2 x 10 ml). The filtrate is concentrated to an oil under high vacuum. The resulting oil is triturated with ethyl acetate. The solid obtained in this way is filtered, washed with ethyl acetate and dried under high vacuum to obtain the desired product.

Part B. Cycle preparation. { ? rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys} Dissolve 0.204 mmoles of cycle. { Orn (-N-benzylcarbamoyl) -Gly-Asp (OBzl) -D-Phe-Lys (Cbz)} in 0.6 ml of trifluoroacetic acid and cooled to -10 ° C. 0.5 ml of trifluoromethanesulfonic acid are added dropwise, maintaining the temperature at -10 ° C. 0.1 ml of anisole is added and the reaction is stirred at -10 ° C for 3 h. Diethyl ether is added, the reaction is cooled to -50 ° C and stirred for 1 h. The crude product is filtered, washed with diethyl ether, dried under high vacuum and purified by preparative CLAP to obtain the desired product.

Part C. Cycle preparation. { 0rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys (N- [acid 2 - [[[5 - [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])} 0.0481 mmol of the cyclic TFA salt are dissolved. { 0rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys} in 2 ml of DMF. Triethylamine (20.1 μl, 0.144 mmol) is added and, after 5 min of stirring, the monosodium salt of [2- [[[5- [[< 2,5-dioxo-l-pyrrolidinyl) oxy] [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (0.0254 g, 0.0577 mmol). The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by preparative CLAP to obtain the desired product.

Example 30 Synthesis of cycle. { Lys-D-Val-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp-Gly) Part A: Cycle preparation. { Lys (Tfa) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Lys (Tfa) -D-Val-D-Tyr (N-Cbz-aminopropyl) -D-Asp (OBzl) -Gly-oxime resin is removed using standard deprotection (50% TFA in CH2C12). After washing with DCM (8x), the resin is neutralized with 10% DIEA / DCM (2 x 10 min). The resin is subsequently washed with DCM (x 5) and dried under high vacuum overnight. The resin (1.0 g, 0.36 mmol / g) is then suspended in 12 ml of N, N-dimethylformamide. Glacial acetic acid (67 ml, 1.16 mmol) is added and the reaction mixture is heated at 55 ° C for 72 h. The resin is filtered, and washed with DMF (3 x 10 ml). The filtrate is concentrated under high vacuum to provide an oil. The resulting oil is triturated with ethyl acetate. The desired product is purified by reverse phase CLAP.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { Lys-D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} .

Cyclic peptide protected cycle. { Lys (Tfa) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} (0.10 mmol) is dissolved in 0.95 ml of trifluoroacetic acid and cooled to -10 ° C in a dry ice / acetone bath. This solution is add 0.12 mmole of trifluoromethanesulfonic acid, followed by 190 ml of anisole. The reaction mixture is stirred at -16 ° C for 3 h. The dry ice / acetone bath is then cooled to -35 ° C and 40 ml of fluid ether is added to the solution. The mixture is stirred for 30 min at -35 ° C, then cooled to -50 ° C and stirred for another 30 min. The crude product is filtered, redissolved in water / acetonitrile (l / l), lyophilized and purified by reverse phase CLAP to provide the desired product.

Part C: Cycle preparation. { Lys-D-Val-D-Ty (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl-D-Asp-Gly.}.

A solution of 0.0216 mmoles of cycle. { Lys (Tfa) -D- Val -D-Tyr (3-aminopropyl) -D-Asp-Gly} in 2 ml of N, N-dimethylformamide add triethylamine (15 ml, 0.108 mmol) and stir at room temperature for 10 min. 0.0260 mmol of the monosodium salt of [2- [[[5- [[(2, 5-dioxo-1-pyrrolidinyl) oxy] [carbonyl] -2-pyridinyl] hydrazono] -methyl] -benzenesulfonic acid are added and The mixture is stirred for 18 h. The mixture is concentrated under high vacuum, the oil is treated with piperidine 20% in DMF and concentrated again in vacuo. The residue is purified by reverse phase CLAP to provide the desired product.

Example 31 Synthesis of cycle. { ? rn (dN-benzylcarbamoyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -D- Asp-Gly} Part A: Cycle preparation. { 0rn (d-N-benzylcarbamoyl) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} The Boc protecting group of the N-terminal part of the peptide sequence Boc-Orn (dN-benzylcarbamoyl) -D-Val-D-Tyr (N-Cbz-aminopropyl) -D-Asp (OBzl) -Gly-oxime resin is remove using standard deprotection (50% TFA in CH2C12). After washing with DCM (8x), the resin is neutralized with DIEA 10 / DCM (2 x 10 min). The resin is washed with DCM (5x) and dried under high vacuum overnight. The resin (1.0 g, approximately 0.36 mmol / g) is then suspended in 12 ml of N, N- dimethylformamide. Glacial acetic acid (67 ml, 1.16 mmol) is added and the reaction mixture is heated at 55 ° C for 72 h. The resin is filtered and washed with DMF (3 x 10 ml). The filtrate is concentrated under high vacuum to provide an oil. The resulting oil is triturated with ethyl acetate. The desired product is purified by reverse phase CLAP.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { Orn (d-N-benzylcarbamoyl) -D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} .

Cyclic peptide protected cycle. { Orn (d-N-benzylcarbamoyl) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} (0.10 mmol) is dissolved in 0.95 ml of trifluoroacetic acid and cooled to -10 ° C in a dry ice / acetone bath. To this solution 0.12 mmole of trifluoromethanesulfonic acid is added followed by 190 ml of anisole. The reaction mixture is stirred at -16 ° C for 3 h. The dry ice / acetone bath is then cooled to -35 ° C and 40 ml of cold ether are added to the solution. The mixture is stirred for 30 min at -35 ° C, then cooled to -50 ° C and stirred another 30 min. The crude product is filtered, redissolved in water / acetonitrile (l / l), lyophilized and purified by reverse phase CLAP to provide the desired product.

Part C: Cycle preparation. { 0rn (dN-benzylcarbamoyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp -Gly} To a solution of 0.0216 mmoles of cycle. { ? rn (d-N-benzylcarbamoyl) -D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} in 2 ml of N, N-dimethyl ormamide, triethylamine (15 ml, 0.108 mmol) is added and stirred at room temperature for 10 min. 0.0260 mmol of the monosodium salt of 2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] and the mixture are added. stir for 18 h. The mixture is concentrated under high vacuum and the residue is purified by reverse phase CLAP to provide the desired product.

Example 32 Synthesis of cycle. { 0rn (dN-2-imidazolinyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D -Asp-Gly} Part A: Cycle preparation. { rn (dN-l-Tos-2-imidazolinyl) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-As (OBzl) -Gly} The Boc protecting group of the N-terminal part of the peptide sequence Boc-0rn (dNl-Tos-2-imidazolinyl) -D-Val-D-Tyr (N-Cbz-aminopropyl) -D-Asp (OBzl) -Gly- Oxime resin is removed using standard deprotection (50% TFA in CH2C12). After washing with DCM (8x), the resin is neutralized with 10% DIEA / DCM. The resin is washed with DCM (2 x 10 min) and dried under high vacuum overnight. The resin (1.0 g, approximately 0.36 mmol / g) is then suspended in 12 ml of N, N-dimethylformamide. Glacial acetic acid (67 ml, 1.16 mmol) is added and the reaction mixture is heated at 55 ° C for 72 h. The resin is filtered and washed with DMF (3 x 10 ml). The filtrate is concentrated under high vacuum to provide an oil. The resulting oil is triturated with ethyl acetate. The desired product is purified by reverse phase CLAP.

Part B: Preparation of the cycloalkyl trifluoroacetic acid salt. { ? rn (d-N-2-imidazolinyl) -D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} .

Cyclic peptide protected cycle. { R n (d-N-l-Tos-2-imidazolinyl) -D-Val-D-Tyr (N-Cbz-3-aminopropyl) -D-Asp (OBzl) -Gly} (0.10 mmol) is dissolved in 0.95 ml of trifluoroacetic acid and cooled to -10 ° C in a dry ice / acetone bath. To this solution is added 0.12 mmoles of trifluoromethanesulfonic acid followed by 190 ml of anisole. The reaction mixture is stirred at -16 ° C for 3 h. The dry ice / acetone bath is then cooled to -35 ° C and 40 ml of cold ether are added to the solution. The mixture is stirred for 30 min at -35 ° C, and then cooled to -50 ° C and stirred for another 30 min. The crude product is filtered, redissolved in water / acetonitrile (l / l), lyophilized and purified by reverse phase CLAP to provide the desired product.

Part C: Cycle preparation. { ? rn (dN-2-imidazolinyl) -D-Val-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) - D-Asp-Gly} A solution of 0.0216 mmoles of cycle. { rn (d-N-2-imidazolinyl) -D-Val-D-Tyr (3-aminopropyl) -D-Asp-Gly} in 2 mmoles of N, N-dimethylformamide add triethylamine (15 ml, 0.108 mmole) and stir at room temperature for 10 min. 0.060 mmol of the monosodium salt of 2 - [[[5- [[(2,5-dioxo-l-pyrrolidinyl) oxy] [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid and the mixture are added stir for 18 h. The mixture is concentrated under high vacuum and the The residue is purified by reverse phase CLAP to provide the desired product.

Radiopharmaceutical examples The following procedures (A, B) describe the synthesis of radiopharmaceuticals of the present invention of the formula "Te (VnA) (tricine) (phosphine) in which (Vna) represents the receptor antagonist of vitronectin bound to Te through of a diazenido portion (-N = N-) or hydrazido (= N-NH-) The diazenido or hydrazido portion results from the reaction of the hydrazinonicotinamido group, present either as free or protected hydrazine as a hydrazone with Tc-99m. The other two ligands in the coordination sphere of Te are tricine and a phosphine.

