HK1138798A - 18f fluoro-benzoyl labelled biological active coumpounds as diagnositic imaging agents as well as benzotriazol-1-yloxy-benzoyl, 2,5-dioxo-pyrrolidin-1-yloxy) benzoyl and trimethylammonio-benzoyl precursers - Google Patents

Description

18F fluoro-benzoyl labelled biologically active compounds as diagnostic imaging agents and benzotriazol-1-yloxy-benzoyl, 2, 5-dioxo-pyrrolidin-1-yloxy) benzoyl and trimethylammonium-benzoyl precursors

Technical Field

The present invention relates to novel substituted benzene compounds which are available halogen-labelled, more particularly¹⁸F-labelled biologically active compounds, and halogen-labelled, more particularly¹⁸F-labelled compounds, preparation thereofHalogen-labelled, more particularly¹⁸Methods for F-labeled compounds, compositions comprising such compounds and their diagnostic imaging uses, kits comprising sealed vials containing predetermined amounts of such novel substituted benzene compounds, and such compounds for use as pharmaceuticals, as diagnostic imaging agents, and most particularly as imaging agents for Positron Emission Tomography (PET).

Background

In vivo scanning using Positron Emission Tomography (PET) has increased in recent years. PET is both a medical tool and a research tool. It is widely used in medical imaging and metastasis finding of tumors in clinical oncology, as well as in clinical diagnosis of certain diffuse brain diseases (e.g., those resulting in various types of dementia). Radiotracers consisting of radionuclides stably bound to biomolecules are used for in vivo imaging of disease.

In designing effective radiopharmaceutical tracers for use as diagnostic agents, the drug must possess suitable in vivo targeting and pharmacokinetic properties. Fritzberg et al (J.Nucl. Med., 1992, 33: 394) further describe that radionuclide chemistry and related linkages enhance the need to optimize chemically modified linkages and labels of biomolecule carriers, diluents, excipients or adjuvants. Thus, the type of radionuclide, the type of biomolecule and the method used to link them to each other can have key effects on the radiotracer properties.

Peptides are biomolecules that play a key role in many physiological processes, including functioning as neurotransmitters, hormones, and antibiotics. Studies have shown their importance in areas such as neuroscience, immunology, pharmacology, and cell biology. Some peptides may act as chemical messengers. They bind to receptors on the surface of target cells and the biological effect of the ligand is transmitted to the target tissue. Thus, the specific receptor binding properties of the ligand can be exploited by labeling the ligand with a radionuclide. Theoretically, the high affinity of the ligand for the receptor promotes retention of the radiolabeled ligand in the receptor expressing tissue. However, it is still under investigation what polypeptides can be effectively labeled and under what conditions labeling will occur. It is well known that the receptor specificity of ligand peptides may be altered during chemical reactions. Therefore, the optimal peptide structure must be determined.

Tumors overexpress various receptor types to which peptides specifically bind. Boerman et al (serum in Nuclear Medicine, 30(3) July, 2000; pp195-208) provide a non-exhaustive list of peptides that bind to tumor-associated receptors, i.e., somatostatin, Vasoactive Intestinal Peptide (VIP), bombesin that binds to the gastrin-releasing peptide (GRP) receptor, gastrin, cholecystokinin (CCK) and calcitonin.

Radionuclides for use in PET scanning are typically isotopes having a short half-life, e.g.¹¹C(～20min)、¹³N(～10min)、¹⁵O(～2min)、⁶⁸Ga (. about.68 min) or¹⁸F (-110 min). Due to their short half-life, radionuclides must be produced in a cyclotron that is not too far from the PET scanner in terms of delivery time. These radionuclides are incorporated into biologically active compounds or biomolecules that function to carry the radionuclide into the body through a targeted site, such as a tumor.

The attachment of the radionuclide to the biomolecule is achieved by various methods resulting in the presence or absence of a linker between the radionuclide and the biomolecule. Thus, various linkers are known. Smith et al ("Radiochemical improvements of¹⁷⁷Lu-DOTA-8-Aoc-BBN[7-14]NH₂: "Nucl. Med.Bio, 30 (2)": 101-9; 2003) disclosed is a radiolabeled bombesin peptide wherein the linker is DOTA-X, wherein X is a carbon linkage (carbon tether). However, radiolabelling¹⁷⁷Lu (semi-failure)Period 6, 5 days) do not match the biological half-life of natural bombesin, which makes it possible to obtain a peptide with a biological half-life of natural bombesin¹⁷⁷Lu-DOTA-X-bombesin is an inappropriate radiotracer for tumor imaging.

Garcia Garayoa et al ("Chemical and biological characterization of newRe (CO)₃/[^99mTc](CO)3 bombricin analogs, "nuclear.med.biol., 17-28; 2007) discloses a radioactive nuclide [ alpha ], [ beta ]^99mTc]And a spacer between bombesin, wherein the spacer is- β -Ala-and 3, 6-dioxa-8-aminocaprylic acid. Garcia Garayoa et al believe that the different spacers do not have a significant effect on stability or on receptor affinity.

The linkers listed above have been specifically designed for a particular type of radionuclide and determine the type and chemical conditions of the radioactive binding process.

More recently, peptides have been coupled to macrocyclic chelators for some time⁶⁴Cu、⁸⁶Y, and⁶⁸ga labeled for PET applications. However, such radionuclides interact with catabolism in the body, leading to undesirable physiological effects and chelate linkages.

¹⁸F-labelled compounds are becoming increasingly important because of their availability and because of the development of methods for labelling biomolecules. Some applications have been shown¹⁸The F-labelled compound produced high quality images. In addition, the first and second substrates are,¹⁸the longer lifetime of F will allow longer imaging times and allow the preparation of batches of radiotracers for multiple patients and the delivery of the tracers to other equipment, making this technique more widely applicable to clinical researchers. In addition, it has been noted that the development of PET cameras and the availability of such equipment is increasing in many PET centers. Thus, new ones were developed¹⁸F-labelled tracers are becoming increasingly important.

Nucleophilic aromatic¹⁸F-fluorination reaction of¹⁸F-labelled radiopharmaceuticals of great value¹⁸F-markThe noted radiopharmaceuticals are used as in vivo imaging agents to target and visualize diseases such as solid tumors.

Has been published to use different precursors or raw materials to obtain¹⁸Various methods of radiofluorination of F-labelled peptides. Due to the small size of the peptides, higher target-to-background ratios and rapid blood clearance can generally be achieved with radiolabeled peptides. Thus, short-lived Positron Emission Tomography (PET) isotopes are potential candidates for labeling peptides. Among many positron emitting nuclides, fluorine-18 appears to be the best candidate for labeling bioactive peptides due to its favorable physical and nuclear characteristics. By using¹⁸The major disadvantage of F-labeled peptides is that¹⁸The preparation of the F-labelling agent is laborious and time-consuming. Due to the complex nature of peptides and the several functional groups associated with the primary structure,¹⁸the F-labeled peptide was not prepared by direct fluorination. Thus, the use of prosthetic groups as shown below reduces¹⁸Difficulties associated with the preparation of F-labelled peptides. Several such prosthetic groups have been proposed in the literature, including N-succinimidyl-4-, [¹⁸F]Fluorobenzoate, m-maleimido-N- (p-)¹⁸F]Fluorobenzyl) -benzamide, N- (p-, [2 ]¹⁸F]Fluorophenyl) maleimide, and 4-, [2 ]¹⁸F]Fluorobenzoylmethyl bromide. Are being used today in¹⁸Almost all methods of F-labeling peptides and proteins utilize active esters of fluorine-labeled synthons.

RM ═ reactive moieties

LG ═ can be¹⁸F-substituted leaving group

X-functional group for reaction with RM

Okarvi et al ("Recent progress in fluorine-18 labeled peptides and peptides," Eur.J.Nucl.Med., 2001 Jul; 28 (7): 929-38) gave¹⁸A review of recent developments in F-labeled biologically active peptides.

Xiaonzhong Zhang et al () "¹⁸F-labeled boron analog for targeting GRPreceptor-expressing pro state cancer, "j.nuclear.med., 47 (3): 492 501(2006)) involves the 2-step process detailed above. [ Lys3]Bombesin ([ Lys 3)]BBN) and aminocaproic acid-bombesin (7-14) (Aca-BBN (7-14)) by treatment with N-succinimidyl-4-¹⁸F-fluorobenzoic acid ester (¹⁸F-SFB) coupling of Lys3 amino group and Aca amino group, respectively¹⁸And F, marking. However, obtained¹⁸F-FB-[Lys3]BBN is relatively metabolically unstable, resulting in a decrease in¹⁸F-FB-[Lys3]The extent of use of BBN in reliable tumor imaging.

Thorsten Poethko et al ("Two-step method for high-yield routing of peptides:¹⁸f-labeled RGD and octreotide analogs, "j.nuclear.med., 2004 May; 45(5): 892-902) involves a 2-step method of labeling RGD and octreotide analogs. The method discloses¹⁸Step of radiosynthesis of F-labeled aldehyde or ketone and¹⁸a step of chemoselective attachment of an F-labelled aldehyde or ketone to the aminooxy-functionalised peptide.

Thorsten Poethko et al ("First¹⁸F-labeled router able for routing of a formatting receiver-expressing modulator using a position emitting dictionary, "Clin. 10(11): 3593-606) application of the 2-step method to¹⁸F-labelled saccharified Tyr (3) -OltrazSynthesis of peptidic acid (octreotate) (TOCA) analogs with optimized pharmacokinetics suitable for clinically routine somatostatin-receptor (sst) imaging.

WO 2003/080544a1 and WO 2004/080492a1 relate to radiofluorination of biologically active peptides for diagnostic imaging using the 2-step method shown above.

The most critical aspect of successful treatment of any cancer is early detection. Also, proper diagnosis of tumors and metastases is critical.

¹⁸The conventional use of F-labeled peptides for in vivo quantitative receptor imaging of receptor-expressing tissues and characterization of receptor status using PET is lacking¹⁸Limitations of suitable radiofluorination methods for routine large-scale synthesis of F-labelled peptides. There is a clear need for a radiofluorination method that can be performed rapidly without loss of receptor affinity of the peptide and with the production of positive images (reduced background), wherein the radiotracer is stable and exhibits enhanced clearance properties.

Substituted mono (predominantly para) substituted phenyltrimethylammonium derivatives¹⁸F]The conversion of the [ fluoro ] benzene derivative has been reported in the literature, and the substituted [2 ]¹⁸F]The fluorobenzene derivatives can be used as radiopharmaceuticals or as small and large molecules¹⁸F-labeled prosthetic groups (Irie et al 1982, Fluorine chem., 27, (1985), 117-.

Scheme 1

There are only a few nucleophilic aromatic derivatives with respect to trimethylammonium substituted aromatic derivatives (said aromatic derivatives containing two or more substituents in addition to the trimethylammonium moiety)¹⁸Publications on F-fluorination:

oya [ sic ] or the like¹⁸F]Potassium fluoride treatment of trifluoromethanesulfonic acid [ 2-chloro-5- (2-dimethylcarbamoyl-phenylthio) -4-nitro-phenyl ] -amide]Trimethyl ammonium and obtaining the desired¹⁸F-labeled compounds (Journal of medicinal Chemistry, 2002, 45 (21): 4716-.

Li et al reported that 4- (N, N, N-trimethylammonium) -3-cyano-3' -iodobenzophenone trifluoromethanesulfonate (Bioconjugate Chemistry, 2003, 14 (2): 287-294)¹⁸F-fluorination reaction.

Enas et al converted trifluoromethanesulfonic acid (2, 2-dimethyl-1, 3-dioxo-indan-5-yl) -trimethylammonium to the desired¹⁸F-labelled Compound Journal of fluoride Chemistry, (1993), 63 (3): 233-41).

Seimbille et al and other groups have been successfully used¹⁸Label F is trifluoromethanesulfonic acid (2-chloro-4-nitro-phenyl) -trimethylammonium (j. laboratory compound. radiopharm., (2005), 48, 11: 829-.

Trimethylammonium trifluoromethanesulfonate (2-benzyloxy-4-formyl-phenyl) -trimethylammonium has been successfully prepared by Langer et al (bioorg. Med. chem., EN; 9; 3; 2001: 677-one 694) at elevated temperatures (130 ℃ C.)¹⁸And F, marking.

Lang et al have been used by¹⁸F]Potassium fluoride radiolabels trimethyl- (2-methyl-4-pentamethylphenylmethoxycarbonyl-phenyl) -ammonium trifluoromethanesulfonate (J.Med.chem., 42, 9, 1999: 1576-.

Trimethyl- (4-nitro-naphthalen-1-yl) -ammonium trifluoromethanesulfonate has been used by Amokhtari et al¹⁸F marker (J.Labelled composite. radiopharm.; S42, 1 (1999): S622-S623).

Lemaire et al have converted trifluoromethanesulfonic acid (2-formyl-5-methoxy-phenyl) -trimethylammonium to the desired compound¹⁸F-labelled product (J.Labelled Compd.Radiophorm, 44, 2001: S857-S859).

VanBrocklin et al describe the preparation of (2-bromo-4-nitro-phenyl) -trimethylammonium trifluoromethanesulfonate¹⁸Label F (J.Label)led Compd.Radiopharm.，44；2001：S880-S882)。

Cetir Centre Medic reported the success of triflic acid (5-chloro-8-hydroxy-quinolin-7-yl) -trimethylammonium¹⁸F-tag (EP 1563852A 1).

These references contain two or more additional substituents¹⁸Most of the F-labelled aromatic derivatives cannot be coupled to chemical functional groups such as amine, thiol, carboxylic acid, phenol or other chemical groups of complex molecules such as peptides without further conversion.

Of more complex radiopharmaceuticals, e.g. peptides¹⁸F labeling was carried out in a two-step or multi-step strategy in all known publications (see scheme 2, review: Eur.J.Nucl.Med., (2001), 28: 929-.

For these types¹⁸A F-labeled, monosubstituted phenyltrimethylammonium derivative is also used, and is used in the first step with [ [2 ] ]¹⁸F]Potassium fluoride to obtain substituted alpha-alpha¹⁸F]-fluorobenzene derivatives. These compounds are then coupled in a second step to larger and more complex molecules (e.g. peptides) or nucleotides (see scheme 2).

Scheme 2

Especially 4-, [2 ]¹⁸F]Fluorobenzaldehyde has been used in many examples of F-18 labeling of complex molecules (e.g., Journal of Nuclear Medicine, (2004), 45 (5): 892-. Furthermore, N-succinimidyl-8- [ 4' -, [2 ]¹⁸F]Fluorobenzylamino]Suberic acid (Bioconjugate chem., (1991), 2: 44-49), 4-, [2 ]¹⁸F]Fluorobenzoylmethyl bromide and 3-, [2 ]¹⁸F]Fluoro-5-nitrobenzimidate (J.Nucl. Med., (1987), 28: 462-¹⁸F]Fluorobenzyl) -benzamide (jCompd.Radiopharm.，(1989)，26：287-289)、N-{4-[4-[¹⁸F]Fluorophenylene (aminooxy) -butyl } -maleimide (Bioconjugate chem., (2003), 14: 1253-¹⁸F]N- (4-fluorobenzyl) -2-bromoacetamide (Bioconjugate chem., (2000), 11: 627-¹⁸F]-3, 5-difluorophenyl azide (and 5 derivatives) (J.org.chem. (1995), 60: 6680-6681) are known examples. Via para-, [¹⁸F]F-18 labeling of peptides with fluorobenzates is also a very common method, either by the corresponding acid with an additional activator (e.g. 1, 3-dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole (DCC/HOAt) or N- [ (dimethylamino) -1H-1, 2, 3-triazolyl [4, 5 ] or]Pyridin-1-yl-methylene]-N-methyl-methylammonium hexafluorophosphate N-oxide (HATU/DIPEA, Eur.J.Nucl.Med.mol.imaging., (2002), 29: 754-¹⁸F]N-succinimidyl fluorobenzoate (Nucl. Med. biol., (1996), 23: 365).

As outlined above, the current state of the art provides trimethylammonium and nitro groups as the only leaving groups to provide¹⁸F-labelled compounds for indirect labelling of peptides via prosthetic groups (see above references), direct labelling of peptides and for small molecules (see EP 06090166), which have not been published at the time of the present application.

Further references:

WO 2004/080492A1, "Methods of radiofluorination of biological activators", was disclosed in 2004 at 9/23.

K.Bruus-Jensen，T.Poethko，M.Schottelius，A.Hauser，M.Schwaiger，H.J.Wester：“Chemoselective hydrazones formation betweenHYNIC-functionalized peptides and(18)F-fluorinated aldehydes.”Nucl MedBiol.，(2006)33(2)：173-83.

T.poethko, m.schottelius, g.thumbshirn, u.hersel, m.herz, g.henriksen, h.kessler, m.schwaiger, h.j.west: "Two-step method for high-yield route radiodiagnosis of peptides: (18) f-labelled RGD and extraceotide analogs. "J nuclear med., 2004 May, 45 (5): 892-902 and references therein.