Procedure A Synthesis of Tc-99m vitronectin receptor complex antagonists of the formula "Te (VnA) (tricine) (phosphine) using stannous reducing agent." 10-30 μg (0.2-0.4 ml) of a reagent of the present invention is dissolved in saline solution or in aqueous ethanol 50%, 40 mg (0.4 ml) of tricine in water, 1-7 mg (0.10-0.30 ml) of phosphine dissolved in water or ethanol, 25 μg (25 μl) of SnCl2-2H20 dissolved in 0.1 M HCl, 0-0.25 ml of ethanol and 50-150 mCi of "Tc04- in saline are combined in a 10 cc bottle.The equipment is heated in a water bath at 100 ° C during 10-20 minutes, then a 50 μl sample is analyzed by CLAP method 3. If necessary, the complex is purified by performing a 300-400 μl injection on the CLAP and collecting the fraction in a protected flask. The collected fraction is evaporated to dryness, redissolved in saline containing 0-5% by volume of Tween 80, and then re-analyzed using CLAP Method 3.

Procedure B Synthesis of Tc-99m vitronectin receptor complex antagonists of the formula "Te (VnA) (tricine) (TPPTS) without using stannous reducing agent To a lyophilized flask containing 4.84 mg of TPPTS, 6.3 mg of tricine, 40 mg of mannitol and 0.25 mmol of succinate buffer, pH 4.8, 0.2-0.4 ml (20-40 μg) of a reagent of the present invention is added. dissolved in saline or 50% aqueous ethanol, 50-100 mCi of "™ Tc04" in saline, and additional saline to provide a total volume of 1.3-1.5 ml. The equipment is heated in a 100 ° C water bath for 10-15 minutes, and then a sample is analyzed by Method 3 of CLAP. If necessary, the complex is purified by making a 300-400 μl injection into CLAP and collecting the fraction in a protected flask. The collected fraction is evaporated to dryness, redissolved in saline containing 0-5% by volume of Tween 80 and re-analyzed using CLAP Method 3.

Table 1. Analytical and performance data for the complexes of "Te (VnA) (tricine) (phosphine) Sample Example of Phosphine% renTA (min) Complex No. Reagent No. 33 33 1 PPTS 88 8.2 34 2 TPPTS 96 19.5 3 TPPTS 91 33.7 36 4 TPPTS 92 21.8 37 5 TPPTS 65 25.1 38 6 TPPTS 91 41.7 39 7 TPPTS 89 20.4 40 8 TPPTS 93 16.4 41 9 TPPTS 90 13.4 42 10 TPPTS 93 12.9 43 12 TPPTS 94 23.5 44 12 TPPTS 93 18.1 45 12 TPPTS 93 13.6 46 13 TPPTS 93 11.2 47 14 TPPTS 79 11.0 48 15 TPPTS 94 11.2 49 16 TPPTS 81 9.2 50 17 TPPTS 97 10.4 The following example describes the synthesis of radiopharmaceuticals of the present invention of the formula "Te (VnA) (tricine) (L) (L = heterocyclic nitrogen-containing imine), in which (VnA) represents the receptor antagonist of vitronectin bound to the Te through a diazenide moiety (-N = N- ) or hydrazide (= N-NH-) The other two ligands in the coordination sphere of Te are tricine and a heterocycle containing nitrogen imine.

Example 51 Synthesis of the vitronectin receptor antagonist complex Tc-99m "Te (VnA) (tricine) (1, 2, 4-triazole) μg of the reagent from Example 1 (0.30 ml 50/50 EtOH / H20), 40 mg tricine (0.25 ml / H20), 8 mg 1,2,4-triazole (0.25 ml / H20), are combined. μg of SnCl2 (25 μl / 0.1 N HCl), 0.50 ml of water and 0.20 ml of 50 ± 5 mCi of "Tc04" in a covered 10 cc bottle, and heat at 100 ° C for 10 minutes. 50 μl of the equipment content is analyzed by CLAP using the method indicated below. The product elutes in a retention time of 8.33 min and has a radiochemical purity of 88.1%.

The reagents of the present invention are comprised of either a DOTA (Example 18), DTPA monoamide (Examples 19 and 20) or chelator of bisamide DTPA (Example 21) that readily form complexes with metal ions of elements 31, 39, 49, and 58-71. The following examples demonstrate the synthesis of complexes with 153Sm; l77Lu, and 90Y, isotopes emitting beta particles used in radiopharmaceutical therapy and 111In, a gamma-ray emitting isotope used in radiopharmaceutical imaging agents. In both types of complexes, the metal ion binds to the chelator portion DOTA, DTPA monoamide or DTPA bisamide of the reagents.

Examples 52 and 53 Synthesis of vitronectin antagonist complexes containing DOTA Y-90 and Lu-177 To a sealed and clean 10 ml bottle is added 0.5 ml of the reagent of Example 18 (200 μg / ml in 0.25 M ammonium acetate buffer, pH 7.0) followed by 0.05 - 0.1 ml gentisic acid (sodium salt, 10 ml). mg / ml in ammonium acetate buffer 0. 5 M, pH 7.0) of solution, 0.3 ml of 0.25 M ammonium acetate buffer (pH 7.0) and 0.05 ml of a solution of 177LuCl3 or a solution of 90YC13 (100- 200 mCi / ml) in 0.05 N HCl. The resulting mixture is heated at 100 ° C for 35 min. After cooling to room temperature, a sample of the resulting solution is analyzed by radio-CLAP and by ITLC. The complex of Example 53 is analyzed by mass spectroscopy (found [M + H *] = 1877.6, calculated 1875.8 for C75H110N23O23Lu) which confirms the identity.

Example 54 Synthesis of a complex vitronectin antagonist containing DOTA L11In To a 300 μl self-sampling flask protected with lead, add 50 μl of gentic acid (10 mg / ml in 0.1 M ammonium acetate buffer, pH 6.75) in solution, followed by 100 μl of the reagent of Example 18 (200 μg). / ml in 0.2 M ammonium acetate buffer, pH 5.0) and 50 μl of a solution of ^ InCl-j (10 mCi / ml) in 0.04 N HCl. The pH of the reaction mixture is about 4.0. The solution is heated at 100 ° C for 25 min. A sample of the resulting solution is analyzed by radio-CLAP and by ITLC.

Table IA: Analytical and performance data for complexes of Y-90, In-111 and Lu-177 of vitronectin receptor antagonists combined with DOTA Isotope Reagent Complex% of ren- Time of Example No. Example No. retention in CLAP (min) 52 18 Y-90 96 16.5 53 18 Lu-177 96 16.5 54 18 In-111 95 16.5 Examples 55 and 56 Synthesis of vitronectin antagonist complexes containing DTPA-monoamide or DTPA-bisamide In-111 0.2 ml of 111 InCl3 (1.7 mCi) in 0.1 N HCl, 0.2 ml of 1.0 M ammonium acetate buffer (pH 6.9) and 0.1 ml of the reagent of the present invention are dissolved in water and combined in a glass flask of water. 10 cc and allowed to react at room temperature for 30 min. The reaction mixture is analyzed by CLAP method 3.

Table 2. Analytical and performance data for complexes of In Example No. Example of% of Reactive Complex Time No. CLAP retention performance (min) 55 19 86 11.1 56 20 96 18.8 Examples 57-59 Synthesis of vitronectin antagonist complexes Sm-153 Combine 0.5 ml of a concentrated solution of 1S3SmCl3 (54 Ci / μmol Sm, 40 mCi / ml) in 0.1 N HCl with the reagent of the present invention (50-fold molar excess) dissolved in ammonium acetate buffer in a flask of glass of 10 cc. The reaction is allowed to proceed at room temperature for ~30 min and then analyzed by ITLC and CLAP (Method 3). If necessary, the complex is purified by performing a 300-400 μl injection into CLAP and collecting the fraction in a covered flask. The fraction collected is evaporated to dryness, redissolved in saline and retested using Method 3 of CLAP.

Table 3. Analytical and performance data for complexes of Sm Example No. Example of% of Reactive Complex Time No. CLAP retention performance (min) 57 19 91 11.7 58 20 84 13.1 59 21 96 16.9 A non-radioactive samarium analogue (occurring naturally) of the radiopharmaceutical of Example 59 is prepared by combining 3.3 mg (2.9 μmol) of the reagent of Example 21 dissolved in 2 ml of 1 M ammonium acetate buffer, pH 7 and 0.29 ml of a 0.01 M solution of SmCl3 in 0.1 N HCl. The reaction is allowed to proceed for ~ 5 h at room temperature and then the product is isolated by Method 3 of CLAP. The volatile fractions are removed by lyophilization. The identity of the complex is confirmed by mass spectroscopy (API-ESMS: found [M + 2H * = 1172.4, Calculated 1172.9 for C43H64N12017Sm] A concentrated solution of the complex is produced in water and its concentration is determined by ICP analysis for use in the determination of the binding affinity of the complex by the vitronectin receptor to "ß,.

The structures of the radiopharmaceutical substances of In-111 (Example 56), Y-90 (Example 5) and Sm-153 (Example 59) of the present invention are shown below.

Examples 60-62 Synthesis of Lu-177 vitronectin antagonist complexes x 10"9 moles of a reagent of the present invention are dissolved in 1.0 ml of 0.1 N acetate buffer, pH 6.8 1 x 10" 9 moles of Lu-177 (40 μl, 3 mCi) dissolved in 0.1 HCl are added. N, and the reaction is allowed to proceed at room temperature for 30-45 min. The reaction mixtures are analyzed by Method 3 of CLAP.

Table 4. Analytical and performance data for complexes of 'Lu Example No. Example of% of Reactive Complex Time No. CLAP retention performance (min) 60 19 98 11.0 61 20 98 15.6 62 21 98 11.7 Example 63 The gadolinium complex of the reagent of the Example 21 according to the following procedure. 3-3.5 mg of the reactant are dissolved in 2 ml of 1 M ammonium acetate buffer at pH 7.0, and an equivalent solution of Gd (N03) 3 (0.02 M in water) is added thereto. The reaction mixture is allowed to stand at room temperature during 3-5 hours and the product is isolated by Method 4 of CLAP. The fraction containing the complex is lyophilized and dissolved in 1 ml of H20, resulting in approximately 2 mM in Gd, determined by ICP analysis. The identity of the complex is confirmed by mass spectroscopy (API -ESMS: Found [M + 2H] * = 1176.9, Calculated 1176.2 for C43H64N12017Gd]. The following Examples describe the synthesis of ultrasound contrast agents of the present invention consisting of target portions for tumor neovasculature that are avß3 receptor antagonists.