Zhang X，Cai W，Cao F，Schreibmann E，Wu Y，Wu J.C，Xing L，Chen X.“¹⁸F-labelled bombesin analogs for targeting GRP receptor-expressing prostatecancer.”J Nucl.Med.(2006)，47(3)：492-501.

Z.Li，Y.S.Ding，A.Gifford，J.S.Fowler，J.S.Gatley.“Synthesis ofstructurally identical fluorine-18 and iodine isotope labeling compounds forcomparative imaging”Bioconjug Chem.，(2003)，14(2)：287-94.

For many of these diagnostic imaging compounds, harsh reaction conditions are experienced during radiolabelling, e.g., in nucleophilic aromatic reactions⁸The high temperatures often used in F-fluorination reactions are detrimental to their targeting activity. This is why in the prior art peptides are labeled via a two-step process, for example as outlined above. This two-step process is time consuming and requires multiple purification steps. The displacement of the trimethylammonium and/or nitro leaving groups is carried out at elevated temperatures, so that it is desirable to provide alternative leaving groups to achieve under mild conditions compatible with the chemical and biological stability of the targeting agent¹⁸And F is doped. Due to the fact that¹⁸The limited half-life of the F isotope of only about 111 minutes is to be able to provide with fewer steps¹⁸There is a high need for compounds and methods for F-radiolabeling compounds.

The problem addressed by the present invention is to provide compounds and processes which allow the use of halogens, more particularly halogens, in a one-step process¹⁸F, carrying out radioactive labeling on the compound.

Disclosure of Invention

A first aspect of the present invention relates to novel substituted benzene compounds of general formula a, wherein K ═ LG-O (general formula I), and to pharmaceutically acceptable salts, hydrates, esters, amides, solvates and prodrugs thereof. These compounds are precursors to the novel substituted benzene compounds of the second aspect of the invention.

A second aspect of the present invention relates to novel substituted benzene compounds of the general chemical formula a, wherein K ═ W (general chemical formula II), and to pharmaceutically acceptable salts, hydrates, esters, amides, solvates and prodrugs thereof.

By a one-step labelling reaction, more preferably with a fluorine isotope, more particularly¹⁸F, wherein a compound of formula a wherein K ═ LG-O (formula I) can be converted into a compound of formula a wherein K ═ W (formula II).

A third aspect of the invention relates to a one-step method of labelling, more preferably radiolabelling, a radiofluorinated compound of general formula a wherein K ═ LG-O to give a compound of general formula a wherein K ═ W.

The fourth aspect of the present invention relates to a composition, more preferably a diagnostic composition, comprising a compound of general formula a wherein K ═ LG-O, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant. According to this fourth aspect, the present invention also relates to a composition, more preferably a diagnostic composition, comprising a radiolabeled compound of general chemical formula a, wherein K ═ W, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

A fifth aspect of the present invention is directed to a method of imaging a disease comprising introducing into a patient a detectable amount of a labeled compound of formula a wherein K ═ W, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof.

A sixth aspect of the present invention relates to a kit for the preparation of a radiopharmaceutical formulation, which kit comprises a sealed vial containing a predetermined amount of a compound of formula a, wherein K ═ LG-O, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof.

A seventh aspect of the present invention relates to a compound of general formula a wherein K ═ LG-O or W, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, for use as a medicament, and, if K ═ W, as a diagnostic imaging agent, more specifically, as a PET imaging agent.

An eighth aspect of the present invention relates to the use of a compound of general chemical formula a, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, wherein K ═ LG-O or W, in the manufacture of a medicament, more particularly in the manufacture of a diagnostic imaging agent, and most particularly in the manufacture of a diagnostic imaging agent for imaging of tissue at a target site using such an imaging agent.

Further aspects of the invention relate to processes and intermediates for the synthesis of tumor imaging compounds having formula a, wherein K ═ LG-O or W, as described herein.

Detailed Description

As used hereinafter in the description of the invention and in the claims, the term "alkyl", by itself or as part of another group, refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. Alkyl groups may also be substituted, e.g. by halogen atoms, hydroxy groups, C₁-C₄Alkoxy or C₆-C₁₂Aryl (which may in turn be substituted, for example, by 1 to 3 halogen atoms). More preferably, alkyl is C₁-C₁₀Alkyl radical, C₁-C₆Alkyl or C₁-C₄An alkyl group.

As used hereinafter in the description of the invention and in the claims, the term "cycloalkyl group", by itself or as part of another group, means a monocyclic or bicyclic alkanyl radical having 3 to 20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. More preferably, cycloalkyl is C₃-C₁₀Cycloalkyl or C₅-C₈Cycloalkyl, most preferably C₆A cycloalkyl group.

As used hereinafter in the description of the invention and in the claims, the term "heterocycloalkyl", by itself or as part of another group, refers to a group having from 3 to 20 monocyclic or bicyclic atoms of a cycloalkyl group and containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms. More preferably, heterocycloalkyl is C₃-C₁₀Heterocycloalkyl radical, C₅-C₈Heterocycloalkyl or C₅-C₁₄Heterocycloalkyl, most preferably C₆A heterocycloalkyl group.

As used hereinafter in the description of the invention and in the claims, the term "aralkyl" refers to aryl-substituted alkyl groups such as benzyl, benzhydryl, trityl, phenethyl, phenylbutyl and diphenylethyl.

As used hereinafter in the description of the invention and in the claims, the term "aryloxy" refers to an aryl group having an oxygen and attached to the core through the oxygen, an example of which is phenoxy.

As used hereinafter in the description of the invention and in the claims, the terms "alkenyl" and "alkynyl" are defined similarly as for alkyl, but contain at least one carbon-carbon double or triple bond, respectively. More preferably C₂-C₆Alkenyl and C₂-C₆Alkynyl.

As used hereinafter in the description of the invention and in the claims, the term "lower unbranched or branched alkyl" shall have the following meaning: substituted or unsubstituted, straight or branched chain monovalent or divalent radicals consisting essentially of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, n-pentyl, 1-dimethylethyl (t-butyl), n-heptyl, and the like.

As used hereinafter in the description of the invention and in the claims, the term "aralkenyl" refers to an aromatic structure (aryl) attached to an alkenyl group as defined above.

As used hereinafter in the description of the invention and in the claims, the terms "alkoxy (or alkyloxy), aryloxy, and aralkyloxy" refer to alkyl, aryl, and aralkenyl groups, respectively, attached to an oxygen atom, wherein the alkyl, aryl, and aralkenyl moieties are as defined above.

As used hereinafter in the description of the invention and in the claims, the terms "inorganic acid" and "organic acid" refer to inorganic acids, including but not limited to: acids, for example carbonic acid, nitric acid, phosphoric acid, hydrochloric acid, perchloric acid or sulfuric acid or their acid salts such as potassium bisulfate, or suitable organic acids, including but not limited to: acids such as fatty acids, alicyclic acids, aromatic fatty acids, heterocyclic acids, carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, methanesulfonic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid (phanthothenic acid), toluenesulfonic acid, trifluoromethanesulfonic acid and sulfanilic acid.

As used hereinafter in the description of the invention and in the claims, the term "aryl", by itself or as part of another group, refers to a monocyclic or bicyclic aromatic group containing 6 to 12 carbon atoms in the ring portion, preferably 6-10 carbon atoms in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.

As used hereinafter in the description of the invention and in the claims, the term "heteroaryl", by itself or as part of another group, refers to a group having from 5 to 14 ring atoms; 6, 10 or 14 pi electrons shared in a ring array; and contains carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms. Examples of heteroaryl groups are: thienyl, benzo [ b ] thienyl, naphtho [2, 3-b ] thienyl, thianthrenyl, furyl, pyranyl, isobenzopyranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, 2, 3-naphthyridinyl, 1, 5-naphthyridinyl, quinazolinyl, 1, 2-naphthyridinyl, pteridinyl, 4 aH-carbazolyl, carbolinyl, phenanthridinyl, acridinyl, peridinaphthyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl (furazanyl), and phenoxazinyl.

Whenever the term "substituted" is used, it is intended to mean that on the atom indicated in the term where "substituted" is used, one or more hydrogens are replaced with a group selected from the indicated groups, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound whose stability is sufficient to undergo separation from the reaction mixture and formulation into a pharmaceutical composition in a useful degree of purity. The substituent is selected from halogen atom, hydroxyl, C₁-C₄Alkoxy or C₆-C₁₂Aryl (which may be further substituted, for example with 1 to 3 halogen atoms).

As used hereinafter in the description of the invention and in the claims, the term "fluorine isotope" (F) refers to all isotopes of the element fluorine atom. The fluorine isotope (F) is selected from radioactive isotopes or nonradioactive isotopes. Isotope of radioactive fluorine selected from¹⁸F. The non-radioactive "cold" fluorine isotopes are selected from¹⁹F。

As used hereinafter in the description of the invention and in the claims, the term "prodrug" refers to any covalently bound compound that releases the active parent drug of formula II.

As used throughout, the term "prodrug" refers to pharmaceutically acceptable derivatives, such as esters, amides and phosphates, such that the resulting in vivo bioconversion products of the derivative are the active drug as defined for the compound of formula (I). The literature of Goodman and Gilman (The pharmaceutical-local Basis of therapeutics, 8ed, McGraw-HiM, int. Ed.1992, "Biotransformation of Drugs", p 13-15) generally describes prodrugs, which are incorporated by reference. Prodrugs of the compounds of the present invention are prepared by modifying functional groups present in the compounds of the present invention in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs of compounds of the present invention include compounds wherein, for example, a hydroxy group (such as on an asymmetric carbon atom) or an amino group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxy or free amino group, respectively.

Typical examples of prodrugs are described in, for example, WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792, all of which are incorporated herein by reference.

Prodrugs are characterized by excellent aqueous solubility, increased bioavailability, and ease of metabolism to active inhibitors in vivo.

As used hereinafter in the description of the invention and in the claims, the term "amino acid sequence" is defined herein as a polyamide obtainable by (polycondensation) condensation of at least two amino acids.

As used hereinafter in the description of the invention and in the claims, the term "amino acid" refers to any molecule comprising at least one amino group and at least one carboxyl group, but which does not have a peptide bond within the molecule. In other words, an amino acid is a molecule that preferably has a carboxylic acid functionality in its alpha position and an amine nitrogen with at least one free hydrogen, but no amide bond in the molecular structure. Therefore, a dipeptide having a free amino group at the N-terminus and a free carboxyl group at the C-terminus is not considered to be an "amino acid" in the above definition. The amide bond between two adjacent amino acid residues, which results from such condensation, is defined as a "peptide bond". Optionally, the nitrogen atoms of the polyamide skeleton (shown above as NH) may be independently alkylated, for example with-C₁-C₆-alkyl, preferably-CH₃Alkylation is carried out.

An amide bond as used herein refers to any covalent bond having the structure:

wherein the carbonyl group is provided by one molecule and the NH-group is provided by another molecule to be attached. The amide bond between two adjacent amino acid residues, which results from such condensation, is defined as a "peptide bond". Optionally, the nitrogen atoms of the polyamide skeleton (shown above as NH) may be independently alkylated, for example with-C₁-C₆-alkyl, preferably-CH₃Alkylation is carried out.

As used hereinafter in the description of the invention and in the claims, an amino acid residue is derived from a corresponding amino acid by forming a peptide bond with another amino acid.

As used hereinafter in the description of the invention and in the claims, an amino acid sequence may include naturally occurring and/or synthetic amino acid residues, proteinaceous amino acid residues, and/or non-proteinaceous amino acid residues. Non-protein amino acid residues can be further classified as (a) homo-analogues of protein amino acids, (b) β -homo-analogues of protein amino acids, and (c) other non-protein amino acid residues.

Thus, the amino acid residues may be derived from the corresponding amino acids, for example from:

● protein amino acids, i.e., Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val; or

● non-protein amino acids, e.g.

Homo-analogues of protein amino acids, in which the side chains have been extended by methylene groups, such as homoalanine (Hal), homoarginine (Har), homocysteine (Hcy), homoglutamine (Hgl), homohistidine (Hhi), homoisoleucine (Hil), homoleucine (Hle), homolysine (Hly), homomethionine (Hme), homophenylalanine (Hph), homoproline (Hpr), homoserine (Hse), homothreonine (Hth), homotryptophan (Htr), homotyrosine (Hty) and homovaline (Hva);

o-homo-analogues of protein amino acids, in which a methylene group has been inserted between the alpha-carbon and the carboxyl group, resulting in a beta-amino acid, such as β -homoalanine (β Hal), β -homoarginine (β Har), β -homoasparagine (β Has), β -homocysteine (β Hcy), β -homoglutamine (β Hgl), β -homohistidine (β Hhi), β -homoisoleucine (β Hil), β -homoleucine (β Hle), β -homolysine (β Hly), β -homomethionine (β Hme), β -homophenylalanine (β Hph), β -homoproline (β Hpr), β -homoserine (β Hse), β -homothreonine (β Hth), β -homotryptophan (β Htr), β -homotyrosine (β Hty), and β -homovaline (β Hva);

other non-protein amino acids, such as alpha-aminoadipic acid (Aad), alpha 3-aminoadipic acid (beta Aad), alpha 0-aminobutyric acid (Abu), alpha 1-aminoisobutyric acid (Aib), beta-alanine (beta Ala), 4-aminobutyric acid (4-Abu), 5-aminopentanoic acid (5-Ava), 6-aminocaproic acid (6-Ahx), 8-aminocaprylic acid (8-Aoc), 9-aminononanoic acid (9-Anc), 10-aminodecanoic acid (10-Adc), 12-aminododecanoic acid (12-Ado), alpha-aminosuberic acid (Asu), mulanine (Aze), beta-cyclohexylalanine (Cha), citrulline (aitruliline, Cit), dehydroalanine (Dha), gamma-carboxyglutamic acid (Gla), Alpha-cyclohexylglycine (Chg), propargylglycine (Pra), pyroglutamic acid (Glp), alpha-tert-butylglycine (Tle), 4-benzoylphenylalanine (Bpa), alpha-2-hydroxylysine (Hyl), 4-hydroxyproline (Hyp), alloisoleucine (aIle), lanthionine (Lan), (1-naphthyl) alanine (1-Nal), (2-naphthyl) alanine (2-Nal), norleucine (Nle), norvaline (Nva), ornithine (Orn), phenylglycine (Phg), 2-pipecolic acid (Pip), sarcosine (Sar), selenocysteine (Sec), statine (Sta), β -thienylalanine (Thi), 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (Tic), visosine.Amino acid (aThr), thiazolidine-4-carboxylic acid (Thz), gamma-aminobutyric acid (GABA), isocysteine (iso-Cys), diaminopropionic acid (Dpr), 2, 4-diaminobutyric acid (Dab), 3, 4-diaminobutyric acid (gamma. beta. Dab), diphenylalanine (Bip), with-C₁-C₆Alkyl, -halogen, -NH₂、-CO₂H or Phe (4-R) (wherein R ═ C₁-C₆Alkyl, -halogen, -NH₂or-CO₂H) Phenylalanine substituted at the para position; peptide nucleic acids (PNA, see p.e. nielsen, acc.chem.res., 32, 624-30);

● or their N-alkylated analogs, such as their N-methylated analogs.

The cyclic amino acids may be proteinogenic or non-proteinogenic amino acids, such as Pro, Aze, Glp, Hyp, Pip, Tic and Thz.

For further examples and details, reference may be made to, for example, j.h.jones, j.peptide sci., 2003, 9, 1-8, which is incorporated herein by reference.

As used hereinafter in the description of the invention and in the claims, the terms "non-protein amino acid" and "non-protein amino acid residue" also include derivatives of protein amino acids. For example, the side chains of protein amino acid residues may be derivatized, thereby rendering the protein amino acid residues "non-proteinogenic". The same applies to C-terminal and/or N-terminal derivatives of the amino acid residues of the proteins of the termination amino acid sequence.

As used hereinafter in the description of the invention and in the claims, protein amino acid residues are derived from protein amino acids selected from the group consisting of: ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, or in L-configuration or D-configuration; the second chiral center in Thr and Ile can have either the R-configuration or the S-configuration. Thus, for example, any post-translational modification, e.g., N-alkylation, of a naturally occurring amino acid sequence renders the corresponding modified amino acid residue "non-proteinogenic", despite the fact that the amino acid residue is incorporated into a protein. Preferably, the modified amino acid is selected from the group consisting of N-alkylated amino acids, β -amino acids, γ -amino acids, lanthionines, dehydroamino acids, and amino acids having an alkylated guanidine moiety.

As used hereinafter in the description of the invention and in the claims, the term "peptidomimetics" refers to molecules that are related to peptides but have different properties. Peptoids are small protein-like chains designed to mimic peptides. They typically result from modification of an existing peptide to alter the properties of the molecule. For example, they may result from modifications that alter the stability or biological activity of the molecule. This may play a role in the development of pharmaceutical classes of compounds from existing peptides. These modifications include changes to the peptide that do not occur naturally.

As used hereinafter in the description of the invention and in the claims, the term "peptide analog" refers per se to a synthetic or natural compound that is structurally and/or functionally similar to a naturally occurring peptide.

As used hereinafter in the description of the invention and in the claims, the term "pharmaceutically acceptable salt" refers to inorganic and organic acid salts, such as inorganic acids, including but not limited to acids such as carbonic acid, nitric acid, or sulfuric acid, or organic acids, including but not limited to: acids such as fatty acids, alicyclic acids, aromatic fatty acids, heterocyclic acids, carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, methanesulfonic acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid (phanthothenic acid), toluenesulfonic acid, and sulfanilic acid.

If a chiral center or another form of an isomeric center is present in a compound of the present invention having the general chemical formula a, I, II, III or IV as given below, all forms of such isomers, including enantiomers and diastereomers, are intended to be included herein. Compounds containing chiral centers can be used as racemic mixtures or as enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques, and the individual enantiomers can be used individually. In the case where the compound has an unsaturated carbon-carbon double bond, both the cis isomer and the trans isomer are within the scope of the present invention. In cases where a compound may exist in tautomeric forms (e.g., keto-enol tautomers), each tautomeric form is contemplated as being included within the scope of the invention, whether existing in equilibrium or predominantly in one form.

As used hereinafter in the description of the invention and in the claims, the term "oligonucleotide" shall have the following meaning: shortNucleotide, its preparation and useSequences, typically of twenty or less bases. Examples are, but are not limited to, the book at Svenn Klussmann: the molecules named and referenced in "The aptamers handbook. functions and The pair application", Wiley-VCH, 2006. An example of such an oligonucleotide is TTA1(J.Nucl.Med., 2006, April, 47 (4): 668-78).

As used hereinafter in the description of the invention and in the claims, the term "aptamer" refers to an oligonucleotide comprising 4 to 100 nucleotides, wherein at least two mononucleotides are linked to each other via a phosphodiester bond. The Aptamers have the ability to specifically bind to a target molecule (see, e.g., MFamulok, G Mayer, "Aptamers as Tools in Molecular Biology and Immunology", in: "Combinatorial Chemistry in Biology, Current diagnostics in Microbiology and Immunology" (M Famulok, CH Wong, EL winnecker, Eds.), Springer Verlag Heidelberg, 1999, Vol.243, 123-jar 136). The skilled person knows many ways how to synthesize such aptamers specific for a certain target molecule. Examples are given in WO 01/09390a, the disclosure of which is hereby incorporated by reference. The aptamers may include substituted or unsubstituted natural and non-natural nucleotides. Aptamers can be synthesized in vitro using, for example, an automated synthesizer. The aptamer according to the present invention can be stabilized against nuclease degradation by substitution of a 2 ' -OH group for the 2 ' -fluoro substituent of the ribose backbone of a pyrimidine and for the 2 ' -O-methyl substituent of a purine nucleic acid. Furthermore, for exonuclease degradation, the 3 ' end of the aptamer may be protected by converting the 3 ' nucleotide to form a new 5 ' -OH group, where a 3 ' -3 ' linkage is formed with the penultimate base.

For the purposes of the present invention, the term "nucleotide" refers to a molecule that includes a nitrogenous base, a 5-carbon sugar, and one or more phosphate groups. Examples of such bases include, but are not limited to, adenine, guanine, cytosine, uracil, and thymine. Non-natural, substituted or unsubstituted bases may also be included. Examples of 5-carbon sugars include, but are not limited to, D-ribose and D-2-deoxyribose. Other natural and non-natural, substituted or unsubstituted 5-carbon sugars may also be included. The nucleotides used in the present invention may comprise one to three phosphates.

As used hereinafter in the description of the invention and in the claims, the term "halogen" refers to F, Cl, Br and I.

In a first aspect, the present invention relates to a compound of formula a, wherein K ═ LG-O (formula I):

wherein:

LG is a leaving group suitable for displacement by nucleophilic aromatic substitution reaction, K is LG-O, wherein-O participates in nucleophilic aromatic substitution and forms with LG a leaving entity known to the skilled person;

-Y¹、-Y²、-Y³、-Y⁴and-Y⁵One of which is a first substituent (-G) selected from the group consisting of-H, -F, -Cl, -Br, -I, -NO₂、-NR⁴COCF₃、-NR⁴SO₂CF₃、-N(CF₃)₂、-NHCSNHR⁴、-N(SO₂R⁵)₂、-N(O)＝NCONH₂、-NR⁴CN、-NHCSR⁵、-N≡C、-N＝C(CF₃)₂、-N＝NCF₃、-N＝NCN、-NR⁴COR⁴、-NR⁴COOR⁵、-OSO₂CF₃、-OSO₂C₆H₅、-OCOR⁵、-ONO₂、-OSO₂R⁵、-O-C＝CH₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-COOR⁴、-CONR⁴R⁵、-C(S)NH₂、-CH＝NOR⁴、-CH₂SO₂R⁴、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CCl₃、-CF₂CF₃、-C≡CR⁴、-CH＝NSO₂CF₃、-CH₂CF₃、-COR⁵、-CH＝NOR⁵、-CH₂CONH₂、-CSNHR⁵、-CH＝NNHCSNH₂、-CH＝NNHCONHNH₂、-C≡CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁴(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁴＝C(CN)₂-1-pyrrolyl, -C (CN) ═ C (CN)₂-C-pyridyl, -COC₆H₅、-COOC₆H₅、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SOR⁵、-S(OR⁵)、-SC≡CR⁴、-SO₂R⁵、-SSO₂R⁵、-SR⁵、-SSR⁴、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂C₆H₅、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃、-S(O)(＝NH)R⁵、-S-C＝CH₂、-SCOR⁵、-SOC₆H₅、-P(O)C₃F₇、-PO(OR⁵)₂、-PO(N(R⁵)₂)₂、-P(N(R⁵)₂)₂、-P(O)R⁵ ₂and-PO (OR)⁵)₂And an electron withdrawing group, wherein each substituent may be in ortho, para or meta position with respect to the K (LG-O) group;

for the purposes of the present invention, the term "electron-withdrawing group" or "electron-withdrawing group" refers to a chemical moiety (substituent) attached to the benzene ring which is capable of reducing the electron density of the benzene ring and which is listed in chem.Rev. (1991), 91, 165-195, Table 1 (and references therein), having σ_mOr σ_pA value of > 0;

-Y¹、-Y²、-Y³、-Y⁴and-Y⁵At least one of (a) is a further substituent (-Q), which is selected independently of one another from the group consisting of-H, -CN, -halogen, -CF₃、-NO₂、-COR⁵and-SO₂R⁵Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group;

wherein R is⁴Is hydrogen or straight or branched C₁-C₆Alkyl, more preferably hydrogen or straight or branched C₁-C₄Alkyl, and most preferably hydrogen or methyl;

R⁵is hydrogen or straight or branched C₁-C₆Alkyl, more preferably hydrogen or straight or branched C₁-C₄Alkyl and most preferably hydrogen or methyl;

wherein-Y¹、-Y²、-Y³、-Y⁴and-Y⁵is-A-B-D-P,

wherein

-A-B-D-is a bond or a spacer, and

p is a targeting agent.

The invention further relates to pharmaceutically acceptable salts or organic or inorganic acids, hydrates, esters, amides, solvates and prodrugs of the compounds of general formula a.

In a preferred embodiment, the targeting agent (P) is selected from a peptide, a peptidomimetic, a small molecule or an oligonucleotide.

Furthermore, the first substituent (-G) may also be selected from the group comprising-H and those members having a Hammett constant σ ≧ 0.35 (compare chem. Rev., 1991, 91: 165, Table 1) and containing fluorine or nitrogen atoms, i.e.: -F, -NO₂、-NR⁴SO₂CF₃、-N(CF₃)₂、-N(SO₂R⁵)₂、-N(O)＝NCONH₂、-N≡C、-N＝NCF₃、-N＝NCN、-NR⁴COR⁴、-OSO₂CF₃、-OCOR⁵、-ONO₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-CONR⁴R⁵、-CH＝NOR⁴、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CF₂CF₃、-CH＝NSO₂CF₃、-CH＝NNHCSNH₂、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁴(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁴＝C(CN)₂、-C(CN)＝C(CN)₂、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃、-S(O)(＝NH)R⁵and-P (O) C₃F₇Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group. R⁴、R⁵And R⁶As given above for use herein.

Even more preferably, the first substituent (-G) may be selected from the group comprising-H and those members of the previous embodiment having a Hammett constant σ ≧ 0.50 (compare chem. Rev., 1991, 91: 165, Table 1) and containing a fluorine atom, that is: -F, -NO₂、-NR⁴SO₂CF₃、-N(CF₃)₂、-N(O)＝NCONH₂、-N＝NCF₃、-N＝NCN、-OSO₂CF₃、-ONO₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CF₂CF₃、-CH＝NSO₂CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁴(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁴＝C(CN)₂、-C(CN)＝C(CN)₂、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃and-P (O) C₃F₇Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above for use herein.

Even more preferably, the first substituent(-G) is selected from the group consisting of-H, -F, -NO₂、-OCF₂CF₃-OCF₃、-C≡N、-COCF₃、-CF₃、-CF₂CF₃、-CF₂-CF₂-CF₃、-COCF₂CF₂CF₃、-SO₂CF₃、-SO₂CN、-SO₂CF₂CF₃、-SO₂N(R⁵)₂And SC (CF)₃)₃Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁵As given above for use herein.

In alternative embodiments, the first substituent (-G) may be selected from the group consisting of-H and those members having a Hammett constant σ ≧ 0.50 (compare chem. Rev., 1991, 91: 165, Table 1) and containing a sulfur or fluorine atom, those members being: -F, -NR⁴SO₂CF₃、-N(CF₃)₂、-N＝NCF₃、-OSO₂CF₃-OCF₂CF₃、-OCOCF₃、-OCF₃、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CF₂CF₃、-CH＝NSO₂CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-COCF₂CF₂CF₃、-C(CF₃)₃、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SO₂R⁵、-SCOCF₃、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃and-P (O) C₃F₇Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above inAs used herein.

Even more preferably, the first substituent (-G) may be selected from the group consisting of-H, -F, -NR⁴SO₂CF₃、-OSO₂CF₃-OCF₂CF₃、-OCF₃、-COCF₃、-CF₃、-SO₂CF₃、SO₂R⁵and-SO₂N(R⁵)₂Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above for use herein.

In alternative embodiments, the first substituent (-G) may be selected from the group consisting of-H, -F, -Cl, -Br, -NO₂、-OSO₂R⁵、-OCF₃、-C≡N、-COOR⁴、-CONR⁴R⁵、-COCF₃、-CF₂CF₃、-COR⁵、-CF₃、-C≡CF₃、-CF₂-CF₂-CF₃、-COC₆H₅、-SO₂CF₃、-SCOCF₃、-SO₂R⁵、-SO₂CF₂CF₃、-SO₂C₆H₅、-SO₂N(R⁵)₂and-PO (OR)⁵)₂Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above for use herein.

Even more preferably, the first substituent (-G) may be selected from the group consisting of-H, -F, -Cl, -Br, -NO₂、-NR⁴SO₂R⁵、-NR⁴COR⁴、-NR⁴COOR⁵、-C≡N、-CONR⁴R⁵、-C≡CR⁴、-COR⁵、-CF₃and-SO₂R⁵Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above for use herein.

Even more preferably, the first substituent (-G) may be selected from the group consisting of-H, -F, -Cl, -Br, -NO₂、-C≡N、-CF₃、-SO₂CF₃、-SO₂R⁵、-SO₂C₆H₅and-SO₂N(R⁵)₂Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and wherein R⁴And R⁵As given above for use herein.

Positive values of the hammett constant are a measure of electron deficiency. Certain combinations of substituents with specific atoms (nitrogen, sulfur and/or fluorine) appear to be more advantageous than others. For example, a nitrogen or fluorine substituent having a combination of positive Hammett constants allows¹⁸F radiolabelling has a relatively high radiochemical yield, whereas the sulphur or fluorine atom appears to ensure that the radiolabelling reaction has only a few side reactions. For example, it is known from The literature that The choice of substituents can influence The ratio of cyclofluorination to formation of methylfluoride in trimethylammonium benzene derivatives having a total of two substituents (review Coenen, "Fluorine-18 laboratory Methods: Features and challenges of Basic Reactions", (2006), in: P.A. Schuber, M.Friebe, L.Lehmann, (eds), PET-Chemistry-The Driving Force in Molecular imaging. Springer, Berlin Heidelberg, p.15-50, in particular p.23-26).

In a further embodiment of the present invention, any of the further substituents (-Q) may be selected independently of each other from the group consisting of-H, -CN, -F, -Cl, -Br and-NO₂Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

More preferably, any of the further substituents (-Q) may be selected independently of each other from the group consisting of-H, -CN, -F and-NO₂Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

Most preferably, any of the further substituents (-Q) may be selected independently of each other from-H, -CN or-F, wherein each substituent may be in ortho, para or meta position with respect to the K (LG-O) group.

In a further preferred embodiment of the invention, the first substituent-Y defined by G¹、-Y²、-Y³、-Y⁴and-Y⁵And said further substituent-Y defined by Q¹、-Y²、-Y³、-Y⁴and-Y⁵Can be selected independently of one another from the group consisting of-H, -CN, -F, -Cl and-CF₃、-NO₂、-COCH₃and-SO₂CH₃Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

More preferably, any one of the first substituents and the further substituent may be independently from each other selected from-H, -CN and-Cl, wherein each substituent may be in ortho, para or meta position with respect to the K (LG-O) group.

In a further embodiment of the invention, -Y¹Can be selected from-H, -F, -Cl, -Br, -I, -NO and-NO₂、-NR⁴COCF₃、-NR⁴SO₂CF₃、-N(CF₃)₂、-NHCSNHR⁵、-N(SO₂R⁶)₂、-N(O)＝NCONH₂、-NR⁵CN、-NHCSR⁶、-N≡C、-N＝C(CF₃)₂、-N＝NCF₃、-N＝NCN、-NR⁵COR⁵、-NR⁵COOR⁶、-OSO₂CF₃、-OSO₂C₆H₅、-OCOR⁶、-ONO₂、-OSO₂R⁶、-O-C＝CH₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-COOR⁵、-CONR⁵R⁶、-CSNH₂、-CH＝NOR⁵、-CH₂SO₂R⁵、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CCl₃、-CF₂CF₃、-C≡CR⁴、-CH＝NSO₂CF₃、-CH₂CF₃、-COR⁶、-CH＝NOR⁶、-CH₂CONH₂、-CSNHR⁶、-CH＝NNHCSNH₂、-CH＝NNHCONHNH₂、-C≡CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁵(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁵＝C(CN)₂-1-pyrrolyl, -C (CN) ═ C (CN)₂-C-pyridyl, -COC₆H₅、-COOC₆H₅、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SOR⁶、-S(OR⁶)、-SC≡CR⁵、-SO₂R⁶、-SSO₂R⁶、-SR⁶、-SSR⁶、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂C₆H₅、-SO₂N(R⁶)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)＝NCF₃、-S(O)＝NR⁶、-S-C＝CH₂、-SCOR⁶、-SOC₆H₅、-P(O)C₃F₇、-PO(R⁶)₂、-PO(N(R⁶)₂)₂、-P(N(R⁶)₂)₂、-P(O)(R⁶)₂、-PO(OR⁶)₂And electron-withdrawing groups, wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group, and

Y⁵can be selected from-CN, -Cl, -F, -Br, -CF₃、-NO₂、-COR⁵and-SO₂R⁵Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

Most preferably, -Y¹and-Y⁵Can be selected independently of one another-CN and-Cl, and more preferably, -Y¹and-Y⁵Only one of (a) may be-CN or-Cl, while the other group is-H. Thus, one or both of the substituents in the ortho position to-K on the phenyl ring is-CN or-Cl.