Example 64 Part A . Syntheses of 1 - (1, 2 - dipalmi toi l - sn-gly icero - 3-phosphoethanolamino) -12 - (cyclo (Arg-Gly-Asp-D-Phe-Lys) -dodecan-1, 12 -dione A solution of dodecane-1,2-dioate disuccinimidyl (0.424 g, 1 mmol), 1, 2-dipalmi toi 1-sn-gl i cer or -3-phosphoethanolamine (1489 g, 1 mmol) and the cyclic TFA salt (Arg-Gly-Asp-D-Phe -Lys) (0.831 g, 1 mmol) in 25 ml of chloroform are stirred for 5 minutes. 1 mmol of sodium carbonate and 1 mmol of sodium sulfate are added, and the solution is stirred at room temperature under nitrogen for 18 h. DMF is removed in vacuo and the crude product is purified to obtain the title compound.

Part B. Preparation of a contrast agent composition The synthesis of 1- (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- (cyclo (Arg-Gly-Asp-D-Phe-Lys) -dodecan- 1,12-dione is mixed with other three lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn- glycero-3-phosphotidylcholine and N- (methoxypolyethylene glycol 5000 carbamoyl) -1, 2 -dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1% by weight: 6% by weight: 54% by weight: 41% by weight . Then an aqueous solution of this lipid mixture (1 mg / ml), sodium chloride (7 mg / ml), glycerin (0.1 ml / ml), propylene glycol (0.1 ml / ml) at pH 6-7 in a bottle is prepared of glass of 2 cc. The air in the bottle is evacuated and replaced with perfluoropropane and the bottle is sealed. The composition of the ultrasound contrast agent is completed by shaking the sealed vial in a dental amalgam for 30-45 seconds to form a white milky solution.

Preparation 65 Part A. Preparation of (? -amino-PEG3400-a-carbonyl) -cycle (Arg-Gly-Asp-D-Phe-Lys) To a solution of the succinimidylester of N-Boc-α-amino-PEG3400-α-carboxylate (1 mmol) and 1 mmol of cyclo (Arg-Gly-Asp-D-Phe-Lys) in 25 ml of DMF are added 3 mols of triethylamine. The reaction mixture is stirred under nitrogen at room temperature overnight and the solvent is removed in vacuo. The crude product is dissolved in 50% trifluoroacetic acid / dichloromethane and stirred for 4 h. The volatile fractions are removed and the title compound is isolated as the TFA salt via trituration in diethyl ether.

Part B. Preparation of 1- (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400-a-carbonyl) -cyclo (Arg-Gly-Asp-D-Phe- Lys)) -dodecan-1, 12-dione A solution of 1 mmol of decanoate disuccinimidyl, 1 mmol of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and 1 mmol of the TFA salt of (? -amino-PEG3400-a-carbonyl) -cyclo (Arg-Gly-Asp-D-Phe-Lys) (1 mmol) in 25 ml of chloroform is stirred for 5 min. Sodium carbonate (1 mmol) and sodium sulfate (1 mmol) are added, and the solution is stirred at room temperature under nitrogen for 18 h. DMF is removed in vacuo and the crude product is purified to obtain the title compound.

Part C. Preparation of the contrast agent composition Mix 1- (1,2-dipalmitoyl-n-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400-a-carbonyl) -cycle (Arg-Gly-Asp-D-Phe-Lys) ) -dodecan-1, l2-dione with three other lipids, 1,2-dipalmitoyl-sn-gl icero-3-phosphotidic acid, 1,2-dipa lm itoi 1 - sn - g 1 icero - 3 - fosfati di 1 co 1 i na and N-methyloxypolyethylene glycol 5000 carbamoyl) -1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1% by weight: 6% by weight: 54% by weight: 41% by weight . An aqueous solution of this lipid mixture (1 mg / ml), sodium chloride (7 mg / ml), glycerin (0.1 ml / ml), propylene glycol (0.1 ml / ml) at pH 6-7 is subsequently prepared in a glass jar 2 cc. The air in the bottle is evacuated and replaced with perfluoropropane and the bottle is sealed. The composition of the ultrasound contrast agent is completed by stirring the vial sealed in a dental amalgam for 30-45 sec, to form a milky white solution.

Example 66 Part A. Preparation of the synthesis of (? -amino-PEG3400-a-carbonyl) -Glu- (cyclo (Arg-Gly-Asp-D-Phe-Lys)) 2 To a solution of 1 mmol of the succinimidylester of N-Boc -? - amino-PEG3400- "-carboxylate and 1 mmol of Glu- (cyclo (Arg-Gly-Asp-D-Phe-Lys)) 2 in 25 ml of DMF is added 3 mmole of triethylamine. The reaction mixture is stirred under nitrogen at room temperature overnight and the solvent is removed in vacuo. The raw product dissolves in acid 50% trifluoroacetic acid / dichloromethane and stirred for 4 h. The volatile fractions are removed and the title compound is isolated as the TFA salt via trituration in diethyl ether.

Part B. Preparation of 1- (1,2-dipalmitoyl-sn-glycero-3-phosphonoethanolamino) -12- ((o-amino-PEG3400- a -carbonyl) -Glu- (cyclo (Arg-Gly-Asp- D-Phe-Lys)) 2) -dodecan-1, 12 -dione A solution of 1 mmol of disuccinimidyl dodecanoate, 1 mmol of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and 1 mmol of the TFA salt of (? -amino-PEG3400-a-carbonyl) -Glu- ( Cyclo (Arg-Gly-Asp-DPhe-Lys)) 2 in 25 ml of cloform is stirred for 5 min. 1 mmol of Sodium carbonate and 1 mmol of sodium sulfate, and the solution is stirred at room temperature under nitrogen for 18 h. The DMF is removed in vacuo and the crude product is purified to obtain the title compound.

Part C. Preparation of a contrast agent composition Mix 1- (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400- a-carbonyl) -Glu- (cyclo (Arg-Gly-Asp-D-Phe -Lys)) 2) -dodecan-1, 12-dione with the other three lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and N - (methoxypolyethylene glycol 5000 carbamoyl) -1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1% by weight: 6% by weight: 54% by weight: 41% by weight. Then an aqueous solution of this lipid mixture (1 mg / ml), 7 mg / ml of sodium chloride, 0.1 ml / glycerin, 0.1 ml / ml of propylene glycol at pH 6 is prepared in a 2-cc glass jar. 7 The air is purged to the bottle and replaced with perfluoropropane and the bottle sealed. The composition of the ultrasound contrast agent is completed by shaking the sealed vial in a dental amalgam for 30-45 seconds to form a milky white solution.

Analytical methods CLAP method 3 Column: Zorbax C18, 25 cm x 4.6 mm or Vydac C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10 mM sodium phosphate buffer, pH 6 Solvent B : 100% acetonitrile Detector: radiometric sodium iodide probe (Nal) or beta detector Gradient A (Examples 33, 51) t (min) 0 20 30 31 40% B 0 75 75 0 0 Gradient B (Examples 39, 40, 43, 44, 45, 46, 48, 50) t (min) 0 20 30 31 35 36 40% B 0 25 25 75 75 0 0 Gradient C (Examples 34, 35, 36, 37, 38, 42): t (min) 0 40 41 46 47 55% B 0 35 75 75 0 0 Gradient D (Example 49) t (min) 0 20 30 31 40% B 0 25 25 0 0 Gradient E (Examples 55, 56): t (min) 0 20 21 30 31 40% B 0 20 50 50 0 0 Gradient F (Examples 57, 58): t (min) 0 15 16 25 26 35% B 0 20 75 75 0 0 Gradient G (Example 59): t (min) 0 20 21 30 31 40% B 0 20 75 75 0 0 Gradient H (Examples 60, 61, 62): t (min) 0 15 16 21 22 40 % B 0 20 50 50 0 0 Gradient I (Examples 52, 53, 54) t (min) 0 20 21 30 31 40 % Solvent B 5 20 60 60 5 5 Gradient J (Example 41). t (min) 0 20 30 31 40% Solvent B 0 50 50 0 0 Gradient K (Example 47) t (min) 0 20 21 30 31 40% Solvent B 10 20 60 60 10 10 CLAP method 4 Column: Zorbax C18, 25 cm x 4.6 mm Flow rate: 1.0 ml / min Solvent A: 10 mM ammonium acetate Solvent B: 100% methanol Gradient: t (min) 0 23 26 27% B 8 100 100 8 UV detection ITLC Method Gelman ITLC-SG strips (2 cm x 7.5 cm) Solvent system: acetone: 1: 1 saline solution Detection using Bioscan System 200.

UTILITY The pharmaceutical substances of the present invention are useful for the imaging of angiogenic tumor vasculature in a patient or for the treatment of cancer in a patient. The radiopharmaceuticals of the present invention are constituted of a gamma-ray emitting isotope which is useful for imaging of pathological processes involving angiogenic neovasculature, including cancer, diabetic retinopathy, macular degeneration, restenosis of blood vessels after angioplasty and healed of wounds. Diagnostic utilities also include imaging of unstable coronary syndromes (eg, unstable coronary plaque). The radiopharmaceuticals of the present invention are constituted by beta, alpha or Auger electron emitting isotopes which are useful for the treatment of pathological processes involving angiogenic neovasculature, by the delivery of a cytotoxic dose of radiation to the site of the angiogenic neovasculature. The treatment of cancer is altered by the systemic administration of radiopharmaceuticals resulting in a dose of cytotoxic radiation to tumors.

The compounds of the present invention comprise one or more magnetic metal ions which are selected from gadolinium, dysprosium, iron and manganese and are useful as contrast agents for magnetic resonance imaging (MRI) of pathological processes involving angiogenic neovasculature. The compounds of the present invention are composed of one or more heavy atoms with an atomic number of 20 or greater and are useful as X-ray contrast agents for X-ray imaging of pathological processes involving angiogenic neovasculature. The compounds of the present invention are constituted of an echogenic gas containing microspheres of surfactants are useful as contrast agents for ultrasound, for sonography of pathological processes involving angiogenic neovasculature. Representative compounds of the present invention are tested in the following in vitro and in vivo assays and it is found that the models are active.