In a further embodiment of the present invention, the first substituent (-G) may be selected from the group consisting of-H, -F, -Cl, -Br, -I, -NO₂、-NR⁴COCF₃、-NR⁴SO₂CF₃、-N(CF₃)₂、-NHCSNHR⁴、-N(SO₂R⁵)₂、-N(O)＝NCONH₂、-NR⁴CN、-NHCSR⁵、-N≡C、-N＝C(CF₃)₂、-N＝NCF₃、-N＝NCN、-NR⁴COR⁴、-NR⁴COOR⁵、-OSO₂CF₃、-OSO₂C₆H₅、-OCOR⁵、-ONO₂、-OSO₂R⁵、-O-C＝CH₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-COOR⁴、-CONR⁴R⁵、-C(S)NH₂、-CH＝NOR⁴、-CH₂SO₂R⁴、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CCl₃、-CF₂CF₃、-C≡CR⁴、-CH＝NSO₂CF₃、-CH₂CF₃、-COR⁵、-CH＝NOR⁵、-CH₂CONH₂、-CSNHR⁵、-CH＝NNHCSNH₂、-CH＝NNHCONHNH₂、-C≡CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁴(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁴＝C(CN)₂-1-pyrrolyl, -C (CN) ═ C (CN)₂-C-pyridyl, -COC₆H₅、-COOC₆H₅、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SOR⁵、-S(OR⁵)、-SC≡CR⁴、-SO₂R⁵、-SSO₂R⁵、-SR⁵、-SSR⁴、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂C₆H₅、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃、-S(O)(＝NH)R⁵、-S-C＝CH₂、-SCOR⁵、-SOC₆H₅、-P(O)C₃F₇、-PO(OR⁵)₂、-PO(N(R⁵)₂)₂、-P(N(R⁵)₂)₂、-P(O)R⁵ ₂and-PO (OR)⁵)₂Wherein each substituent may be in ortho, para or meta position to the K (LG-O) group or another electron withdrawing group;

one of the further substituents (-Q) is selected from-H, -CN, halogen, -SO₂-R⁵and-NO₂Wherein R is⁵Is hydrogen or C₁-C₆A linear or branched alkyl group, wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group, and

other further substituents (-Q) are hydrogen,

so that

Wherein when-Y¹、-Y²、-Y³、-Y⁴and-Y⁵One is-a-B-D-P, RG-LG-O-and-B-Y-E-a-B-D-P.

In all of the above cases where a first substituent (-G) and a further substituent (-Q) are mentioned, at least one of them is not-H.

In a further embodiment of the invention, R⁴May be hydrogen or straight or branched C₁-C₄An alkyl group. Furthermore, R⁵May be hydrogen or straight or branched C₁-C₄An alkyl group.

In a further embodiment of the invention, G and Q may never be simultaneously-H.

In a preferred embodiment of the compounds of formula I, -G and-Q are each independently selected from the group consisting of-H, -CN, CF₃and-Cl.

In a more preferred embodiment, -G and-Q are independently of each other H, -CF₃Or CN.

In an even more preferred embodiment, -G and-Q are independently of each other H, -CF₃or-CN, and at least-G or-Q is-CF₃or-CN.

In a further preferred embodiment, -A-may preferably be selected from the group consisting of a bond, -CO-, -SO₂-、-(CH₂)_d-CO-、-SO-、-C≡C-CO-、-[CH₂]_m-E-[CH₂]_n-CO-、-[CH₂]_m-E-[CH₂]_n-SO₂-、-C(＝O)-O-、-NR¹⁰-、-O-、-(S)_p-、-C(＝O)NR¹²-、-NR¹²-、-C(＝S)NR¹²-、-C(＝S)O-、C₁-C₆Cycloalkyl, alkenyl, heterocycloalkyl, unsubstituted and substituted aryl, heteroaryl, aralkyl, heteroaralkyl, alkenyloxy, aryloxy, aralkyloxy, -SO₂NR¹³-、-NR¹³SO₂-、-NR¹³C(＝O)O-、-NR¹³C(＝O)NR¹²-, -NH-and-NH-O-,

wherein

d is an integer of 1 to 6,

m and n are independently any integer from 0 to 5;

-E-is a bond, -S-, -O-or-NR⁹-，

Wherein R is⁹Is H, C₁-C₁₀Alkyl, aryl, heteroaryl or aralkyl,

p is any integer from 1 to 3;

R¹⁰、R¹¹and R¹²Independently is H, C₁-C₁₀Alkyl, aryl, heteroaryl or aralkyl, and R¹³Is H, substituted or unsubstituted straight or branched C₁-C₆Alkyl, aryl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

More preferably, -A-may be selected from-CO-, -SO₂-and-C ≡ C-CO-.

Most preferably, -A-may be selected from-CO-and-SO₂-。

-B-may preferably be-NH-or-NR' -,

wherein R' is a branched, cyclic or straight chain C₁-C₆An alkyl group.

The C is₁-C₆Alkyl may preferably be CH₃Or C₂H₅。

-B-may preferably be-NH-or-NCH₃。

-D-may preferably be- (CH)₂)_p-CO-, wherein p is an integer from 1 to 10, or- (CH)₂-CH₂-O)_q-CH₂-CH₂-CO-, wherein q is an integer from 1 to 5.

Alternatively, the-B-D-moieties together may form a bond, which may be one amino acid residue, an amino acid sequence having two (2) to twenty (20) amino acid residues, or a non-amino acid group.

-B-D-may preferably be an amino acid sequence having two (2) to twenty (20) amino acid residues. More preferably, the amino acid sequence may comprise a natural or non-natural amino acid sequence or a mixture thereof.

Even more preferably, -B-D-may be Arg-Ser, Arg-Ava, Lys (Me)2- β -ala, Lys (Me)2-Ser, Arg- β -ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S-S-alkyl) or

Wherein k and l are independently selected in the range of 0 to 4.

Even more preferably, -B-D-may be a non-amino acid moiety selected from the group comprising:

-NH-(CH₂)_p-CO-, wherein p is an integer from 1 to 10,

-NH-(CH₂-CH₂-O)_q-CH₂-CH₂-CO-, wherein q is an integer from 1 to 5,

-NH-cycloalkyl-CO-, wherein cycloalkyl is selected from C₅-C₈Cycloalkyl, more preferably C₆An atomic cycloalkyl group, and

-NH-heterocycloalkyl- (CH)₂)_v-CO-, wherein the heterocycloalkyl group is chosen from C containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms, more preferably 1 to 2 heteroatoms, even more preferably 1 heteroatom₅-C₈Heterocycloalkyl, and v is an integer from 1 to 4, more preferably v is an integer from 1 to 2.

In a highly preferred embodiment of the invention, -Y¹、-Y²、-Y³、-Y⁴and-Y⁵Each of which may be, independently of the others, -H, -CN, -Cl, -F, -CF₃、-NO₂、-COCH₃or-SO₂CH₃H, CN and Cl are more preferred, and the most preferred isOptionally, Y₁And Y₅May be, independently of one another, CN or Cl, or Y₁Or Y₅May be CN or Cl, provided that-Y¹、-Y²、-Y³、-Y⁴and-Y⁵Only one residue of (a) is A-B-D-P, wherein

-A-is-CO-or-SO₂-, more preferably-CO-,

further, or:

-B-is-NH-or-NR '-, wherein R' is branched, cyclic or linear C₁To C₆Alkyl, more preferably CH₃Or C₂H₅Most preferably, B is NH or NCH₃，

-D-is- (CH)₂)_p-CO-, wherein p is an integer from 1 to 10, more preferably- (CH)₂)₄-CO-or-D-is- (CH)₂-CH₂-O)_q-CH₂-CH₂-CO-, wherein q is an integer from 1 to 5,

or:

-B-D-together are a bond or an amino acid residue or an amino acid sequence having two (2) to twenty (20) amino acid residues,

p is a targeting agent, and

LG is a leaving group suitable for displacement by nucleophilic aromatic substitution reactions.

P is a targeting agent.

For the purposes of the present invention, the term "targeting agent" shall have the following meaning: targeting agents are compounds or moieties that target or direct a radionuclide to which it is attached to a specific site in a biological system. The targeting agent can be any compound or chemical entity that binds to or accumulates at a target site in the mammalian body, i.e., the compound is localized to a greater extent at the target site than at the surrounding tissue.

The compounds of the invention are useful for imaging various cancers, including but not limited to: carcinomas such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, tumors of the hematological system of lymphoid and myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma (keratoxanthoma), thyroid cancer, small cell carcinoma and kaposi's sarcoma. Most preferably, the use is not only for imaging of tumors, but also for imaging of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or alzheimer's disease, or angiogenesis-related diseases, such as growth of solid tumors and rheumatoid arthritis.

Preferably, the targeting agent is a peptide, peptidomimetic or oligonucleotide, particularly one having specificity to target the complex to a specific site in a biological system. Small molecules that effectively target certain sites in a biological system may also be used as targeting agents.

Small molecules may be "small chemical entities. As used in this application, the term "small chemical entity" shall have the following meaning: small chemical entities are compounds with a molecular weight of from 150 to 700, more preferably from 200 to 700, more preferably from 250 to 700, even more preferably from 300 to 700, even more preferably from 350 to 700 and most preferably from 400 to 700. Small chemical entities as used herein may further contain at least one aromatic or heteroaromatic ring and may also have primary or secondary amines, attached thiol or hydroxyl groups, via which the benzene ring structures in compounds of general chemical formulas I and II are attached via-a-B-D-. Such targeting moieties are known in the art, as are methods for their preparation.

The small molecule targeting agent may preferably be selected from the following references: jager, m.a.korte, m.n.lub-de Hooge, a.van Waarde, k.p.koopmans, p.j.perik and e.g.e.devries, Cancer Imaging, (2005)5, 27-32; w.d.heiss and k.herholz, j.nuclear.med., (2006)47(2), 302-; and those described in t.higuchi and m.schwaiger, curr.cardiol.rep., (2006)8(2), 131-. More specific examples of small molecule targeting agents are listed below:

name (R)	Abbreviations	Target
			18F-2 b-carbomethoxy-3 b- (4-fluorophenyl) tropane	CFT	DAT (dopamine transporter)
18F-fluoroethylpiperidinone	FESP	D2 (dopamine 2 receptor), 5-HT2(5-Hydroxytryptamine receptor)
			18F-Fallypride		D2 (dopamine 2 receptor)
18F-astatanserin		5-HT2A receptor
			18F-Cyclofoxy		Opioid receptors
18F-CPFPX		Adenosine a1 receptor
			Batimastat		MMP
Fatty acids and analogs
			Choline analogs (metabolism)
Flumazenil		Benzodiazepine receptors
			Raclepride		D2 receptor
Dihydrotestosterone and analogs		AR
			Tamoxifen and analogues
Deoxyglucose
			Thymidine		Proliferation marker thymidine kinase
DOPA
			Benzazepine		D1Antagonists
N-methyl spiro piperidones and derivatives thereof		Dopamine receptors
			Benzamide benzodiazepine; benzamide derivatives, such as fallopride, iodobenzamide; chloro-azapine and quetiapine		D2Receptors
Nomifensin, substituted analogues of cocaine, e.g. tropane-type derivatives of cocaine, methylpiperidine acetate		DAT
			2 beta-carboxymethoxy-3 beta- (4-iodophenyl) tropane	CIT	DAT
	CIT-FE、CIT-FM	DAT
			Altanserin, sertindole, and ketosertraline		5-HT2A
	McN5652, 403U76 derivatives ADAM, DASP, MADAM	5-HTT
			Acetylcholine analogues	MP3A、MP4A、PMP；QNB、TKB、NMPB，	Acetylcholine receptors
Scopolamine and benztropine		Acetylcholine receptors
			Flumazenil		GABA receptors
	RO-15-4513、FDG	GABA receptors
				PK-11195	Benzodiazepine receptors
Xanthine analogs	CPFPX、MPDX	Adenosine receptors
			Carphenatanib, diprenorphine		Opioid receptors

Further various small molecule targeting agents and their targets are given in table 1 in w.d.heiss and k.herholz, supra, and in fig. 1 in t.higuchi, m.schwaiger, supra.

Further preferred biomolecules are sugars, oligosaccharides, polysaccharides, amino acids, nucleic acids, nucleotides, nucleosides, oligonucleotides, proteins, peptides, peptidomimetics, antibodies, aptamers, lipids, hormones (steroid and non-steroid), neurotransmitters, drugs (synthetic or natural), receptor agonists and antagonists, dendrimers, fullerenes, viral particles and other targeting molecules/biomolecules (e.g. cancer targeting molecules).

P may be a peptide comprising 4 to 100 amino acids, wherein the amino acids may be selected from natural and unnatural amino acids, and may further comprise modified natural and unnatural amino acids.

Examples of peptides as targeting agents (P) are, but not limited to, somatostatin and derivatives and phases thereofPeptide, somatostatin receptor-specific peptide, neuropeptide Y, derivative thereof, and related peptide, neuropeptide Y₁And analogs thereof, bombesin and derivatives and related peptides thereof, gastrin-releasing peptide and derivatives and related peptides thereof, epidermal growth factor (EGF of various origins), Insulin Growth Factor (IGF) and IGF-1, integrin (alpha)₃β₁、α_vβ₃、α_vβ₅、αIIb₃) LHRH agonists and antagonists, transforming growth factors, especially TGF-alpha; angiotensin peptides; cholecystokinin receptor peptides, cholecystokinin (CCK) and analogs thereof; neurotensin and analogs thereof, thyrotropin-releasing hormone, pituitary adenylate cyclase-activating peptide (PACAP) and related peptides, chemokines, substrates and inhibitors of cell surface matrix metalloproteinases, prolactin and analogs thereof, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, Vasoactive Intestinal Peptide (VIP) and related peptides.

More preferably, the targeting agent (P) may be selected from bombesin, somatostatin, neuropeptide Y₁And Vasoactive Intestinal Peptide (VIP). Even more preferably, the targeting agent (P) may comprise bombesin, somatostatin, neuropeptide Y₁And the like. Even more preferably, the targeting agent (P) may be bombesin and derivatives as well as related peptides and analogues thereof.

Bombesin is a fourteen amino acid peptide that is an analog of human gastrin-releasing peptide (GRP) that binds with high specificity to human GRP receptors present in prostate tumors, breast tumors, and metastases. In a more preferred embodiment, the bombesin analog has the following sequence having formula III:

AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-AA₈-NT₁T₂(form A) formula III, wherein:

T₁＝T₂h or T₁＝H，T₂OH or T₁＝CH₃，T₂＝OH

AA₁＝Gln、Asn、Phe(4-CO-NH₂)

AA₂＝Trp、D-Trp

AA₃＝Ala、Ser、Val

AA₄＝Val、Ser、Thr

AA₅＝Gly、(N-Me)Gly

AA₆＝His、His(3-Me)、(N-Me)His、(N-Me)His(3-Me)

AA₇Sta, pepstatin analogs and isomers, 4-Am, 5-MeHpA, 4-Am, 5-MeHxA, gamma-substituted amino acids

AA₈Leu, Cpa, Cba, CpnA, Cha, t-buty, tBuAla, Met, Nle, iso-Bu-Gly.

In a more preferred embodiment, the bombesin analog has the following sequence of formula IV:

AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-AA₈-NT₁T₂(form B) formula IV wherein:

T₁＝T₂h or T₁＝H，T₂OH or T₁＝CH₃，T₂＝OH

AA₁Gln, Asn or Phe (4-CO-NH)₂)

AA₂＝Trp、D-Trp

AA₃＝Ala、Ser、Val

AA₄＝Val、Ser.Thr

AA₅＝βAla、β²-and β³Amino acids, as shown below

Where SC represents the side chain found in protein amino acids and homologs of protein amino acids,

AA₆＝His、His(3-Me)、(N-Me)His、(N-Me)His(3-Me)

AA₇＝Phe、Tha、Nal，

AA₈leu, Cpa, Cba, CpnA, Cha, t-buty, tBuAla, Met, Nle, iso-Bu-Gly.

Thus, in an even more preferred embodiment of the invention, the targeting agent (P) may be selected from the group comprising bombesin analogues having sequence III or IV.

In a more preferred embodiment, the bombesin analog has the following sequence:

●Seq ID P

●Seq ID 1 Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂

●Seq ID 2 Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH₂

●Seq ID 3 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH₂

●Seq ID 4 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH₂

●Seq ID 7 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

●Seq ID 8 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 12 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 17 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 23 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Cpa-NH₂

●Seq ID 27 Gln-Trp-Ala-Val-NMeGly-His-EA02010-Cpa-NH₂

●Seq ID 28 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuGly-NH₂

●Seq ID 30 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-tBuGly-NH₂

●Seq ID 32 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 33 Gln-DTrp-Ala-Val-Gly-His-4-Am，5-MeHpA-tbuGly-NH₂

●Seq ID 34 Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂

●Seq ID 35 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

●Seq ID 36 Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂

●Seq ID 42 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Cpa-NH₂

●Seq ID 43 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-tBuGly-NH₂

●Seq ID 46 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 48 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Cpa-NH₂

●Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 50 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 51 Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂

●Seq ID 52 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-Cpa-NH₂

●Seq ID 53 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Cpa-NH₂

●Seq ID 54 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Leu-NH₂

●Seq ID 55 Gln-Trp-Ala-Val-βAla-DHis-Phe-Leu-NH₂

●Seq ID 56 Gln-Trp-Ala-Val-βAla-His-βhLeu-Leu-NH₂

●Seq ID 57 Gln-Trp-Ala-Val-βAla-His-βhIle-Leu-NH₂

●Seq ID 58 Gln-Trp-Ala-Val-βAla-His-βhLeu-tbuGly-NH₂

●Seq ID 59 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Tha-NH₂

●Seq ID 60 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Nle-NH₂

●Seq ID 61 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-tbuGly-NH₂

●Seq ID 62 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-tbuGly-NH₂

●Seq ID 63 Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-tbuGly-NH₂

●Seq ID 64 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Cpa-NH₂

●Seq ID 65 Gln-Trp-Ala-NMeVal-βAla-His-Phe-Leu-NH₂

●Seq ID 66 Gln-Trp-Ala-Val-βAla-His-NMePhe-Leu-NH₂

●Seq ID 67 Gln-DTrp-Ala-Val-βAla-His-Phe-Leu-NH₂

●Seq ID 68 Gln-Trp-DAla-Val-βAla-His-Phe-Leu-NH₂

●Seq ID 69 Gln-Trp-Ala-DVal-βAla-His-Phe-Leu-NH₂

●Seq ID 70 Gln-Trp-Ala-Val-βAla-His-DPhe-Leu-NH₂

●Seq ID 71 Gln-Trp-Ala-Val-βAla-His-βhIle-tbuGly-NH₂

●Seq ID 72 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-Cpa-NH₂

●Seq ID 73 Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂

●Seq ID 74 Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂

●Seq ID 75 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuAla-NH₂

●Seq ID 77 Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH₂

●Seq ID 82 Gln-Trp-Ala-Val-Gly-His(3Me)-FA4-Am，5-MeHpA-Leu-NH₂

●Seq ID 90 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

●Seq ID 91 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

● Seq ID 101 Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am-5-MeHpA-4-amino-5-methylheptanoic acid-Leu-NH₂

● Seq ID 102 Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am-5-MeHpA-4-amino-5-methylheptanoic acid-Cpa-NH₂

Thus, the invention also relates to bombesin analogs that specifically bind to human GRP receptors present in prostate, breast and metastatic foci. In a preferred embodiment, the bombesin analogue is a peptide having a sequence from Seq ID 1 to Seq ID 102 and preferably has one of them. More preferably, the bombesin analogue is additionally labelled with a fluorine isotope (F), wherein the fluorine isotope (F) is selected from¹⁸F or¹⁹F. More preferably, the bombesin analogues are used¹⁸F, performing radioactive labeling. Bombesin analogs are preferably radiolabeled using the radiofluorination methods of the present invention.

In a more preferred embodiment, the somatostatin analog has the following sequence:

●Seq ID 104----c[Lys-(NMe)Phe-1Nal-D-Trp-Lys-Thr]

●Seq ID 105----c[Dpr-Met-(NMe)Phe-Tyr-D-Trp-Lys]

in a more preferred embodiment, neuropeptide Y₁The analogs have the following sequence:

●Seq ID 106-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH₂

●Seq ID 107-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH₂

(__ denotes a disulfide bridge)

In a more preferred embodiment, the peptide is a tetrapeptide having the sequence:

valyl-beta-alanyl-phenylalanyl-glycinamide

Valyl-beta-alanyl-histidyl (pi-Me) -glycinamide

In a further preferred embodiment of the invention, the targeting agent P may comprise a combination of any of the aforementioned biomolecules suitable for binding to the target site together with a reactive moiety acting as the biologically active molecule and the compound of the invention (formula I, formula,II. III), wherein the reactive moiety is selected from the group consisting of-NR⁴、-NR⁴-(CH₂)_n-、-O-(CH₂)_n-or-S- (CH)₂)_n-, wherein R⁴Is hydrogen or alkyl, and n is an integer from 1 to 6, and wherein suitable bioactive molecules are selected from peptides, peptidomimetics, oligonucleotides or small molecules.

In a preferred embodiment, P is NR⁷-peptide, or- (CH)₂)_n-peptide, -O- (CH)₂)_n-peptide or-S- (CH)₂)_n-peptide, NR⁷-small molecule, or- (CH)₂)_n-small molecule, -O- (CH)₂)_n-small molecule or-S- (CH)₂)_n-small molecule, NR⁷-oligonucleotide, or- (CH)₂)_n-oligonucleotide, -O- (CH)₂)_n-oligonucleotide or-S- (CH)₂)_n-an oligonucleotide, wherein n is an integer from 1 to 6.

In a more preferred embodiment, P is-NR⁴-peptide, - (CH)₂)_n-peptides, wherein n is an integer from 1 to 6.

In another preferred embodiment, P is-NR⁴-oligonucleotide or- (CH)₂)_n-an oligonucleotide, wherein n is an integer from 1 to 6.

In another preferred embodiment, P is-NR⁴-small molecule or- (CH)₂)_n-small molecules, wherein n is an integer from 1 to 6.

In a preferred embodiment, the precursor for the one-step radiolabelling method (formula I) may be the following precursor bombesin analogue:

in a preferred embodiment, the precursor (formula I) is one of the following precursor peptide analogs:

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide,

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-histidyl (π -Me) -glycinamide,

● 3-cyano-4- ([1, 2, 3] triazolo [4, 5-b ] pyridin-3-yloxy) -benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide,

● 4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide,

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

● 4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -FA4-Am, 5-MeHpA-Leu-NH₂，

● 3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoic acid methyl esteracyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 3-chloro-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

● 3-chloro-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂。

In a further preferred embodiment, the targeting agent (P) may be selected from oligonucleotides comprising 4 to 100 nucleotides.

A preferred oligonucleotide is TTA1 (see Experimental section).

In a preferred embodiment, the precursor (formula I) is one of the following precursors with small molecules:

3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -N- (thymidyl-propyl) -benzamide:

3-cyano-4- (benzotriazol-1-yloxy) -N- (thymidyl-propyl) -benzamide:

in a preferred embodiment of the compounds of formula I, the leaving group LG is selected from

Wherein the content of the first and second substances,

t is H or Cl,

q is a group selected from the group consisting of CH and N,

k is absent or C ═ O.

In a more preferred embodiment, LG is selected from

The compounds of formula I are used as precursors for compounds of formula II wherein the leaving group LG-O is replaced by a fluorine isotope in a labelling reaction, more preferably by¹⁸F or¹⁹F. Even more preferably by¹⁸And F replacing.

In a second aspect, the present invention relates to a compound of formula II,

wherein the residue and the substituent-Y¹、-Y²、-Y³、-Y⁴and-Y⁵Have the same meaning as described above for the compounds of the general chemical formula I. In particular, this includes the above for the residue and substituent-Y¹、-Y²、-Y³、-Y⁴and-Y⁵All preferred embodiments mentioned under-A-, -B-, -D-and-P, and to pharmaceutically acceptable salts, hydrates, esters, amides, solvates and prodrugs of inorganic or organic acids thereof.

W is a fluorine isotope (F) selected from radioactive or non-radioactive fluorine isotopes. Isotope of radioactive fluorine selected from¹⁸F. The non-radioactive "cold" fluorine isotopes are selected from¹⁹F。

If W is preferably¹⁸F, then use¹⁸F the inventive compounds of formula II, which are radiolabeled, have the following formula IIA:

most preferably, when W ═ is¹⁹F, then the compound of formula II has formula IIB:

in a preferred embodiment of the compounds of formula II, -Y¹、-Y²、-Y³、-Y⁴and-Y⁵Independently of one another, from the group consisting of-H, -CN and-Cl.

In a more preferred embodiment, -Y¹、-Y²、-Y³、-Y⁴and-Y⁵Independently of one another, CN or Cl.

In a preferred embodiment, the use of¹⁸F or¹⁹The F-labelled compound of formula II is selected from the following list, wherein the targeting agent (P) is selected from the group consisting of peptides, peptidomimetics, smaller organic molecules or oligonucleotides and all preferred forms disclosed above.

More preferably, the targeting agent (P) of the compound of formula II is a bombesin analogue:

●IIA-a-1 4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIA-a-2 4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (Me) -Sta-Leu-NH₂，

●IIA-a-3 4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-4 4-[18]Fluoro-3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-5 4-[18]fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-6 4-[18]fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-7 4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

●IIA-a-8 4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -FA4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a-9 4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-10 4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-11 4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-12 4-[18]fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a-13 4-[18]fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a-14 4-[18]fluoro-3-cyano-benzoyl-Lys (Me)2-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a--15 4-[18]fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-16 4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a-17 4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am, 5-MeHpA-Leu-NH₂，

●IIA-a-18 4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-LeuNH₂，

●IIA-a-19 4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-20 4-[18]Fluoro-3-trifluoromethyl-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-21 4-[18]fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIA-a-22 4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-23 4-[18]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-24 4-[18]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-25 4-[18]-fluoro-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-26 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a-27 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-FA 02010-Cpa-NH₂，

●IIB-a-28 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

●IIB-a-29 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-30 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-tBuGly-NH₂，

●IIB-a-31 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-32 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-33 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

●IIB-a-34 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂，

●IIB-a-35 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

●IIB-a-36 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂，

●IIB-a-37 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a-38 3，4-[18]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-39 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-40 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-41 3，4-[18]-difluorobenzoyl-Arg-beta Ala-Arg-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-42 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Cpa-NH₂，

●IIB-a-43 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-tBuGly-NH₂，

●IIB-a-44 3，4-[18]-difluorobenzoyl-Arg-Arg-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-45 3，4-[18]-difluorobenzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-46 3，4-[18]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-47 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-48 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-49 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-49 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-50 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-51 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂，

●IIB-a-52 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-Cpa-NH₂，

●IIB-a-53 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Cpa-NH₂，

●IIB-a-54 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Leu-NH₂，

●IIB-a-55 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-DHis-Phe-Leu-NH₂，

●IIB-a-56 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-Leu-NH₂，

●IIB-a-57 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-Leu-NH₂，

●IIB-a-58 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-tbuGly-NH₂，

●IIB-a-59 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Tha-NH₂，

●IIB-a-60 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Nle-NH₂，

●IIB-a-61 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-tbuGly-NH₂，

●IIB-a-62 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-tbuGly-NH₂，

●IIB-a-63 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Tha-tbuGly-NH₂，

●IIB-a-64 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Cpa-NH₂，

●IIB-a-65 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-NMeVal-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-66 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-NMePhe-Leu-NH₂，

●IIB-a-67 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-68 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-DAla-Val-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-69 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-DVal-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-70 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-DPhe-Leu-NH₂，

●IIB-a-71 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-tbuGly-NH₂，

●IIB-a-72 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-73 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂，

●IIB-a-74 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂，

●IIB-a-75 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuAla-NH₂，

●4-[18]Fluoro-3-cyano-benzoyl- (piperidinyl-4-carbonyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●4-[18]Fluoro-3-cyano-benzoyl- (piperazin-1-yl-acetyl) -Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH₂，

●4-[18]Fluoro-3-cyano-benzoyl-1, 4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a-1 4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a--2 4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-His (Me) -Sta-Leu-NH₂，

●IIB-a-3 4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-4 4-[19]-fluoro-3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-5 4-[19]-fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-6 4-[19]-fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-7 4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

●IIB-a-8 4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-9 4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-10 4-[19]-fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-11 4-[19]-fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-12 4-[19]-fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-13 4-[19]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-14 4-[19]-fluoro-3-cyano-benzoyl-Lys (Me)2-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-15 4-[19]-fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-16 4-[19]-fluoro-3-cyano-benzoyl-Lys (Me)2- β Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-17 4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-18 4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-19 4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-20 4-[19]-fluoro-3-trifluoromethyl-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-21 4-[19]-fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-22 4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-23 4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am，5-MeHpA-Cpa-NH₂，

●IIB-a-24 4-[19]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-25 4-[19]-fluoro-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-26 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a-27 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-FA 02010-Cpa-NH₂，

●IIB-a-28 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

●IIB-a-29 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-30 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-tBuGly-NH₂，

●IIB-a-31 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-32 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-33 3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

●IIB-a-34 3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂，

●IIB-a-35 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

●IIB-a-36 3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂，

●IIB-a-37 3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

●IIB-a-38 3，4-[19]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-39 3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-40 3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-41 3，4-[19]-difluorobenzoyl-Arg-beta Ala-Arg-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-42 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Cpa-NH₂，

●IIB-a-43 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-tBuGly-NH₂，

●IIB-a-44 3，4-[19]-difluorobenzoyl-Arg-Arg-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-45 3，4-[19]-difluorobenzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

●IIB-a-46 3，4-[19]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-47 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-48 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-49 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NmeHis-4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-49 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-50 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NmeHis-4-Am, 5-MeHpA-Leu-NH₂，

●IIB-a-51 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂，

●IIB-a-52 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-Cpa-NH₂，

●IIB-a-53 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Cpa-NH₂，

●IIB-a-54 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Leu-NH₂，

●IIB-a-55 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-DHis-Phe-Leu-NH₂，

●IIB-a-56 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-Leu-NH₂，

●IIB-a-57 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-Leu-NH₂，

●IIB-a-58 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-tbuGly-NH₂，

●IIB-a-59 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Tha-NH₂，

●IIB-a-60 3，4-[19]-difluorobenzoyl group-Ava-Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Nle-NH₂，

●IIB-a-61 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-tbuGly-NH₂，

●IIB-a-62 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-tbuGly-NH₂，

●IIB-a-63 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Tha-tbuGly-NH₂，

●IIB-a-64 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Cpa-NH₂，

●IIB-a-65 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-NMeVal-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-66 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-NMePhe-Leu-NH₂，

●IIB-a-67 3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-68 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-DAla-Val-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-69 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-DVal-beta Ala-His-Phe-Leu-NH₂，

●IIB-a-70 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-DPhe-Leu-NH₂，

●IIB-a-71 3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-tbuGly-NH₂，

●IIB-a-72 4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-Cpa-NH₂，

●IIB-a-73 4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂，

●IIB-a-74 4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂，

●IIB-a-75 4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuAla-NH₂，

●4-[19]Fluoro-3-cyano-benzoyl- (piperidinyl-4-carbonyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●4-[19]Fluoro-3-cyano-benzoyl- (piperazin-1-yl-acetyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

●4-[19]Fluoro-3-cyano-benzoyl-1, 4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

In a preferred embodiment, the use of¹⁸F or¹⁹The F-labelled radiopharmaceutical is selected from the following list, wherein the targeting agent (P) is a somatostatin analogue:

● IIA-a-76: 4- [18] fluoro-3-cyano-benzoyl-Ava- ε -c [ Lys- (NMe) Phe-1Nal-D-Trp-Lys-Thr ]

● IIA-a-77: 4- [18] fluoro-3-cyano-benzoyl-Ava- β -c [ Dpr-Met- (NMe) Phe-Tyr-D-Trp-Lys ]

● IIB-a-76: 4- [19] fluoro-3-cyano-benzoyl-Ava- ε -c [ Lys- (NMe) Phe-1Nal-D-Trp-Lys-Thr ]

● IIB-a-77: 4- [19] fluoro-3-cyano-benzoyl-Ava- β -c [ Dpr-Met- (NMe) Phe-Tyr-D-Trp-Lys ]

In a preferred embodiment, the use of¹⁸F or¹⁹The F-labelled radiopharmaceutical is selected from the list wherein the targeting agent (P) is neuropeptide Y₁The analogues:

●IIA-a-78：4-[18]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH₂

●IIA-a-79：4-[18]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH₂

●IIA-a-78：4-[19]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH₂

●IIA-a-79：4-[19]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH₂

In a preferred embodiment, the use of¹⁸F or¹⁹The F-labelled radiopharmaceutical is selected from the following list, wherein the targeting agent (P) is a tetrapeptide:

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-phenylalanyl-glycinamide [2 ]¹⁹F]，

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-phenylalanyl-glycinamide [2 ]¹⁸F]，

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-histidyl (pi-Me) -glycinamide [2 ], [ solution of N, N-acetyl-L-alanine ]¹⁹F]，

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-histidyl (pi-Me) -glycinamide [2 ], [ solution of N, N-acetyl-L-alanine ]¹⁸F]，

3-cyano-4-fluoro-benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide [2 ], [ solution of (I)¹⁹F]，

3-cyano-4-fluoro-benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide [2 ], [ solution of (I)¹⁸F]。

In a preferred embodiment, the use of¹⁸F or¹⁹The F-labelled radiopharmaceutical is selected from the following list, wherein the targeting agent (P) is a small molecule:

3-cyano-4- [ F-19] fluoro-N- (thymidylyl-propyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-propyl) -benzamide;

3-cyano-4- [ F-19] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide;

3-cyano-4- [ F-19] fluoro-N- (thymidyl-hexyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-hexyl) -benzamide;

3-cyano-4- [19F ] fluoro-N- (thymidyl-butyl) benzamide,

3-cyano-4- [18F ] fluoro-N- (thymidyl-butyl) benzamide;

wherein F is¹⁸F or¹⁹F，

3-cyano-4-fluoro-N- (trifluoromethylthymidylyl-hexyl) benzamide,

3-cyano-4-fluoro-N- (trifluoromethyl-thymidylyl-hexyl) benzamide;

wherein F is¹⁸F or¹⁹F，

3-cyano-4-fluoro [ F-18] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide;

3-cyano-4-fluoro [ F-19] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide;

3-CN，4-F-Bz-Ava-Gln-Trp-Ala-Val-Gly-His-FA01010-Leu-NH2，

4F，3CN-Bnz-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2，

3-CF3, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2,

3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH2,

3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2, wherein F is¹⁸F or¹⁹F。

In a third aspect, the present invention relates to a process for the preparation of a compound of formula II using a suitable fluorinating agent (fluorination process). Said method comprising a (single) step of coupling a compound of general formula I with a fluorine isotope, more preferably with a radioactive or non-radioactive ("cold") fluorine isotope derivative, even more preferably, respectively with¹⁸F or¹⁹F is coupled, and most preferably with¹⁸F coupling (radiofluorination). In the latter case, the reagent that converts the compound of formula I to the compound of formula II is a fluorinating agent. More preferably, the compound of formula II may then be converted into its pharmaceutically acceptable inorganic or organic acid salts, hydrates, complexes, esters, amides, solvates and prodrugs thereof, if desired. Reagents, solvents and conditions useful for such fluorination are common and well known to those of ordinary skill in the art. See, e.g., j. fluorine chem., 27 (1985): 117-191.