Human placental avß3 receptor assay immobilized Test conditions were developed and validated using [1-125] vitronectin. The validation of the assay includes Scatchard format analysis (n = 3) where the number of receptors (Bmax) and Kd (affinity) are determined. The assay format is such that the compounds are preliminarily analyzed at final concentrations of 10 and 100 nM before of the IC50 determination. Three standards were evaluated for IC50 determination (vitronectin, antibody against avß3, LM609 and antibody against avß5, P1F6) and five reference peptides. Briefly, the method involves immobilizing previously isolated receptors in 96-well plates and incubating them overnight. The receptors are isolated from normal, fresh non-infectious human placenta (free of HIV, hepatitis B and C, syphilis and HTLV). The tissue is smoothed and the tissue residues are removed via centrifugation. The lysate is filtered. The receptors are isolated by affinity chromatography using immobilized avß3 antibody. The plates are then washed 3x with wash buffer. The blocking buffer is added and the plates are incubated for 120 minutes at room temperature. During this time, the compounds to be tested and [1-125] vitronectin are pre-mixed in a reservoir plate. The blocking buffer is removed and the compound mixture is extracted by pipette. The competition is carried out for 60 minutes at room temperature. The unbound material is then removed and the wells are separated and counted by gamma scintillation. - 26? -Other receiver binding assays Whole cell assays for binding affinity determination of pharmaceutical substances of the present invention by the VEGF, Flk-1 / KDR and Flt-1 receptors are described in Ortega, et al., Amer. J. Pathol., 1997, 151, 1215-1224, and Dougher, et al., Growth Factors, 1997, 14, 257-268. An in vitro assay for determining the affinity of pharmaceutical substances of the present invention for the VFGF receptor is described in Yayon et al., Proc. Nati Acad. Sci USA, 1993, 90, 10643-10647. Gho et al., Cancer Research 1997, 57, 3733-40, describes assays for angiotensin receptor binding peptides. Senger et al., Proc. Nati Acad. Sci USA, 1997, 94, 13612-13617 describe assays for integrin antagonists alBl and a2Bl. US 5,536,814 discloses assays for compounds that bind a5Bl integrin.

Formation of images in Onoomouse1" The study involves the use of c-Neu Oncomouse ™ mice and FVB mice simultaneously as controls. The mice are anesthetized with sodium pentobarbital and injected with approximately 0.5 mCi of radiopharmaceutical. Before the injection, the tumor localization of each Oncomouse ™ mouse and the size of the tumor is measured using calibrators. The animals are placed on the head of the camera so that an image is formed of the anterior "" * or posterior of the animals. 5-minute images are acquired serially for 2 hours using a 256x256 matrix and a 2x zoom. Upon completion of the study, the images are evaluated by circumscribing them as a target region of interest (ROI) and the background site in the neck area and near the salivary glands of the carotid. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention comprised of beta, alpha or Auger electron emitting isotopes. The radiopharmaceuticals are administered in appropriate amounts and the uptake in the tumors can be quantified either non-invasively by imaging for those isotopes with a coincident gamma emission coincident, or by cutting the tumors and by counting the amount of radioactivity present by standard techniques. The therapeutic effect of the radioactive substances can be determined by monitoring the growth rate of the tumors in control mice versus those in which the mice were administered the pharmaceutical substances of the present invention.

This model can also be used to determine the compounds of the present invention constituted of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the entire animal can be placed in a commercially available magnetic resonance imaging forceps to image the tumors. The effectiveness of contrast agents can easily be observed by comparison with the images obtained from animals to which they are not given a contrast agent. This model can also be used to determine the compounds of the present invention consisting of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the entire animal can be placed in a commercially available X-ray imager for imaging tumors. The effectiveness of the contrast agents can be easily observed by comparison with the images obtained from animals to which contrast agents have not been administered. This model can also be used to determine the compounds of the present invention constituted of an echogenic gas containing surfactant microspheres as contrast agents for ultrasound. After the administration of the appropriate amount of the compounds echogenic, tumors in the animal can be visualized using an ultrasound probe that keeps tumors close. The effectiveness of the contrast agents can be easily observed by comparison with the images obtained from animals to which a contrast agent is not administered.

Model of Matrigel rabbit This model is adopted from the matrigel model designed for the study of angiogenesis in mice. Matrigel (Becton &Dickinson, USA) is a basement membrane rich in laminin, collagen IV, entactin, HSPG and other growth factors. When combined with growth factors such as bFGF [500 ng / ml] or VEGF [2 μg / ml] it injects subcutaneously into the middle abdominal region of the mice, solidifies into a gel and stimulates angiogenesis at the site of injection into the Next -8 days. In the rabbit model, New Zealand white rabbits (2.5-3.0 kg) are injected with 2.0 ml of matrigel, plus 1 μg of bFGF and 4 μg of VEGF. Then the radiopharmaceutical is injected 7 days later, and the images are obtained. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention comprised of isotope-emitting beta, alpha or Auger electrons. The radiopharmaceuticals are administered in appropriate amounts and the uptake at the angiogenic sites can be quantified either non-invasively by imaging for those isotopes with matching gamma-emitting emission, or by cutting the angiogenic sites and counting the amount of radioactivity present, by standard techniques. The therapeutic effect of the radiopharmaceuticals can be determined by monitoring the growth rate of the angiogenic sites in control rabbits versus that obtained in the rabbits to which the radiopharmaceuticals of the present invention are administered. This model can also be used to determine the compounds of the present invention constituted of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the entire animal is placed in a commercially available magnetic resonance imaging forceptor to image the angiogenic sites. The effectiveness of the contrast agents can be easily observed in comparison with the images obtained for animals that have not been administered a contrast agent.

This model can also be used to determine the compounds of the present invention consisting of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the whole animal can be placed in a commercially available X-ray imager for imaging angiogenic sites. The effectiveness of contrast agents can easily be observed by comparison with images obtained from animals that are not administered a contrast agent. This model can also be used to determine the compounds of the present invention constituted of an echogenic gas containing microspheres of surfactant as ultrasound contrast agents. After the administration of the appropriate amount of the echogenic compounds, the angiogenic sites in the animal can be imaged using an ultrasound probe that remains close to the tumors. The effectiveness of contrast agents can be easily seen compared to images obtained from animals that have not been given a contrast agent.

Spontaneous canine tumor model Seed with xylazine (20 mg / kg) / atropine (1 ml / kg) to adult dogs with spontaneous mammary tumors. At the time of sedation, the animals were intubated using ketamine (5 mg / kg) / diazepam (0.25 mg / kg) for complete anesthesia. Chemical restriction is continued with ketamine (3 mg / kg) / xylazine (6 mg / kg) titrating as necessary. If required, the animals are ventilated with ambient air by means of an endotracheal tube (12 breaths / minute, 25 ml / kg) during the study. The peripheral veins are catheterized using 20G i.v. catheters, one serving as an infusion port for the compound while the other serves for the extraction of blood samples. The cardiac and EKG sequences are monitored using a caridotachometer (Biotech, Grass Quincy, MA) activated by an electrode II electrocardiogram generated by electrodes in the extremities. Blood samples are usually taken at ~ 10 minutes (control), end of infusion (1 minute), 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes for the total number of blood cells and the count. The radiopharmaceutical dose is 300 μCi / kg administered as a bolus i.v. with saline discharge. The parameters are continuously monitored in a polygraph recorder (Model 7E Grass) at a paper speed of 10 mm / min or 10 mm / sec.

The formation of images of the lateral parts is carried out during 2 hours with a 256x256 matrix, without approach, of dynamic images of 5 minutes. A known source of the image field (20-90 μCi) is placed to evaluate the region of attraction of interest. The images are also acquired 24 hours after the injection to determine the retention of the compound in the tumor. The uptake is determined by taking the fraction of the total accounts in an area registered for ROI / source and multiplied by the μCi. The result is μCi for ROI. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention consisting of beta, alpha or Auger electron emitting isotopes. The radiopharmaceuticals are administered in appropriate amounts and the uptake in the tumors can be quantified either non-invasively by imaging those isotopes with an image-forming gamma emission, or by cutting the tumors and counting the amount of radioactivity present by standard techniques. The therapeutic effect of radiopharmaceuticals can be determined by monitoring the size of the tumors with respect to time. This model can also be used to determine the compounds of the present invention comprised of metals paramagnetic agents as contrast agents of MRI. After administration of the appropriate amount of the paramagnetic compounds, the whole animal can be placed in a commercially available magnetic resonance imaging for tumor imaging. The effectiveness of the contrast agents can easily be observed by comparison with the images obtained from animals to which a contrast agent is not administered. This model can also be used to determine the compounds of the present invention comprised of heavy atoms as X-ray contrast agents. After appropriate administration of the X-ray absorbing compounds, the whole animal is placed in an image commercially available X-rays to image the tumors. The effectiveness of the contrast agents can be easily observed in comparison with the images obtained from animals that are not administered a contrast agent. This model can also be used to determine the compounds of the present invention constituted of an echogenic gas containing microspheres of surfactant as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, images of the tumors in the animal using an ultrasound probe that stays close to the tumors. The effectiveness of the contrast agents can be easily observed by comparison with the images obtained from animals that are not administered a contrast agent. Obviously, numerous modifications and variations are possible in the present invention in light of the above teachings. Therefore, it should be understood that, within the scope of the appended claims, the invention may be practiced otherwise than specifically described herein. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound, characterized in that it comprises: a target portion and a chelator, wherein the target portion that binds to a chelator is a peptide or peptidomimetic, and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linking groups between the target portion and the chelator.

2. The compound according to claim 1, characterized in that the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-l / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, avß3, a.β5, < -5ß., A4ß1, Ojßx, and o2ß2 and the linking group is present between the target portion and the chelator.

3. The compound according to claim 2, characterized in that the receptor is the avß3 integrin and the compound is of the formula: (Q) d-L "-Ch O (Q) d-Ln- (Ch) d. wherein Q is a peptide that is independently selected from the group: f XM? 'f VJ - VJ v ~ R? \ VJ VJ K is an L-amino acid that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, dN-2-imidazolinylornitine, dN-benzylcarbamoylornithine, and acid β-2-benzylimidazol-ilacet-1, 2-diaminopropionic acid; K 'is a D-amino acid that is independently selected, each time it is presented, from group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoeth ilcysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and β-2-benzimide zol i 1 acet i 1 - 1, 2-diaminopropionic acid; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M1 is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, f-enylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to L ", which is independently selected, each time it is presented, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid , tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-1-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid , cysteine, penicillamine, methionine and 2-aminothiazole-4-acetic acid; R3 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group-, glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-l-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-d i ami nobu t i r i c o, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homofenilalanine, D-l-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-di ami nobu t i r i c o, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, Lf enylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homofenilalanine, Ll-naphthylalanine, L-lysine, L-serine, L-ornithine, acid L-1, 2-diaminobutyric acid, L-1, 2- diaminopropionic acid, L-cysteine, L-penicillamine, L-methionine and 2-aminothiazole-4-acetic acid; with the proviso that one of R1, R2, R3, R "and R5 in each Q is substituted with a bond to L", and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine, and with the additional proviso that when R 4 is 2-aminothiazole-4-acetic acid, K and K 1 are N-methylarginine, and with the additional proviso that when R 5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Ln is a linking group that has the formula: (CR6R7) 3- (W) h- (CRSaRa) _ '- (Z) k () h, - (CR8R9) g.- (W) ".- (CrBaR9a) g .. with the proviso that g + h + g1 + k + h '+ g "+ h" + g "' are deferent of 0; W is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (OCH2CH2) s, (CH2CH20) "', (0CH2CH2CH2) .., (CH2CH2CH20) r and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of C3.10 substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R10, - R6, R6a, R7, R, a, R, R a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, C-C5 alkyl substituted with 0 -3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10, alkoxy of C-_5 substituted with 0-3 of R10, NHC ^ OJR11, C (= 0) NHR, NHC (= 0) NHR11, NHR11, R11 and a bond to Ch; R10 is independently selected, each time the group is presented: a link to Ch, COOR11, OH, NHR11, S03H, P03H, aryl substituted with 0-3 of R11, alkyl of Cj .. substituted with 0-1 of R12, alkoxy of Cj ^ substituted with 0-1 of R12, and a heterocyclic ring system of 5-10 members which 1-4 heteroatoms that are independently selected from N, S and 0, and substituted with 0-3 of R11; R11 is independently selected, each time it is presented, from group H, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and 0, and substituted with 0-1 of R12, cycloalkyl of C3_l0 substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, polycarboxyalkyl substituted with 0-1 of R12, polyazaalkyl substituted with 0-1 of R12, peptide substituted with 0-1 of R12, wherein the peptide is composed of 2-10 and a binding to Ch; R12 is a link to Ch; k is selected from 0, 1 and 2; h is selected from 0, 1 and 2; h 'is selected from 0, 1, 2, 3, 4 and 5; h "is selected from 0, 1, 2, 3, 4 and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; g 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g "i is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 , 9 and 10 s1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 s "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7 , 8, 9 and 10 Ch is a unit that joins metal that has a formula that is selected from the group: A1, A2, A3, A ", A5, A6, A7 and A8 are independently selected, each time they are presented, from the group: N, NR13, NR13R14, S, SH, S (Pg), O, OH, PR13, PR "R14, P (0) R15R16 and a link to L"; E is a bond, CH or a spacer group that is independently selected, each time it occurs, from the group: alkyl substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C3.10 substituted with 0-3 of R17, C1.10 heterocycloalkyl substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O, aryl (C6.10) C1.10 alkyl, substituted with 0-3 of R17, alkyl (C1.10) -aryl of C6_10, substituted with 0-3 of R17, and a heterocyclic ring system of 5- 10 members containing 1-4 heteroatoms that are independently selected from N, S and O, and substituted with 0-3 of R17; R13 and R "each is independently selected from the group: a bond to L", hydrogen, alkyl of C ^ -Cj.- substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C? ? a replaced with 0-3 of R17, C ^ o heterocycloalkyl substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 member heterocycle ring system containing 1-4 heteroatoms that are independently selected from N, S and 0, aryl (C6. 10) -alkyl of C ^^ substituted with 0-3 of R17, alkyl (Cj.! -) -aryl of C6_10, substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-3 of R17 and one electron, with the proviso that when one of R13 or R14 is an electron, the other is also an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R15 and R16 are each independently selected from the group: a bond to Ln, -OH, alkyl of -Cm substituted with 0-3 of R17, alkyl of C ^ -Cj.- substituted with 0-3 of R17, substituted aryl with 0-3 of R17, cycloalkyl of C3.10 substituted with 0-3 of R17, heterocycloalkyl of C ^ - substituted with 0-3 of R17, wherein the heterocycle group is a heterocyclic ring system of 5-10 members which contains 1-4 heteroatoms that are independently selected from N, S and O, aryl (C6.10) -alkyl CJ.ÍO substituted with 0-3 of R17, alkyl (C._10) -aryl of C6-? OS substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R17; R17 is independently selected, each time it is presented, from the group: a bond for L ", = 0, F, Cl, Br, I, -CF3, -CN, -C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CHO, -CH2OR18, -OC (= 0) Rlß, -OC (= 0) 0R18a, -OR18, -OC (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0 ) OR18a, NR19C (= 0) N (R18) 2, -NR "S02N (R18) 2, -NR19S02R18a, -S03H, -S02Rlβa, -SR18, -S (= 0) R1Ba, -S02N (R18) 2, -N (R18) 2, - NHC (= S) NHR18, = N0R18, N02, - C (= 0) NHOR18, -C (= 0) NHNRlßR18a, -OCH2C02H, 2, 1- (morpholino) ethoxy, Ci-Cs alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, aryl substituted with 0-2 of Rlß and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O; Rlß, R1Ba and R19 are independently selected, each time they are presented from the group: a bond for L ", H, alkyl of CJ-CJ, phenyl, benzyl, CJ-CJ alkoxy, halide, nitro, cyano and trifluoromethyl; Pg is a thiol protective group; R20 and R21 are independently selected from the group: H, C ^ C ^ alkyl, -CN, -C02R25, -C (= 0) R25, C (= 0) N (R25) 2, 1-C2-C10 alkene substituted with 0-3 of R23, 1-C2-C10 alkyne substituted with 0-3 of R23, aryl substituted with 0-3 of R23, a 5-10 membered unsaturated heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R23, and an unsaturated C3.10 carbocycle, substituted with 0-3 of R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: and R23 are independently selected from the group: H, R24, C1-C10 alkyl substituted with 0-3 of R24, C2-C10 alkenyl substituted with 0-3 of R24, C2-C10 alkynyl substituted with 0-3 of R24 , aryl substituted with 0-3 of R24, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 substituted with 0-3 of R24, and a C3 carbocycle. 10 substituted with 0-3 of R24; alternatively, R22, R23, taken together form a fused aromatic part of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O; a and b indicate the positions of the optional double bonds and n is 0 or 1; R24 is independently selected, each time it is presented from the group: = 0, F, Cl, Br, I, -CF3, -CN, -C02R25, -C (= 0) R25, -C (= 0) N (R25 ) 2, -N (R25) 3+, -CH20R25, - OC (= 0) R25, -OC (= 0) OR25a, -OR25, -OC (= 0) N (R25) 2, NR26C (= 0) R25, -NR26C (= 0) OR25a, -NR26C (= 0) N (R25) 2, -NR6S02N (R25) 2, -NR26S02R25 \ -S03H, -S02R25a, -SR25, -S (= 0) R25a, -S02N (R25) 2, -N (R25) 2, = NOR25, -C (= 0) NHOR25, -OCH2C02H, and 2- (1-morpholino) ethoxy; Y, R25, R25a and R26 each are independently selected, each time they occur, from the group: hydrogen and CÍ-CJ alkyl, - and a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, characterized in that the present invention provides a compound wherein: L is glycine; R1 is an amino acid optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, tyrosine, phenylalanine , phenylglycine, cyclohexylalanine, homophenylalanine, lysine, ornithine, 1,2-diaminobutyric acid and 1,2-diaminopropionic acid; R2 is an amino acid optionally substituted with a bond to Ln, which is independently selected, each time it is presented, from the group: valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine , L-1-naphthylalanine, D-1-naphthylalanine, lysine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid and 2-aminothiazole-4-acetic acid; R3 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-acid 2- aminobutyric acid, D-tyrosine, D-phenylalanine, D-phenylglycine, D-cyclohexy-1-amino, D-homophenylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-diaminobutyric acid, D-1, 2- diaminopropionic acid; R4 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-acid 2- aminobutyric acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-ornithine, D-1, 2-diaminobutyric acid, D-acid 1, 2- diaminopropionic acid and 2-aminothiazole-4-acetic acid; R5 is an amino acid, optionally substituted with a bond to Ln, which is independently selected, each time it occurs, from the group: L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-acid 2- aminobutyric acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homophenylalanine, L-1-naphthylalanine, L-lysine, L-ornithine, L-2-diaminobutyric acid, acid Ll, 2- diaminopropionic acid and 2-aminothiazole-4-acetic acid; d is selected from 1, 2 and 3; W is independently selected, each time it is presented, from the group: 0, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (OCH2CH2) s, (CH2CH20) a ', (OCH2CH2CH2) s. and (CH2CH2CH20) t; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of C3.10 substituted with 0-1 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O and substituted with 0-1 of R10; Re, R6a, R7, Ra, R8, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, alkyl substituted with 0-1 of R10, aryl substituted with 0-1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of substituted with 0-1 of R10, NHC (= 0) R11, C (= 0) NHR ", NHC (= 0) NHR11, NHR11, R11 and a link to Ch; R10 is independently selected, each time it is presented from the group: COOR11, OH, NHR11, S03H, aryl substituted with 0-1 of R11, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected of N, S and 0, and substituted with 0-1 of R11, C-C- alkyl substituted with 0-1 of R12, Cj-C alkoxy; substituted with 0-1 of R12, and a bond to C "; R11 is independently selected, each time it is presented, from the group: H, aryl substituted with 0-1 of R12, a heterocyclic ring system of 5-10 members containing 1-4 heteroatoms that are independently selected from N, S and 0, and substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0- 1 of R12, amino acid substituted with 0-1 of R12, and a bond to Ch; k is 0 or 1; h is 0 or 1; h 'is 0 or 1; s is selected from 0, 1, 2, 3, 4 and 5 s' is selected from 0, 1, 2, 3, 4 and 5 s "is selected from 0, 1, 2, 3, 4 and 5 t is selected of 0, 1, 2, 3, 4 and 5 A1, A2, A3, A4, A5, Ad, A7 and A8 are independently selected, each time they are presented, from the group: NR13, NR13R14, S, SH, S (Pg), OH and a bond to L "; E is a bond, CH or a spacer group that is independently selected, each time it occurs, from the group: alkyl substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of C3.10 substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17; R "and R14 are each independently selected from the group: a bond to Ln, hydrogen, C ^ -Cn alkyl, substituted with 0-3 of R17, aryl substituted with 0-3 of R17, a heterocycle ring system of 5 -10 limbs containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17, and one electron, with the proviso that when one of R13 or R14 is an electron, the other also it is an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R17 is independently selected, each time it is presented, from the group: a bond for L ", = 0, F, Cl, Br, I, -CF3, -CN, -C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CH2OR18, -OC (= 0) R18, -OC (= 0) OR18a, -OR18, -OC (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0) OR18a, -NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a, -S03H, -S02R18a, -S02N (R18) 2, -N (R18) 2, -NHC (= S) NHR18, = NOR18, -C (= 0) NHNRlβR18a, - OCH2C02H and 2, 1- (morpholino) ethoxy; R18, R18"and R19 are independently selected, each time they are presented from the group: a bond for L", H and C! -C6 alkyl R20 and R21 are independently selected from the group: H, C1-C3 alkyl, -C02R25, C2-C5 1-alkene substituted with 0-3 of R23, C2-C5 1-alkyne substituted with 0-3 of R23, aryl substituted with 0-3 of R23 and a heterocyclic ring system of 5-10 unsaturated members containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R23; alternatively, R2 ° and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H and R2 ' alternatively, R22, R23, taken together form a fused aromatic part of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0; R24 is independently selected, each time it is presented from the group: -C02R25, -C (= 0) N (R25) 2, -CH20R25, -OC (= 0) R25, -OR25, -S03H, -N (R25) 2 and -0CH2C02H; Y R25 is independently selected, each time it is presented, from the group: H and alkyl of C.-C3.