In a preferred embodiment of the process, the compound of formula I and pharmaceutically acceptable inorganic or organic acid salts thereof, hydrates, complexes, esters, amides, solvates and prodrugs thereof are any of the preferred compounds described above for obtaining any of the preferred compounds of formula II, more particularly any of the preferred compounds of formula IIA and IIB, or pharmaceutically acceptable salts, hydrates, esters, amides, solvates or prodrugs thereof, as described above.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature of 90 ℃ or below 90 ℃.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature selected from the range of 10 ℃ to 90 ℃.

In a preferred embodiment, the fluorination process, more preferably the radiofluorination process, is carried out at a reaction temperature from room temperature to 80 ℃.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature selected from the range of 10 ℃ to 70 ℃.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature selected from the range of 30 ℃ to 60 ℃.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature selected from the range 45 ℃ to 55 ℃.

In a preferred process for the preparation of the compound of formula II, the fluorination step, more preferably the radiofluorination step, of the compound of formula I is carried out at a temperature of 50 ℃.

More preferably, the radioactive fluorine isotope derivative is 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Hexacosane K18F (crown ether salt Kryptofix K18F), K¹⁸F、H¹⁸F、KH¹⁸F₂、Cs¹⁸F、Na¹⁸F or¹⁸Tetraalkylammonium salts of F (e.g. [ F-18]]Tetrabutylammonium fluoride). Most preferably, the radioactive fluorine isotope derivative is K¹⁸F、H¹⁸F. Or KH¹⁸F₂。

In a preferred embodiment, the fluorinating agent is a non-radioactive isotope of fluorine. More preferably, the nonradioactive fluorine isotope is¹⁹F derivatives, most preferably¹⁹F。

In a preferred embodiment, the solvent used in the present method may be DMF, DMSO, MeCN, DMA, DMAA, or a mixture thereof, preferably the solvent is DMSO.

A new process has proven to be feasible, in which the end product is prepared in one step from the precursor. Only one purification step is required, so that the preparation can be carried out in a short time (taking into account that¹⁸Half-life of F) is completed. In a typical prosthetic group preparation, very common temperatures of 100 ℃ and higher are used. The invention provides a method for achieving said preparation at a temperature (80 ℃ or below) that preserves the biological properties of the final product. Furthermore, a single purification step is optionally carried out, whereby the preparation can be carried out in a short time (in view of the fact that¹⁸Half-life of F) is completed.

In a tenth aspect, the present invention relates to a compound having the general chemical formula V:

wherein N is⁺(R¹)(R²)(R³)、X^--G, and-Q, have the same meanings as described above for the compound of formula I. This includes in particular the above for the residue and the substituent R¹、R²、R³、X^--G, and-Q and all residues such as R used to define such residues and substituents⁴、R⁵Etc. all of the preferred embodiments mentioned.

R⁶Is C (O) OH.

In a preferred embodiment of the compounds of formula V, -G and-Q are independently of each other selected from the group consisting of-H, -CN, CF₃and-Cl.

In a more preferred embodiment of the compound of formula V, -G and-Q are independently of each other H, -CF₃Or CN.

In an even more preferred embodiment of the compound of formula V, -G and-Q are independently of each other H, -CF₃or-CN, and at least one member of the group comprising-G or-Q is-CF₃or-CN.

Preferred compounds of formula VI are selected from the group comprising

Trifluoro-methanesulfonic acid (4-carboxy-

2-cyano-phenyl) -trimethyl-ammonium; 2-trifluoromethyl-phenyl) -trimethyl-ammonium;

the compound of formula V is suitably coupled to a targeting agent to give a compound of formula I, which is the starting material for the radiolabelling reaction to give a compound of formula I or formula a.

In an eleventh aspect, the present invention relates to a process for the synthesis of a compound of formula I (formula A) wherein K is LG-O from a compound of formula V. The process for obtaining a compound of formula I comprises the step of reacting a compound of formula V with a targeting agent selected from a peptide, peptidomimetic, smaller organic molecule or oligonucleotide, a condensing agent selected from DCC, DIC, HBTU, HATU or TNTU and a nucleophile selected from HOBt, HOAt, HOSu or N-hydroxy-5-norbornene-2, 3-dicarboximide or LG-OH (LG as defined above).

The condensing agent used for the purpose of the present invention is a chemical substance capable of reacting with a carboxylic acid and an amine to give the corresponding carboxylic acid amide, and a hydrate of the condensing agent is formed as a byproduct. The term condensing agent refers to Coupling agents, which are commonly used in Peptide chemistry, for the formation of Peptide bonds, and which are well known to those of ordinary skill in the art (Fmoc Solid Phase Peptide Synthesis A reactive approach, U.S. Pat. No. W.C. and P.D. white, Oxford University Press 2000; Peptide Coupling Reagents: Names, Acronyms and References, Technical Reports, Vol.4, No.1, Albany molecular research, Inc., 1999). Examples of condensing agents are DCC, DIC, HBTU, HATU, TNTU and other examples mentioned in the publications cited above.

Nucleophiles for the purposes of the present invention are a group of atoms capable of forming a chemical bond with its reaction partner by donating two bonding electrons. More precisely, in this context, nucleophiles are N-hydroxy derivatives or anions thereof, which are capable of replacing the aromatic trimethylammonium group during a typical Peptide bond formation reaction (Fmoc solid phase Peptide Synthesis A reactive approach, W.C. Chan and P.D. white, Oxford university Press 2000; Peptide Coupling Reagents: Names, Acronyms and references, Technical Reports, Vol.4, No.1, Albany Molecular Research, Inc., 1999). Representative examples of such nucleophiles are the activating additives HOBt, HOAt, HOSu or N-hydroxy-5-norbornene-2, 3-dicarboximides commonly used in peptide synthesis.

The compound of formula V may be condensed to a targeting agent with or without a spacer using typical condensing agents known to those of ordinary skill in the art to obtain a compound of formula I (formula a) as defined above. Suitable condensing agents are, for example, DCC, DIC and 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylpiperidine tetrafluoroborate (J.Am.chem.Soc.2005, 127, 48, 169912-169920). Examples of such reactions are described in schemes 3 and 4.

Labeling example:

azeotropic drying by heating at 110 ℃ and 120 ℃ for 20-30 minutes under a stream of nitrogen in the presence of Kryptofix 222(5mg in 1.5ml MeCN) and cesium carbonate (2.3mg in 0.5ml water)¹⁸F-fluoride (up to 40 GBq). During this time, 3X 1ml of MeCN was added and evaporated. After drying, a solution of the precursor (2mg) in 150. mu.l DMSO was added. The reaction vessel was sealed and heated at 50-70 ℃ for 5-15 minutes to effect labeling. The reaction was cooled to room temperature and diluted with water (2.7 ml). The crude reaction mixture was analyzed using analytical HPLC. The product was obtained by preparative radio-HPLC to give the desired¹⁸F labeling the peptide.

In a fourth aspect, the present invention relates to a composition comprising a compound of general formula I or II, more specifically formula IIA or IIB, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, and further comprising a pharmaceutically acceptable carrier, diluent, excipient or adjuvant. Pharmaceutically acceptable carriers, diluents, excipients or adjuvants may include any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic agents, enzyme inhibitors, delivery ligands such as glucoheptonate, tartrate, citrate or mannitol and the like. Such compositions may be formulated as sterile, pyrogen-free, parenterally acceptable aqueous solutions, which may optionally be supplied in lyophilized form. The compositions of the present invention may be provided as a component of a kit, which may include buffers, additional vials, instructions for use, and the like.

In a fifth aspect, the present invention relates to a method of imaging a disease comprising introducing into a patient a detectable amount of a labeled compound of formula II, more specifically formula IIA, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof.

In a sixth aspect, the present invention relates to a kit comprising a sealed vial containing a predetermined amount of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, and optionally a pharmaceutically acceptable carrier, diluent, excipient or adjuvant. More preferably, the present invention relates to a kit comprising a compound or composition as defined above in powder form, and a container containing a suitable solvent for preparing a solution of said compound or composition for administration to a mammal, including a human.

In a seventh aspect, the present invention relates to a compound of general formula I or II, more particularly formula IIA or IIB, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, for use as a medicament or as a diagnostic imaging agent, more preferably as a Positron Emission Tomography (PET) imaging agent.

In an eighth aspect, the present invention relates to the use of a compound of general formula I or II, more specifically formula IIA or IIB, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, in the manufacture of a medicament or in the manufacture of a diagnostic imaging agent. In a more preferred embodiment, the use relates to a medicament or diagnostic imaging agent for therapy or Positron Emission Tomography (PET), respectively. In an even more preferred embodiment, the use is for imaging tissue at a target site via the targeting agent.

The compounds of the invention are useful for imaging various cancers including, but not limited to: carcinomas such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, tumors of the hematological system of lymphoid and myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid pouch cancer and kaposi's sarcoma.

Most preferably, the use is not only for imaging of tumors, but also for imaging of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or alzheimer's disease, or angiogenesis-related diseases, such as growth of solid tumors and rheumatoid arthritis.

More specifically, as long as the compound of formula a includes bombesin or bombesin analogs, the compound specifically binds to human GRP receptors present in prostate tumors, breast tumors, and metastases.

Furthermore, compounds of the general formula II, where W is¹⁹F or other non-radioactive ("cold") halogen elements, useful in bioassays and chromatographic identification. More preferably, the present invention relates to the use of a compound of formula I for the preparation of a compound of formula IIB as a dosing agent.

The compounds of the present invention having the general chemical formulas I and II and their respective pharmaceutically acceptable salts, hydrates, esters, amides, solvates or prodrugs can be chemically synthesized in vitro. Where P is selected as a peptide, such peptides can generally be advantageously prepared on a peptide synthesizer. Preferably, especially when B-D is a sequence of amino acids and P is a peptide and the two together form a fusion peptide, the fusion peptide may be sequentially synthesized, i.e. comprising an amino groupThe parts of the sequences B-D and the targeting agent P can be obtained by sequential addition of suitable activated and protected amino acid derivatives or preformed amino acid sequences to the growing amino acid chain. For details on peptide synthesis, reference may be made, for example, to b. Synthesis, Structures, and Applications ", Academic Press, 1995; chan et al "Fmoc solid phase Peptide Synthesis: a Practical Approach ", Oxford University Press, 2000; jones "amino Acid and Peptide Synthesis", 2^nded., Oxford University Press, 2002; m. Bodanszky et al, "Principles of Peptide Synthesis", 2^nd ed.，Springer，1993。

The radiolabeled compound of formula II provided herein may be administered intravenously as a pharmaceutical composition for intravenous injection in any pharmaceutically acceptable carrier (e.g., conventional media such as saline media) or in plasma media. Such media may also contain conventional pharmaceutical materials such as pharmaceutically acceptable salts for regulating osmotic pressure, buffers, preservatives and the like. Physiological saline and plasma are preferred media. Suitable pharmaceutically acceptable carriers are known to those of ordinary skill in the art. In this regard, reference is made to, for example, Remington's Practice of Pharmacy, 11^thed. and J.of.pharmaceutical Science&Technology, Vol.52, No.5, Sept-Oct, pp.238-311, see Table, pp.240-311, both publications being incorporated herein by reference.

The concentration of the compound of formula II and the pharmaceutically acceptable carrier, for example in an aqueous medium, varies with the particular field of application. When satisfactory visualization of the imaging target (e.g., tumor) is available, a sufficient amount is present in the pharmaceutically acceptable carrier.

According to the invention, the radiolabeled compound of formula II, or as a neutral composition or salt with a pharmaceutically acceptable counter ion, is administered in a single unit injectable dose. Any common carrier known to those of ordinary skill in the art, such as sterile saline or plasma, can be used after radiolabelling to prepare injection solutions for diagnostic imaging of various organs, tumors, etc. according to the invention. Generally, for diagnostic agents, the unit dose administered has a radioactivity of about 0.1mCi to about 100mCi, preferably 1mCi to 20 mCi. For radiotherapeutic agents, the therapeutic unit dose has a radioactivity of about 10 to 700mCi, preferably 50 to 400 mCi. The solution injected in a unit dose is about 0.01ml to about 30 ml. For diagnostic purposes after intravenous administration, in vivo imaging of organs or tumors can occur in a matter of minutes. Preferably imaging occurs between two minutes and two hours after injection into the patient. In most cases, a sufficient amount of the administered dose will accumulate in the imaging region within about 0.1 hour to allow for scintigraphic imaging. Any conventional scintigraphic method for diagnostic purposes may be utilized in accordance with the present invention.

In general, the fluorine isotope can be used, and more preferably, the fluorine isotope is used¹⁸F or¹⁹F. And is optimally selected and used¹⁸F labels the compound of formula I and produces the compound of formula II from the compound of formula I. The methods and conditions for such labeling reactions are well known to the skilled worker (F.W ust, C.Hultsch, R.Bergmann, B.Johannsen and T.Henle.apple.apple.radial.Isot., 59, 43-48 (2003); Y.S.Ding, C.Y.Shiue, J.S.Fowler, A.P.Wolf and A.J.Plenevaux, Fluorine Chem., 48, 189-205 (1990).

Scheme 3 illustrates a general synthetic route for the production of compounds of formula I and followed by e.g. the use of¹⁸F or¹⁹F radiolabelling the compound to give a compound of general formula II. Scheme 3 describes the formation of the O-benzotriazolyl substituted aromatic moiety, Compound 1, attached to a peptide, which is understood to be a general representation of the compounds of formula I, and the subsequent direct radiolabelling, respectively, of the corresponding¹⁸F-or¹⁹F-labelled Compound 2, which represents a compound of formula II. Compound 1 containing an O-benzotriazolyl moiety through 1-hydroxybenzeneThe benzotriazole mediated coupling of trimethylammonium benzoate, compound 3, to the resin bound protective peptide was prepared with concomitant replacement of the trimethylammonium with O-benzotriazole. Cleavage from resin was performed according to methods well known in Peptide chemistry (w.c. chan and p.d. white (Editors) "Fmoc solvent Phase Peptide Synthesis", Oxford University Press (2000), and references therein) to yield compound 1. The oxabenzotriazole moiety may be substituted under standard conditions¹⁸F or¹⁹F substitution (F.W ust, C.Hultsch, R.Bergmann, B.Johannsen and T.Henle.appl.Radiat.Isot., 59, 43-48 (2003); Y.S.Ding, C.Y.Shiue, J.S.Fowler, A.P.Wolf and A.J.Plenevaux, FluorineChem., 48, 189-¹⁹F) And (4) substitution. In general, the method is suitable for the production of all compounds of the general chemical formula I and for the subsequent radiolabelling of such compounds to give compounds of the general chemical formula II.

Scheme 3

Scheme 4 describes an alternative method for producing compounds of general formula I. According to this method, 4-oxobenzotriazolylbenzoic acid, Compound 6, can be prepared separately and later attached to the end of the resin bound B-D-P. Compound 1, which is understood to be a general representation of any compound of the general chemical formula I, is obtained by cleavage from a resin according to methods well known in peptide chemistry. In general, the method is suitable for the production of all compounds of the general formula I.

Scheme 4

The invention also relates to two other independent processes for the preparation of compounds of general formula I. These methods are illustrated in schemes 5 and 6. Likewise, these methods are suitable for the production of all compounds of the general formula I.

Intermediate 6 may also be prepared from the corresponding boronic acid 7 by Copper-promoted substitution according to the methods described, for example, in p.y.s.lam, g.charles, c.g.clark, s.saubern, j.adams, m.kristin, k.m.averill, m.t.chan, a.combs. "Copper protein der/structured Heterocyclic C-N Bond Cross-Coupling with Arylboronic acid and aryl" synlette, 5, 674 (2000).