5. A compound according to claim 4, the present invention provides an acterized compound because Q is a peptide selected from the group: R1 is L-valine, D. valine, D-lysine optionally substituted with the -amino group with a linkage to Ln or L-lysine optionally substituted with the e-amino group with a link to Ln; R2 is L-phenylalanine, D-phenylalanine, Dl-naphthylalanine, 2-aminothiazole-4-acetic acid, L-lysine optionally substituted in the amino group with a linkage to Ln or tyrosine, tyrosine is optionally substituted in the group hydroxy with a link to L "; R3 is D-valine, D-phenylalanine or L-lysine optionally substituted in the amino group with a link to In; R 4 is D-phenylalanine, D-tyrosine substituted on the hydroxy group with a bond to L n, or L-lysine optionally substituted on the amino group with a link to L n; with the proviso that one of R1 and R2 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1 or 2; is independently selected, each time it is presented from the group: NHC (= 0), C (= 0) NH, C (= 0), (CH2CH20) s, and (CH2CH2CH20) t; R6, Rda, R7, R7a, RB, R8a, R9 and R9a are independently selected, each time they are presented from the group: H, NHC (= 0) R11 and a bond to Ch; k is 0; h "is selected from 0, 1, 2 and 3; g is selected from 0, 1, 2, 3, 4 and 5; g1 is selected from 0, 1, 2, 3, 4 and 5; g" is selected from 0, 1, 2, 3, 4 and 5; g "'is selected from 0, 1, 2, 3, 4 and 5, s' is 1 or 2, t is 1 or 2; Ch is A1 is selected from the group: OH, and a link to Ln; A2, A4 and A6 are each N; A3, A5 and A8 are each OH; A7 is a link to Ln or NH link to L "; E is a C2 alkyl substituted with 0-1 of R1 ' R17 is = 0; alternatively, Ch is X ^ ß A A1 is NH2 or N = C (R20) (R21); E is a link; A2 NHR13; R13 is a heterocycle substituted with R17, the heterocycle is selected from pyridine and pyrimidine; R17 is selected from a bond to Ln, C (= I) NHR18; and C (= 0) R18; R18 is a link to Ln; R24 is selected from the group: -C02R25, -OR25, -S03H and -N (S25) 2; R25 is independently selected, each time it is presented from the group: hydrogen and methyl; i. - alternatively, Ch is A1, A2, A3 and A4 are each N; A5, A6 and A8 are each OH; A7 is a link to Ln; E is a C2 alkyl substituted with 0-1 of R1 es = 0

6. The compound according to claim 3, characterized in that the present invention provides a compound selected from the group: (a) cycle. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic] -3-aminopropyl) -Val}; (b) cycle. { Arg-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -18- amino-14-aza-4,7,10 -oxi-15-oxo-octadecoyl) -3-aminopropyl) -Val}; (c) 2- [[[5- [Carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo {D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp}) -cycle. { D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp}; (d) cycle. { Arg-Gly-Asp-D-Tyr-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (e) cycle. { Arg-Gly-Asp-D-Phe-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] (f) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Phe.}.) - cycle. { Lys-Arg-Gly-Asp-D-Phe}; (g) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Phe-Glu (cyclo. {Lys-Arg-Gly-Asp-D-Phe.}. ) -cycle. { Lys-Arg-Gly-Asp-D-Phe}; (h) cycle. { Arg-Gly-Asp-D-Nal-Lys ([2- [[[5- [carbonyl] - 2-pi r i dini 1] hid a z ono] me t i 1] - benzenesulfonic acid])}; (i) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-Arg-Gly-Asp-D-Nal.}.) -cycle. { Lys-Arg-Gly-Asp-D-Nal}; (j) cycle. { Arg-Gly-Asp-Lys ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -D-Val.}; (k) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { Lys-D-Val-Arg-Gly-Asp {) - cycle. { Lys-D-Val-Arg-Gly-Asp}; (1) cycle. { Arg-D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic] -3-aminopropyl) -D-Asp-Gly acid}; (m) cycle. { D-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] benzenesulfonic acid]) -D-Phe-D-Asp-Gly-Arg.}.; (n) [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic acid] -Glu (cyclo { D-Lys-D-Phe-D-Asp-Gly-Arg}) -cycle. { D-Lys-D-Phe-D-Asp-Gly-Arg}; (o) cycle. { D-Phe-D-Lys- ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -D-Asp-Gly-Arg.}; (p) cycle. { N-Me-Arg-Gly-Asn-ATA-D-Lys ([2- [[[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (q) cycle) Cit-Gly-Asp-D-Phe-Lys ([2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid])}; (r) 2- (1,4, 7, 10-tetraaza-4, 7, 10 -tris (carboxymethyl) -1- cyclododecyl) acetyl-Glu (cyclo .. Lys -Arg-Gly-As -D- Phe .}.) -cycle. { Lys-Arg-Gly-Asp-D-Phe} ) (s) cycle. { Arg-Gly-Asp-D-Phe-Lys (DTPA)}; (t) cycle (Arg-Gly-Asp-D-Phe-Lys. {2 (DTPA); (u) cycle. { Arg-Gly-Asp-D-Ty (N-DTPA-3-aminopropyl) -Val}; (v) cycle. { ? rn (d-N-2-imidazolinyl) -Gly-Asp-D-Tyr (N- [acid 2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] benzenesulfonic] -3-aminopropyl) -Val}; (w) cycle. { Lys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid] -3-aminopropyl) -Val}; (x) cycle. { Cys (2-aminoethyl) -Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val}; (and) cycle. { HomoLys-Gly-Asp-D-Tyr (N- [2- [[[5- [carbonyl] - 2-pi ri dini 1] hi dr az ono] me ti 1] - benzenesulfonic] -3-aminopropyl) - Val}; (z) cycle. { ? rn (d-N-benzylcarbonyl) -Gly-Asp-D-Tyr (N- [acid 2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -Val}; (aa) cycle. { Dap (b- (2-benzimidazolylacetyl))) -Gly-Asp-D-Tyr (N- [2- [[[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid] -3- aminopropyl) - Val}; (bb) cycle. { 0 rn (d-N-2-im? Dazolinyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid])}; (cc) cycle. { 0rn (d-N-benzylcarbamoyl) -Gly-Asp-D-Phe-Lys (N- [2- [[[[5- [carbonyl] -2-pyridinyl] hydrazono] -methyl] -benzenesulfonic acid])}; (dd) cycle. { Lys-D-Val-D-Tyr (N- [2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -3-aminopropyl) -D-Asp-Gly}; (ee) cycle. { ? rn (dN-benzylcarbonyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -D- Asp-Gly}; Y (ff) cycle. { 0rn (dN-2-imidazolinyl) -D-Val-D-Tyr (N- [2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic] -3-aminopropyl) -D -Asp-Gly}; or a pharmaceutically acceptable salt form thereof.

7. A kit characterized in that it comprises a compound according to claim 3, or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.

8. The equipment according to claim 7, characterized in that the equipment further comprises one or more auxiliary ligands and a reducing agent.

9. The equipment according to claim 8, characterized in that the auxiliary ligands are tricine and TPPTS.

10. The equipment according to claim 9, characterized in that the reducing agent is tin (II).

11. A diagnostic or therapeutic metal-pharmaceutical composition, characterized in that it comprises: a metal, a chelator capable of chelating the metal and a target portion, wherein the target portion is attached to the chelator, which is a peptide or peptidomimetic and which binds to a receptor that is activated during angiogenesis, and the compound has 0-1 linking groups between the target portion and the chelator.

12. The composition according to claim 11, characterized in that the metapharmaceutical substance is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group: 99pTc, 95Tc, ^ In, d2Cu, 64Cu, d7Ga and dBGa, the portion target is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-l / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, avß3, « v ß5, av ß17 a4 ß1, aj ß Y a2 ß2 and the linking group is present between the target portion and the chelator.

13. The composition according to claim 12, characterized in that the target portion is a cyclic pentapeptide at avß3 receptors,

14. The composition according to claim 13, characterized in that the radioisotope is 99Tc or 95Tc, the radiopharmaceutical further comprises a first auxiliary ligand and a second auxiliary ligand capable of stabilizing the radiopharmaceutical.

15. The composition according to claim 14, characterized in that the radioisotope is 99 Tc _

16. The composition according to claim 15, characterized in that the radiopharmaceutical is selected from the group: 99mTc (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -Val)); 99mTc (tricine) (TPPMS) (cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly)); "" Te (tricine) (TPPDS) (cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly) ); 99Tc (tricine) (TPPTS) (cyclo (Arg-D-Val-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) -D-Asp-Gly)); "• Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Phe-Lys (N- [[5 - [carbonyl] -2-pyridinyl] diazenido]))); "Te (tricine) (TPPTS) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] iazenido]]))); 99mTc (tricine) (TPPTS) ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic acid] -Phe- Glu (cyclo { Lys-Arg-Gly-Asp-D -Phe.}.) -cycle { Lys-Arg-Gly- Asp-D-Phe.}.); "Te (tricine) (TPPTS) (Cyclo { Arg-Gly-Asp-D-Nal-Lys ([Acid 2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic]]}); "Te (tricine) (TPPTS) ([2- [[[5- [carbonyl] -2-pyridinyl] -hydrazono] methyl] -benzenesulfonic acid] -Glu (cyclohexane. {Lys-Arg-Gly-Asp-D} -Nal.}.) -cycle { Lys-Arg-Gly-Asp-D-Nal.}.); "Te (tricine) (TPPTS) (Cyclo { Arg-Gly-Asp-D-Tyr ((N- [[5- [carbonyl] -2-pyridinyl] diazenido] -18-amino-14-aza-4 , 7, 10-oxy-15-oxo-octadecoyl) -3-aminopropyl) -Val)); "Te (tricine) (TPPTS) (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -Glu (0-cyclo (Lys-Arg-Gly-Asp-D-Phe)) -O-cyclo ( Lys-Arg-Gly-Asp-D-Phe)); "Te (tricine) (TPPTS) (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -Glu (O-cyclo (D-Tyr (3-aminopropyl) -Val-Arg-Gly-Asp)) - 0-Cyclo (D-Ty (3-aminopropyl) -Val-Arg-Gly-Asp)); "Te (tricine) (TPPT?) (Cyclo (Arg-Gly-Asp-Lys (N- [[5- [carbonyl] -2- pyridyl] diazenido]) -D-Val; "Te (tricine) (TPPTS) (cycle {D-Lys ([2- [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] benzenesulfonic acid]) D-Phe-D- Asp-Gly -Arg.}.); 99 Tc (tricine) (TPPTS) (2 - [[[5 - [carboni 1] - 2-pyridinyl] hydrazono] met il] -benzenesulfonic acid] - Glu (cyclo {D-Lys-D-Phe-D] -Asp-Gly-Arg.}.) -cyclo {D-Lys-D-Phe-D-Asp-Gly-Arg.}.); "Te (tricine) (TPPTS) cycle {D-Phe-Lys ([acid2- [[[5- [carbonyl] -2- pyridinyl] hydrazono] methyl] benzenesulfonic]) -D-Asp- Gly-Arg .}.); "Te (tpcin) (TPPTS) (cyclo (N-Me-Arg-Gly-Asp-ATA-D-Lys (N- [[5- [carbonyl] -2-pyridinyl] diazenido]))); "Te (tricine) (TPPTS) (Cyclo { Cit-Gly-Asp-D-Phe-Lys ([Acid 2 - [[[5- [carbonyl] -2-pyridinyl] hydrazono] methyl] -benzenesulfonic]]} ); Y Tc (tricine) (1, 2, 4-tr? Azol) (cyclo (Arg-Gly-Asp-D-Tyr (N- [[5- [carbonyl] -2-pyridinyl] diazenido] -3-aminopropyl) - Val)).

17. A composition according to claim 13, characterized in that the radioisotope is 1L1In.

18. A composition according to claim 17, characterized in that the radiopharmaceutical is selected from the group: (DOTA-111In) -Glu (cyclo (Lys-Arg-Gly-Asp-D-Phe) -cyclo. {Lys-Arg-Gly-Asp-D-Phe.}; Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA- ^ In)); Y Cyclo (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-1:? In).

19. The composition according to claim 11, characterized in that the metapharmaceutical substance is a therapeutic radiopharmaceutical substance, the metal is a radioisotope selected from the group: 186R, 188Re, 153Sm, lddHo, 177Lu, 149Pm, 90Y, 212Bi, 103Pd, 109Pd , 159Gd, 140La, 198Au, 199Au, 169Yb, 175Yb, ld5Dy, d7Cu, 105Rh, lAg and 192Ir, the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk- l / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, avß3, avß5, avß !, a4ß ?, a-ßi Y < -2ß2 and the linking group is present between the target portion and the chelator.

20. The composition according to claim 19, characterized in that the target portion is a cyclic pentapeptide at avß3 receptors,

21. The composition according to claim 20, characterized in that the radioisotope is 153Sm.

22. The composition according to claim 21, characterized in that the radiopharmaceutical is selected from the group: Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA-153Sm); Cyclo (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-153Sm); Y Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (153Sm) -3-aminopropyl) -Val).

23. The composition according to claim 20, characterized in that the radioisotope is 177Lu.

24. The composition according to claim 23, characterized in that the radiopharmaceutical is selected from the group: Cyclo (Arg-Gly-Asp-D-Phe-Lys (DTPA-177Lu)); (DOTA-177Lu) -Glu (cyclo (Lys-Arg-Gly-Asp-D-Phe.).) -cyclo. {Lys-Arg-Gly-Asp-D-Phe.}; Cyclo (Arg-Gly-Asp-D-Phe-Lys) 2 (DTPA-177Lu); Y Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (17Lu) -3-aminopropyl) -Val).

25. The composition according to claim 20, characterized in that the radioisotope is 90Y.

26. The composition according to claim 25, characterized in that the radiopharmaceutical is: (DOTA-90Y) -Glu (cycle { Lys-Arg-Gly-Asp-D-Phe.).) -cycle. { Lys-Arg-Gly- Asp-D-Phe};

27. The composition according to claim 11, characterized in that the substance Metalopharmaceutical is an MRI contrast agent, the metal is a paramagnetic metal ion that is selected from the group: Gd (III), Dy (III), Fe (III) and Mn (II), the target portion is a peptide or a mimetic thereof and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-l / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, avß3, < xv5, < -vß ?, a4ß1, Ojßi and a2ß2 and the linking group is present between the target portion and the chelator.

28. A composition according to claim 27, characterized in that the target portion is a cyclic pentapeptide at avß3 receptors,

29. The composition according to claim 28, characterized in that the metal ion is Gd (III).

30. The composition according to claim 29, characterized in that the contrast agent is: Cyclo (Arg-Gly-Asp-D-Tyr (N-DTPA (Gd (III)) -3-aminopropyl) -Val).

31. The composition according to claim 11, characterized in that the substance Metalpharmaceutical is an X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag and Ir, the target portion is a cyclic pentapeptide, the receptor is avß3, and the linker group is present between the target portion and the chelator.

32. The composition according to claim 11, characterized in that it is used in the treatment of rheumatoid arthritis.

33. The composition according to claim 11, characterized in that it is for use in the treatment of cancer.

34. The composition according to claim 11, characterized in that it is for use in imaging the formation of new blood vessels.

35. The composition according to claim 12, characterized in that it is for use in the formation of cancer images with flat or SPECT gamma scintigraphy, or for positron emission tomography.

36. The composition according to claim 27, characterized in that it is for use in cancer imaging by means of magnetic resonance imaging.

37. A composition according to claim 31, characterized in that it is for use in the formation of cancer images with X-ray computed tomography.

38. A compound, characterized in that it comprises: a target portion and a surfactant, wherein the target portion is bound to the surfactant, which is a peptide or peptidomimetic, and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linking groups between the objective portion and the surfactant.

39. The compound according to claim 38, characterized in that the target portion is a peptide or a mimetic thereof, and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-l / KDR, Flt-1, Tek, Tie , neuropoline-1, endoglin, endosialin, Axl, avß3, avß-, «Pi» a5ß1 (aß1 and a2ß2 and the linking group is present between the target portion and the surfactant.