Scheme 5

Compound 6 is converted to compound 1, which is understood to be a general representation of any compound of the general formula I, as shown in scheme 4.

Compound 1, which is understood to be a general representation of any compound of general formula I, can also be prepared in solid phase, as shown in scheme 6.

Scheme 6

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative of the remainder of the disclosure and not limitative of the remainder of the disclosure in any way whatsoever. The following examples may be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Example (b):

dependent on the fraction LG-O- (C)₆Y¹Y²Y³Y⁴) - (-) the compounds of the invention of the general chemical formula I can be synthesized. The peptide portion of-A-B-D-P can be conveniently prepared according to generally established techniques known in the art of peptide synthesis, such as solid phase peptide synthesis. They are amenable to Fmoc-solid phase peptide synthesis, employing alternating protection and deprotection. These methods are well discussed in the peptide literature. (reference: "Fmoc Solid Phase Peptide Synthesis A reactive approach", W.C. Chan and P.D. white, Oxford University Press 2000) (for abbreviations, see Descriptions).

Summary of the invention

Peptide synthesis was performed according to standard strategies (G.B.fields, R.L.noble, "Solid phase peptide synthesis 9-fluoromethylenecarbonyl amino acids", int.J.Pept. protein Res., 1990; 35: 161-214) using Rink amide resin (0,68 mmol/g). All amino acid residues are L-amino acid residues, if not indicated otherwise.

Fmoc-deprotection (general procedure)

The resin bound Fmoc peptide was treated with 20% piperidine (v/v) in DMF for 5min and a second 20 min. With DMF (2X), CH₂Cl₂The resin was washed (2 ×) and DMF (2 ×).

HBTU/HOBT coupling (general method)

A solution of Fmoc-Xaa-OH (4 equiv.), HBTU (4 equiv.), HOBT (4 equiv.), DIEA (4 equiv.) in DMF was added to the resin bound free amine peptide and shaken for 90 minutes at room temperature. Repeating the processCoupling for 60min with DMF (2X), CH₂Cl₂The resin was washed (2 ×) and DMF (2 ×).

Radiolabelling (general methods)

Via a¹⁸O(p，n)¹⁸(ii) a nuclear reaction of F [ alpha ], [ alpha ]¹⁸O]H₂Irradiation of O to produce a carrier-free added aqueous [ alpha ], [¹⁸F]Fluoride ions. The water content [2 ] is carried out by filtration through QMA SepPak¹⁸F]Resolubilization of fluoride (500-1500MBq) with 5ml 0.5M K for QMA SepPak₂CO₃Pretreatment, washing with 5ml of water and drying by air-displacement. Make 100. mu.l¹⁸F was passed through SepPak and dried by air-flushing. Will be provided with¹⁸F eluted into a column containing 4ml Kryptofix/MeCN/K₂CO₃Erlenmeyer flask for water/water mixture. The resulting solution (50-500MBq) was at 120 ℃ in N₂The stream was azeotropically dried four times. To contain anhydrous [ alpha ], [ alpha ]¹⁸F]The vial of fluoride was charged with the fluorinated precursor (1-4mg) in DMSO (300-500. mu.l). After incubation at 50-70 ℃ for 15-60min, analytical HPLC (Column Zorbax SB C18, 50X 4.6mm, 1.8. mu.l, 2ml/min, solvent A: H) was used₂O, solvent B: MeCN, gradient: 5% -95% B, 7min, or Column Econosphere C18, 53X 7mm, 3 μ, 3ml/min (Alltech), solvent A: h₂O + 0.1% TFA, solvent B: MeCN/H₂O9/1+ 0.1% TFA, gradient: 5-95% B, 7min), the crude reaction mixture was analyzed.

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl-beta-alanyl-phenylalanyl-glycyl Synthesis and labeling of amines (1a, example 1, see scheme 3):

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide was synthesized by binding the tetrapeptide and (4-carboxy-2-cyano-phenyl) -trimethylammonium triflate through the corresponding resin, followed by cleavage and deprotection, as shown below.

In the presence of K₂CO₃And KryptofixIn the case of the DMSO solution of (2), the solution of (2)¹⁸F]Potassium fluoride fluorinates the peptide to produce¹⁸F-labeled peptide.

Resin-bound tetrapeptides were prepared according to the general procedure described above. A solution of trifluoromethanesulfonic acid (4-carboxy-2-cyano-phenyl) -trimethylammonium (4 equiv.), HBTU (4 equiv.), HOBT (4 equiv.), and DIPEA (4 equiv.) in DMF was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 4 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (1a) (5-95% acetonitrile/12 min) was analyzed by RP-HPLC: t is t_r6.72min, and ESI-MS: 654.2(M + H) M/z⁺.

Labeling was performed according to the general method described above. On an Econsphere analytical HPLC, by using a non-radioactive F-19 fluorine standard¹⁹F]Confirmation of F-18 labeled product (,) by coinjection¹⁸F]-2a)。

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-phenylalanyl-glycinamide (F-19 fluoro standard) Article [2 ] ¹⁹ F]Synthesis of (a)

According to the general procedure described above, resin-bound tetrapeptides (H-valyl-. beta. -alanyl-phenylalanyl)aminoacyl-glycyl-Rink amide resin). A solution of 3-cyano-4-fluoro-benzoic acid (4 eq), HBTU (4 eq), HOBT (4 eq) and DIPEA (4 eq) in DMF was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 4 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (¹⁹F]-2a) (5-95% acetonitrile/12 min): t is t_r6.03min, and ESI-MS: 539.1(M + H)⁺.

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl-beta-alanyl-histidyl (pi-Me) -glycyl Synthesis and labeling of aminoamides (1b, example 2, see scheme 3):

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-histidyl (π -Me) -glycinamide was synthesized by binding the tetrapeptide with trifluoromethanesulfonic acid (4-carboxy-2-cyano-phenyl) -trimethylammonium followed by cleavage and deprotection via the corresponding resin as shown below.

In the presence of K₂CO₃And KryptofixIn the case of the DMSO solution of (2), the solution of (2)¹⁸F]Potassium fluoride fluorinates the peptide to produce¹⁸F-labeled peptide.

Resin-bound tetrapeptides were prepared according to the general procedure described above. Trifluoromethanesulfonic acid (4-carboxy-2-cyano-phenyl) -trimethylammonium (4 equiv.), HBTU (4 equiv.), HOBT (4 equiv.), and DIPEA (4 equiv.) in DMFThe solution of (a) was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 12 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (1b) (5-95% acetonitrile/12 min) was analyzed by RP-HPLC: t is t_r5.22min, and ESI-MS: m/z 658.1(M + H)⁺.

Labeling was performed according to the general method described above. On an Econsphere analytical HPLC, by using a non-radioactive F-19 fluorine standard (, etc.)¹⁹F]-2b) coinjection to confirm the F-18 labeled product ([ 2 ]¹⁸F]-2b)。

3-cyano-4-fluoro-benzoyl-valyl-beta-alanyl-histidyl (pi-Me) -glycinamide (F-19 fluoro-standard) Quasi [2 ] ¹⁹ F]-synthesis of 2 b):

resin-bound tetrapeptides (H-valyl-. beta. -alanyl-histidyl (π -Me) -glycyl-Rink amide resins) were prepared according to the general procedure described above. A solution of 3-cyano-4-fluoro-benzoic acid (4 eq), HBTU (4 eq), HOBT (4 eq) and DIPEA (4 eq) in DMF was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 4 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (¹⁹F]-2b) (5-95% acetonitrile/12 min): t is t_r4.45min, and ESI-MS: m/z 543.1(M + H)⁺.

3-cyano-4- ([1, 2, 3)]Triazolo [4, 5-b]Pyridin-3-yloxy) -benzoyl- (5-aminopentanoyl) -phenylpropyl Aminoacyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide (10, example 3, see scheme 3) Synthesis and labeling of (2):

synthesis of 3-cyano-4- ([1, 2, 3] by binding tetrapeptide and (4-carboxy-2-cyano-phenyl) -trimethylammonium triflate via the corresponding resin, followed by cleavage and deprotection, as shown below]Triazolo [4, 5-b]Pyridin-3-yloxy) -benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide. In the presence of K₂CO₃And KryptofixIn the case of the DMSO solution of (2), the solution of (2)¹⁸F]Potassium fluoride fluorinates the peptide to produce¹⁸F-labeled peptide.

Resin-bound tetrapeptides were prepared according to the general procedure described above. A solution of trifluoromethanesulfonic acid (4-carboxy-2-cyano-phenyl) -trimethylammonium (4 equiv.), HBTU (4 equiv.), HOBT (4 equiv.), and DIPEA (4 equiv.) in DMF was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 12 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (10) (5-95% acetonitrile/12 min) was analyzed by RP-HPLC: t is t_r6.33min, and ESI-MS: m/z 797.4(M + H)⁺.

Labeling was performed according to the general method described above. On an Econsphere analytical HPLC, by using a non-radioactive F-19 fluorine standard (, etc.)¹⁹F]-2c) coinjection to confirm the F-18 labeled product ([ 2 ])¹⁸F]-2c)。

3-cyano-4-fluoro-benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) Heptayl-leucinamide (F-19 fluoro standard substance [, ] ¹⁹ F]-synthesis of 2 c):

a resin-bound tetrapeptide (H- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucyl-Rink amide resin) was prepared according to the general method described above. A solution of 3-cyano-4-fluoro-benzoic acid (4 eq), HBTU (4 eq), HOBT (4 eq) and DIPEA (4 eq) in DMF was added to the resin bound free amine tetrapeptide and shaken at ambient temperature for 4 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (¹⁹F]-2c) (5-95% acetonitrile/12 min): t is t_r6.35min, and ESI-MS: m/z 681.1(M + H)⁺.

Synthesis of 4- (benzotriazol-1-yloxy) -3-cyano-benzoic acid methyl ester (11, example 4, see scheme 4) The composition is as follows:

methyl 4- (benzotriazol-1-yloxy) -3-cyano-benzoate was synthesized from trifluoromethanesulfonic acid (2-cyano-4-methoxycarbonyl-phenyl) -trimethylammonium as follows.

Methyl 3-cyano-4- (trimethylammonium) trifluoromethanesulfonate, HOBT and DIPEA were dissolved in DMF and stirred for 8 h. The solvent was removed and the residue was purified by RP-HPLC. The purified product (11) (5-95% acetonitrile/12 min) was analyzed by RP-HPLC)：t_r8.62min, and ESI-MS: m/z 295.0(M + H)⁺.

4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-valyl-beta-alanyl-phenylalanyl-glycinamide (12, example 5, see scheme 6):

4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide was synthesized by binding the tetrapeptide and 2-chloro-4-carboxy-phenylboronic acid via the corresponding resin followed by copper mediated displacement of the boronic acid moiety with HOBT, followed by cleavage, as shown below.

Resin-bound tetrapeptides were prepared according to the general procedure described above. The boronic acid derivative (4 eq) was dissolved in DMF along with HBTU (4 eq), HOBT (4 eq) and DIPEA (4 eq). The solution was shaken with the resin-bound tetrapeptide for 4 h. Then, with DMF (4X) and CH₂Cl₂(4X) washing the resin. The resin was then reacted with HOBT (4 equiv.), copper (II) acetate (6 equiv.) and triethylamine (8 equiv.) in CH₂Cl₂Solution of (1) and (4)The molecular sieves were shaken together at ambient temperature for 48 h. During the reaction, the solution was exposed to air. Then, with DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. Cleavage of the product from the resin was performed by treatment with TFA/water (80: 20 v-%) for 2 h. The peptide was precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product (12) (5-95% acetonitrile/12 min) was analyzed by RP-HPLC: t is t_r5.79min and ESI-MS: m/z 663.2(M + H)⁺.

Synthesis of 5- [ 3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoylamino ] - (5-aminopentanoyl) -octapeptide amide (13, example 6, see scheme 3):

synthesis of 5- [ 3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoylamino-s-a-mine from the corresponding resin bound tetrapeptide and (4-carboxy-2-cyano-phenyl) -trimethylammonium triflate as shown below]- (5-aminopentanoyl) -octapeptide amide, followed by cleavage and deprotection. In the presence of K₂CO₃And KryptofixIn the case of the DMSO solution of (2), the solution of (2)¹⁹F]Potassium fluoride fluorinates the peptide to produce¹⁹F-labeled peptide.

Resin-bound tetrapeptides were prepared according to the general procedure described above. A solution of trifluoromethanesulfonic acid (4-carboxy-2-cyano-phenyl) -trimethylammonium (4 equiv.), diisopropylcarbodiimide (DIC, 4 equiv.), N-hydroxysuccinimide (NHS, 4 equiv.) and DIPEA (4 equiv.) in DMF was added to the resin bound free amine nonapeptide and shaken at ambient temperature for 12 h. With DMF (4X) and CH₂Cl₂(4X) the resin was washed and dried in vacuo. The peptide was cleaved from the resin by treatment with a mixture of TFA, water, phenol and triisopropylsilane (85: 5 v-%). The peptide was then precipitated with methyl-tert-butyl ether, the solvent was removed by centrifugation, and the crude product was purified by RP-HPLC. The purified product was confirmed by RP-HPLC and ESI-MS (13). According to the above method, the composition can be used in the form of a composition¹⁹F]Potassium fluoride compound 13 is fluorinated. The fluorination product [2 ], [ solution ] can be confirmed by HPLC-MS of the crude reaction mixture¹⁹F]-2d。

For the following step LG is selected from

Wherein T is H or Cl, Q is CH or N, K is absent or C ═ O, having the general chemical formula I.

Step of substituting trimethylamino group by N-hydroxy-type Leaving Group (LGOH):

r ═ H or alkyl

3-cyano-4- (trimethylamino) benzoic acid or its corresponding alkyl ester is dissolved in DMF, DMSO, acetonitrile, DMPU or any solvent suitable for nucleophilic aromatic substitution reactions. To this solution is added a leaving group of the N-hydroxy type as defined above. A base such as a tertiary amine (triethylamine, DIPEA), potassium carbonate, or sodium hydroxide or similar bases may be added. The solution is then stirred at room temperature, elevated temperature or under microwave conditions. After removal of the solvent and purification of the crude product by reverse phase chromatography or normal phase chromatography, the product is obtained.

Replacement of the boronic acid group by a leaving group of the N-hydroxy type (LGOH):

r ═ H or alkyl

X＝Cl，CN，NO₂Or SO₂CH₃

Dissolving substituted 4-carboxyphenylboronic acids or their corresponding alkylcarboxylates in CH₂Cl₂DMF, DMSO, acetonitrile, DMPU or mixtures thereof. To this solution is added a leaving group of the N-hydroxy type, as defined above, an amine base (such as triethylamine)DIPEA or pyridine), copper (II) acetate or similar copper salts, and molecular sieves. Ionic liquids (BMI or related) may be added. Then, the solution is stirred at room temperature in the presence of air or molecular oxygen. Alternatively, the reaction may be carried out using an oxidizing agent such as TEMPO, possibly at elevated temperatures. After removal of the solvent and purification of the crude product by reverse phase chromatography or normal phase chromatography, the product is obtained.

Saponification procedure for 3-cyano-4- (LGO) -benzoic acid alkyl ester:

the alkyl ester is treated with a mixture of TFA and water at ambient or elevated temperature. Then, the solvent is removed and the crude benzoic acid is purified by normal phase chromatography or reverse phase chromatography. The benzoic acid derivative is coupled to the resin bound free amine peptide using one of various standard coupling conditions known in the literature.

Analytical data for non-radioactive compounds

In thatCompounds were analysed on C-18 using a 4x 125mm, 5 μm pore size, 1ml/min, solvent a: h₂O + 0.1% TFA, solvent B: MeCN + 0.1% TFA, gradient: 5-95% B, 12 min. The product was confirmed by ESI-MS. Purity was assessed by UV (215 nm). The following table summarizes the retention times and observed ESI-MS signals for the compounds shown.

Preparation example Retention time [ M + H]⁺

Analysis of F-18-fluorinated Compounds and comparison with labeling of the corresponding trimethylammonium precursors

The identity of the F-18 labeled compound product was confirmed by co-injection with non-radioactive F-19 fluorine standards on Econosphere analytical HPLC (see general methods for radiolabeling).

FIG. 1 shows the radiation trace of the crude reaction mixture after incubation of precursor 1a and "F-18" for 60 minutes according to the general radioactivity method described above.

FIG. 2 shows the radiation trace of the crude reaction mixture after incubation of precursor 13 and "F-18" for 60 minutes according to the general radioactivity method described above for comparison.

FIG. 3 shows the fluorine standard [2 ] according to FIG. 1 and F-19¹⁹F]-2a radiation and UV traces of the co-injected reaction.

FIG. 4 shows the fluorine standard [2 ] according to FIG. 2 and F-19¹⁹F]-2a radiation and UV traces of the co-injected reaction.