40. The compound according to claim 39, characterized in that the receptor is the avß3 integrin and the compound is of the formula: (Q) d-Ln-Sf wherein Q is a cyclic pentapeptide which is independently selected from the group: VJ - VJ K is an L-amino acid that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, j¡¡ ^^ and β-2-benzylimidazolylacet-1, 2-diaminopropionic acid; K1 is a D-amino acid that is independently selected, each time it occurs, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, dN-2-imidazolinylornithine, dN-benzylcarbamoylornithine, and beta-acid - 2-benzylimidazole i lacet il -1,2-diaminopropionic; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M1 is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, f-enylglycine, cyclohexylalanine, homophenylalanine, 1- naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine, methionine and 2- aminothiazole -4-acetic acid, - R3 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-di-aminobutyric acid, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homofenilalanine, D-naphthylalanine, D-lysine, D- serine, D-ornithine, D-1, 2-di-aminobutaric acid, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, L-phenylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homofenilalanine, L-naphthylalanine, L-lysine, L- serine, L-ornithine, L-1, 2-di am i nobu tic acid, Ll, 2- acid diaminopropionic, L-cysteine, L-penicillamine, L-methionine and 2-aminothiazole-4-acetic acid, - with the proviso that one of R1, R2, R3, R4 and Rs in each Q is substituted with a bond to Ln. , and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine, and with the additional proviso that when R4 is 2-aminothiazole-4-acetic acid, K and K 'are N-methylarginine, and with the additional proviso that when R5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Sf is a surfactant which is a lipid or a compound of the formula: 9β-A; A A9 is selected from the group: OH and OR27; A10 is OR27; is C (= 0) C1 alkyl .: E1 is alkylene of C1.10 substituted with 1-3 of R2 ' R28 is independently selected, each time it is presented, from the group: R30, -P03H-R30; = 0, -C02R29, -C (= 0) R29, -C (= 0) N (R9) 2, -CH2OR29, -OR29, -N (R29) 2, Cj-Cj alkyl and C2-C4 alkenyl; R29 is independently selected, each time the group is presented: R30, H, C ^ Cj alkyl, phenyl, benzyl and trifluoromethyl; R30 is a link to Ln; Ln is a linking group that has the formula: (CR6R7) g- () h- (CR6aR7a) g '- (Z) k (W) h, - (CR8R9) g .- () h .- (Cr8aR9a) g .. it is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (0CH2CH2) 20_200, (CH2CH20) 20_200, (0CH2CH2CH2) 20_200, (CH2CH2CH2O) 20,200 and (aa),.,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of C3.10 substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R10; Rd, Rda, R7, R7a, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, Cj-Cj alkyl substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and alkoxy of CLB substituted with 0-3 of R10, NHC ^ OIR11, C (= 0) NHR11, NHC (= 0) NHR11, NHR11 , R11 and a link to Sf; R10 is independently selected, each time it is presented from the group: a bond for Sf, COOR11, OH, NHR11, S03H, P03H, aryl substituted with 0-3 of R11, alkyl of C1.5 substituted with 0-1 of R12, alkoxy of Ca_5 substituted with 0-1 of R12, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O, and substituted with 0-3 of R11; R11 is independently selected, each time it occurs, from group H, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 , and substituted with 0-1 of R12, C3_10 cycloalkyl substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, and a bond to S £; R12 is a link to Sf; k is selected from 0, 1 and 2; h is selected from 0, 1 and 2; h 'is selected from 0, 1, 2, 3, 4 and 5; h "is selected from 0, 1, 2, 3, 4 and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g 'is selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10 g "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 g" 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 t1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and a pharmaceutically acceptable salt thereof.

41. The compound according to claim 48, characterized in that the compound is of the formula: Q-L "-S £ £ wherein, Q is a cyclic pentapeptide that is independently selected from the group: K is an L-ammocida that is independently selected, each time it is presented, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoetc-cysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and ß-2-benzylimidazol-ilacet-1, 2-diaminopropionic acid, - K 'is a D-amino acid that is independently selected, each time it occurs, from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethecysteine, dN-2-imidazolinylornithine, dN-benzylcarbamoylornithine, and acid β-2-benzyl imidazole ilacet i 1 -1,2-diaminopropionic; L is independently selected, each time it is presented, from the group: glycine, L-alanine and D-alanine; M is L-aspartic acid; M 'is D-aspartic acid; R1 is an amino acid substituted with 0-1 bonds to L ", which is independently selected, each time it is presented, from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid , 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, f-enylglycine, cyclohexylalanine, homophenylalanine, 1- naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine and methionine; R2 is an amino acid, substituted at 0-1 bonds to Ln, which is independently selected, each time it occurs, from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-1-naphthylalanine, D-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine, methionine and 2- aminothiazole -4 -acetic acid; R3 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-phenylalanine, D-thienylalanine, D-phenylglycine, D-cyclohexylalanine, D-homophenylalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, acid D-1, 2-d i am i nobu t i r i c o, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine and D-methionine; R4 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, D-valine, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-2-aminobutyric acid, D-2-aminohexanoic acid, D-tyrosine, D-phenylalanine, D-thienylalanine, Df-enylglycine, D-cyclohexylalanine, D-homofenilalanine, D-naphthylalanine, D-lysine, D-serine, D-ornithine, D-1, 2-di-mybutene, D-1, 2- diaminopropionic acid, D-cysteine, D-penicillamine, D-methionine, and 2-aminothiazole-4-acetic acid; R5 is an amino acid, substituted with 0-1 bonds to Ln, which is independently selected, each time it is presented, from the group: glycine, L-valine, L-alanine, L-leucine, L-isoleucine, L-norleucine, L-2-aminobutyric acid, L-2-aminohexanoic acid, L-tyrosine, L-enylalanine, L-thienylalanine, L-phenylglycine, L-cyclohexylalanine, L-homofenylalanine, L-naphthylalanine, L-lysine, L-serine, L-ornithine, Ll, 2-diaminobutyric acid, Ll, 2- acid diaminopropionic, L-cysteine, L-penicillamine, L-methionine and 2-aminothiazole-4-acetic acid; with the proviso that one of R1, R2, R3, R4 and R5 in each Q is substituted with a bond to Ln, and with the additional proviso that when R2 is 2-aminothiazole-4-acetic acid, K is N- methylarginine, and with the additional proviso that when R 4 is 2-aminothiazole-4-acetic acid, K and K 'are N-methylarginine, and with the additional proviso that when R 5 is 2-aminothiazole-4-acetic acid, K 'is N-methylarginine; S £ is a surfactant which is a lipid or a compound of the formula:; Ace is OR2 is OR2 is C (= 0) C ^ alkyl E1 is C1_10 alkylene substituted with 1-3 of R28 R28 is independently selected, each time it is presented, from the group: R30, -P03H-R30; = 0, -C02R29, -C (= 0) R29, -CH2OR29, -OR29, and C, -C5 alkyl; R29 is independently selected, each time the group is presented: R30, H, C1-C6 alkyl, phenyl, and benzyl; R30 is a link to Ln; Ln is a linking group that has the formula: (CR6R7) 3- (W) h- (CR6aR7a) g '- (Z) k () h, - (CR8R9) g .- () h .- (CrαaR9a) g ", W is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, C (= 0), C (= 0) 0, OC (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (OCH2CH2) so-2oo 'Xx CH2CH20) 20.200, (OCH2CH2CH2) 20.200, (CH2CH2CH2O) 20.200 and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, C3_10 cycloalkyl substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O and substituted with 0-3 of R10, - Rd, Rda, R7, R7a, R8, R8a, R9 and R9a are independently selected, each time they occur, from the group: H, = 0, C-C5 alkyl substituted with 0-3 of R10 and C-alkoxy ^. substituted with 0-3 of R10 and a link to S £; R10 is independently selected, each time it is presented from the group: a bond for Sf, COOR11, OH, NHR11, C ^ alkyl. substituted with 0-1 of R12 and C ^ alkoxy substituted with 0-1 of R12; R11 is independently selected, each time it occurs, from group H, aryl substituted with 0-1 of R12, cycloalkyl of C3.10 substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, and a bond to S £; R12 is a link to S £; k is selected from 0, 1 and 2; h is selected from 0, 1 and 2; h1 is selected from 0, 1, 2, 3, 4 and 5 h "is selected from 0, 1, 2, 3, 4 and 5 g is selected from 0, 1, 2, 3, 4, 5 g 'is selected of 0, 1, 2, 3, 4, 5 g "is selected from 0, 1, 2, 3, 4, 5 g" 'is selected from 0, 1, 2, 3, 4, 5 s is selected from O , 1, 2, 3, 4, 5 s1 is selected from 0, 1, 2, 3, 4, 5 s "is selected from 0, 1, 2, 3, 4, 5 t is selected from 0, 1, 2 , 3, 4, 5 t 'is selected from 0, 1, 2, 3, 4, 5 and a pharmaceutically acceptable salt thereof.

42. The compound according to claim 41, characterized in that the present invention provides a compound selected from the group: 1- (1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- (cyclo (Arg-Gly-Asp-D-Phe-Lys) -dodecane-1,2-dione; 1- (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400-a-carbonyl) -cyclo (Arg-Gly-Asp-D-Phe-Lys)) -dodecane -1, 12-dione; Y 1- (1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamino) -12- ((? -amino-PEG3400-a-carbonyl) -Glu (cyclo (Arg-Gly-Asp-D-Phe-Lys)) 2) -dodecano-1, 12 -diona.

43. The contrast agent composition for ultrasound, characterized in that it comprises: (a) a compound according to claim 40, comprising: a cyclic pentapeptide that binds the integrin to avß3, a surfactant and a linking group between the cyclic pentapeptide and the surfactant; (b) a parenterally acceptable carrier; and (c) an ecogenic gas.

44. The composition of ultrasound contrast agent characterized in that it further comprises: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and N- (methoxypolyethylene glycol 5000 carbamoyl) - 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.

45. The composition of ultrasound contrast agent, characterized in that the echogenic gas is a C2.5 perfluorocarbon.

46. The composition according to claim 40, characterized in that it is for use in cancer imaging with sonography.

47. The composition according to claim 40, characterized in that it is for use in the image formation of the formation of new blood vessels.

48. A therapeutic radiopharmaceutical composition characterized in that it comprises: (a) a therapeutic radiopharmaceutical substance, according to claim 11, and (b) a parenterally acceptable carrier.

49. The diagnostic radiopharmaceutical composition, characterized in that it comprises: (a) a diagnostic radiopharmaceutical, an MRI contrast agent, or an X-ray contrast agent according to claim 11; and (b) a parenterally acceptable carrier.

50. A therapeutic radiopharmaceutical composition characterized in that it comprises: a radiolabelled target portion, wherein the target portion is a Q compound of agreement with claim 3 and the radiolabel or Radiolabel is a therapeutic isotope that is selected from the group of: 35S, 32P, 15I, 131I and 211At.

51. A therapeutic radiopharmaceutical composition, characterized in that it comprises: a radiolabeled target portion, wherein the target portion is a compound Q according to claim 5 and the radiolabel is a therapeutic isotope which is 131I.