For F-18-2a pic, FIGS. 1 and 2 are superimposable. The same is observed for fig. 3 and 4.

Biodistribution of F-18-bombesin analogs

FIG. 6:

wherein the bombesin analog is Gln-Trp-Ala-Val-Gly-His-FA01010-Leu-NH2

Radiolabelling of bombesin analogues with F-18 was performed via the described method. The radiochemical yield in 50. mu.l of ethanol was about 27% (corrected for decay) to give 76MBq, with a radiochemical purity > 99% by HPLC and a specific activity of-480 GBq/mmol.

Nude mice carrying human prostate cancer PC-3 were injected with 100. mu.l of radioactive peptide containing 135kBq dissolved in PBS per animal. For blocking, 100. mu.g of unlabelled gastrin-releasing peptide were co-injected. One hour after injection, animals were sacrificed and organs were dissected for counting in a gamma counter. Values are expressed as percent injected dose per gram organ weight.

	1h％ID/g	1h Block% ID/g
			Tumor (% ID/g)	1,00±0,01	0,18±0,03
Blood (% ID/g)	0,05±0,01	0,12±0,00
			Muscle (% ID/g)	0,02±0,00	0,03±0,02
Pancreas (% ID/g)	0,34±0,03	0,10±0,02
			Liver (% ID/g)	0,35±0,13	0,39±0,05
Kidney (% ID/g)	0,24±0,02	0,71±0,12
Tumor/tissue ratio
			T/blood	21,03±11,92	1,57±0,22
T/muscle	59,99±29,53	6,31±3,27

As can be seen,¹⁸f-labeled bombesin analogs accumulate in tumors and targeting agents¹⁸F-labeled bombesin is specific because in the case of tumors, the blocking values are low, while for other tissues no change occurs.

¹⁸ Comparison of F-labeled bombesin analogs

The scheme is as above

TABLE 1

Table 1 shows the biodistribution in nude mice carrying human prostate cancer PC-3, wherein nude mice were injected with 100. mu.l of radioactive peptide containing 135kBq dissolved in PBS per animal.

Bombesin analogs of PET: comparison with 18F-Choline (FCH) and 18F-FB-Lys-BN

FIG. 5 shows that the tumor-tissue ratio of bombesin analog Gln-Trp-Ala-Val-Gly-His-FA01010-Leu-NH2 is 2.5 times higher than 18F-choline (FCH) and 18F-FB-Lys-BN.

Synthesis of H-Y-E: solid Phase Peptide Synthesis (SPPS) involves the stepwise addition of amino acid residues to a growing peptide chain attached to an insoluble support or matrix, such as polystyrene. The C-terminal residue of the peptide is first anchored to a commercially available support (e.g., Rink amide resin) with the amino group protected with the N-protector Fluorenylmethoxycarbonyl (FMOC). The amino protecting group is removed with a suitable deprotecting agent of FMOC (e.g., piperidine), and the next amino acid residue (N-protected form) is added with a coupling agent (e.g., Dicyclohexylcarbodiimide (DCC), di-isopropyl-cyclohexylcarbodiimide (DCCI), hydroxybenzotriazole (HOBt)). Once the peptide bond is formed, the reagent is washed from the carrier. After the last residue (Y) was added, the peptide attached to the solid support was ready for RG- -L₁--B₁-coupling of OH.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications and changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. The entire disclosures of all applications, patents, and publications cited herein are incorporated by reference.

Peptide sequences	Binding affinity (IC50)	Tumor% ID/g	Pancreas% ID/g	Sealing of	T/B	T/M
							3-CN，4-F-Bz-Ava-Gln-Trp-Ala-Val-Gly-His-FA01010-Leu-NH2	6-10nM	1	0,34	＞70％	21,03	59,99
3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2	1.9-2.7nM	1,8	1,3	40-70％	6,82	12,75
							3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH2	1nM	1,38	4,16	30-90％	5,65	13,84
3-CF3, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2	0.3-1.8nM	1,28	1,42	＞70％	4,56	25,3
							4F，3CN-Bnz-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2	2.3nM	1,59	3,51	50-80％	2,57	16,77

Sequence listing

<110> Bayer Xianling medicine GmbH

<120> 18F fluoro-benzoyl labelled biologically active compounds and benzotriazol-1-yl groups as diagnostic imaging agents

Oxy-benzoyl, 2, 5-dioxo-pyrrolidin-1-yloxy) benzoyl and trimethylammonium-benzoyl precursors

<130>53435AWO

<140>

<141>

<160>11

<170>PatentIn version 3,1

<210>1

<211>7

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(4)..(6)Seq ID 1：Gly(5)is N-methylated and Sta between His(6)andLeu(7)；

Seq 2：His(6)is methylated and Sta between His(6)and Leu(7)；

Seq 3：Gly(5)is N-methylated，His(6)is methylated and Sta between His(6)and Leu(7)；

Seq 4：His(6)is methylated and Sta between His(6)and Leu(7)；

Seq 8：His(6)is methylated and 4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 17：4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 32：Gly(5)is N-methylated，His(6)is methylated and 4-Am，5-MeHpAbetween His(6)and Leu(7)；

Seq 49：His(6)is N-methylated+3 methyls and 4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 50：His(6)is N-methylated and 4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 51：Gly(5)is N-methylated and AHMHxA between His(6)and Leu(7)；

Seq 82：His(6)is methylated，and FA4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 90：His(6)is methylated，and 4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 91：4-Am，5-MeHpA between His(6)and Leu(7)；

Seq 101：His(6)is methylated，and 4-Am-5-MeHpA-4-amino-5-methylheptanoicacid-between His(6)and Leu(7)；

<223>

<400>1

Gln Trp Ala Val Gly His Leu

1 5

<210>2

<211>6

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(4)..(6)Seq 7：Gly(5)is N-methylated，His(6)is methylated，Sta-Cpaafter His(6)；

Seq 23：Gly(5)is N-methylated，His(6)is methylated and 4-Am，5-MeHpA-Cpaafter His(6)；

Seq 27：Gly(5)is N-methylated and FA02010-Cpa after His(6)；

Seq 34：Trp(2)is DTrp，4-Am，5-MeHxA-Cpa after His(6)；

Seq 35：Gly(5)is N-methylated，His(6)is methylated and Sta-cpa after His(6)；

Seq 49：His(6)is N-methylated+3 methyls and 4-Am，5-MeHpA-Cpa after His(6)；

Seq 72：Gly(5)is N-methylated，and 4-Am，5-MeHpA-Cpa after His(6)；

Seq 73：Gly(5)is N-methylated，and Sta-Cpa after His(6)；

Seq 102：Gly(5)is N-methylated，His(6)is methylated，and

4-Am-5MeHpA4-amino-5-methylheptanoic acid-Cpa after His(6)；

<223>

<400>2

Gln Trp Ala Val Gly His

1 5

<210>3

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(7)Seq 42：His(6)is methylated and Sta-Cpa after His(6)；

<223>

<400>3

Gln Trp Ala Val Gly Ala His Ala

1 5

<210>4

<211>7

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(7)Seq 53：Ala(5)is βAla，His(6)is N-methylated，Cpa after

Phe(7)；

Seq 59：Ala(5)is βAla，His(6)is methylated，and Tha after Phe(7)；

Seq 60：Ala(5)is βAla，His(6)is methylated，and Nle after Phe(7)；

Seq 64：Ala(5)is βAla，His(6)is methylated，and Cpa after Phe(7)；

<223>

<400>4

Gln Trp Ala Val Ala His Phe

1 5

<210>5

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 54：Ala(5)is βAla，and His(6)is N-methylated；

Seq 55：Ala(5)is βAla，and His(6)is DHis；

Seq 65：Ala(5)is βAla，and Val(4)is N-methylated；

Seq 66：Ala(5)is βAla，Phe(7)is N-methylated；

Seq 67：Trp(2)is DTrp，and Ala(5)is βAla；

Seq 68：Ala(3)is DAla，and Ala(5)is βAla；

Seq 69：Val(4)is DVal，and Ala(5)is βAla；

Seq 70：Ala(5)is DAla，and Phe(7)is DPhe；

<223>

<400>5

Gln Trp Ala Val Ala His Phe Leu

1 5

<210>6

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 56：Ala(5)is βAla，and Leu(7)is βhLeu；Seq 71：

<223>

<400>6

Gln Trp Ala Val Ala His Leu Leu

1 5

<210>7

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 57：Ala(5)is βAla，and ILe(7)is βhIle；

<223>

<400>7

Gln Trp Ala Val Ala His Ile Leu

1 5

<210>8

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 58：Ala(5)is βAla，and Leu(7)is βhleu，and Gly(8)istbuGly；

<223>

<400>8

Gln Trp Ala Val Ala His Leu Gly

1 5

<210>9

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 61：Ala(5)is βAla，His(6)is N-methylated，and Gly(8)is tbuGly

<223>

<400>9

Gln Trp Ala Val Ala His Phe Gly

1 5

<210>10

<211>8

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(6)..(8)Seq 71：Ala(5)is βAla，Ile(7)is βhIle，and Gly(8)is tbuGly；

<223>

<400>10

Gln Trp Ala Val Ala His Ile Gly

1 5

<210>11

<211>6

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(4)..(6)Seq 77：His(5)is methylated，Sta between His(5)and Leu(6)；

<223>

<400>11

Gln Trp Ala Val His Leu

1 5

<210>12

<211>7

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(7)Seq 28：Gly(5)is N-methylated，4-Am，5-MeHpA between His(6)and Gly(7)，and Gly(7)is-tbuGly；

Seq 30：Gly(5)is N-methylated，His(6)is methylated，Sta between His(6)andGly(7)and Gly(7)is-tbuGly；

Seq 33：Trp(2)is DTrp，4-Am，5-MeHpA between His(6)and Gly(7)and Gly(7)is-tbuGly；

Seq 43：His(6)is methylated，Sta between His(6)and Gly(7)，and Gly(7)is-tbuGly；

<223>

<400>12

Gln Trp Ala Val Gly His Gly

1 5

<210>13

<211>7

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(7)sEQ 36：Trp(2)is DTrp，Sta between His(6)and Ala(7)andAla(7)is tbuAla；

Seq 74：Gly(5)is N-methylated，Sta after His(6)，and Ala(7)is tbuAla；

Seq 75：Gly(5)is N-methylated，4-Am，5-MeHpA after His(6)，and Ala(7)istbuAla；

<223>

<400>13

Gln Trp Ala Val Gly His Ala

1 5

<210>14

<211>6

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(6)sEQ 52：Ala(5)is βAla，His(6)is N-methylated，and Tha-Cpaafter His(6)；

<223>

<400>14

Gln Trp Ala Val Ala His

1 5

<210>15

<211>7

<212>PRT

<213>mammalian

<220>

<221>MISC_FEATURE

<222>(5)..(7)Seq 62：Ala(5)is βAla，His(6)is N-methylated，and Thabetween His(6)and Gly(7)，Gly(7)is-tbuGly；

Seq 63：Ala(5)is βAla，His(6)is methylated，and Tha between His(6)andGly(7)，Gly(7)is-tbuGly；

<223>

<400>15

Gln Trp Ala Val Ala His Gly

1 5

Claims (49)

1. A compound having the general chemical formula a:

wherein

-Y¹、-Y²、-Y³、-Y⁴and-Y⁵One of which is a first substituent (-G) selected from the group consisting of-H, -F, -Cl, -Br, -I, -NO₂、-NR⁴COCF₃、-NR⁴SO₂CF₃、-N(CF₃)₂、-NHCSNHR⁴、-N(SO₂R⁵)₂、-N(O)＝NCONH₂、-NR⁴CN、-NHCSR⁵、-N≡C、-N＝C(CF₃)₂、-N＝NCF₃、-N＝NCN、-NR⁴COR⁴、-NR⁴COOR⁵、-OSO₂CF₃、-OSO₂C₆H₅、-OCOR⁵、-ONO₂、-OSO₂R⁵、-O-C＝CH₂、-OCF₂CF₃、-OCOCF₃、-OCN、-OCF₃、-C≡N、-C(NO₂)₃、-COOR⁴、-CONR⁴R⁵、-C(S)NH₂、-CH＝NOR⁴、-CH₂SO₂R⁴、-COCF₃、-CF₃、-CF₂Cl-CBr₃、-CClF₂、-CCl₃、-CF₂CF₃、-C≡CR⁴、-CH＝NSO₂CF₃、-CH₂CF₃、-COR⁵、-CH＝NOR⁵、-CH₂CONH₂、-CSNHR⁵、-CH＝NNHCSNH₂、-CH＝NNHCONHNH₂、-C≡C-CF₃、-CF＝CFCF₃、-CF₂-CF₂-CF₃、-CR⁴(CN)₂、-COCF₂CF₂CF₃、-C(CF₃)₃、-C(CN)₃、-CR⁴＝C(CN)₂-1-pyrrolyl, -C (CN) ═ C (CN)₂-C-pyridyl, -COC₆H₅、-COOC₆H₅、-SOCF₃、-SO₂CF₃、-SCF₃、-SO₂CN、-SCOCF₃、-SOR⁵、-S(OR⁵)、-SC≡CR⁴、-SO₂R⁵、-SSO₂R⁵、-SR⁵、-SSR⁴、-SO₂CF₂CF₃、-SCF₂CF₃、-S(CF₃)＝NSO₂CF₃、-SO₂C₆H₅、-SO₂N(R⁵)₂、-SO₂C(CF₃)₃、-SC(CF₃)₃、-SO(CF₃)＝NSO₂CF₃、-S(O)(＝NH)CF₃、-S(O)(＝NH)R⁵、-S-C＝CH₂、-SCOR⁵、-SOC₆H₅、-P(O)C₃F₇、-PO(OR⁵)₂、-PO(N(R⁵)₂)₂、-P(N(R⁵)₂)₂、-P(O)R⁵ ₂and-PO (OR)⁵)₂And an electron withdrawing group, wherein each substituent may be in ortho, para or meta position with respect to the K (LG-O) group;

-Y¹、-Y²、-Y³、-Y⁴and-Y⁵At least one of (a) is a further substituent (-Q), which is selected independently of one another from the group consisting of-H, -CN, -halogen, -CF₃、-NO₂、-COR⁵and-SO₂R⁵Wherein the individual substituents may be in ortho-, para-or meta-position with respect to the K (LG-O) group,

wherein R is⁴Is hydrogen or straight or branched C₁-C₆An alkyl group, a carboxyl group,

R⁵is hydrogen or straight or branched C₁-C₆An alkyl group, a carboxyl group,

wherein-Y¹、-Y²、-Y³、-Y⁴and-Y⁵is-A-B-D-P,

wherein

-A-B-D-is a bond or a spacer,

p is a targeting agent, and

k is LG-O or W,

wherein:

LG is a leaving group suitable for displacement by nucleophilic aromatic substitution, and

w is a fluorine isotope (F),

and pharmaceutically acceptable salts or organic or inorganic acids, hydrates, esters, amides, solvates and prodrugs thereof.

2. The compound of claim 1, whereinW is a radioactive or non-radioactive isotope of fluorine, more preferably¹⁸F。

3. A compound as claimed in any one of the preceding claims wherein LG-is selected from

Wherein

T is H or Cl,

q is a group selected from the group consisting of CH and N,

k is absent or C ═ O.

4. A compound as claimed in any one of the preceding claims wherein LG-is selected from

5. The compound of any one of the preceding claims, wherein the first substituent (-G) is selected from-H, -F, -Cl, -Br, -NO₂、-OSO₂R⁵、-OCF₃、-C≡N、-COOR⁴、-CONR⁴R⁵、-COCF₃、-CF₂CF₃、-COR⁵、-CF₃、-C≡CF₃、-CF₂-CF₂-CF₃、-COC₆H₅、-SO₂CF₃、-SCOCF₃、-SO₂R⁵、-SO₂CF₂CF₃、-SO₂C₆H₅、-SO₂N(R⁵)₂and-PO (OR)⁵)₂Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

6. The compound of any one of the preceding claims, wherein the further substitutionThe radicals (-Q) may be chosen independently of one another from the group-H, -CN, -F, -Cl, -Br and-NO₂Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

7. The compound of any one of the preceding claims, wherein any one of the first substituent and the further substituent is independently from each other selected from-H, -CN, -F, -Cl, -CF₃、-NO₂、-COCH₃and-SO₂CH₃Wherein the individual substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

8. The compound of any one of the preceding claims, wherein any one of the first substituent and the further substituent is independently from each other selected from-H, -CN and-Cl, wherein each substituent may be in ortho, para or meta position with respect to the K (LG-O) group.

9. A compound according to any one of the preceding claims wherein Y is¹And Y⁵One of which is selected from CN and Cl, wherein the respective substituents may be in ortho, para or meta position with respect to the K (LG-O) group.

10. A compound according to any one of the preceding claims, wherein R⁴Is hydrogen or straight or branched C₁-C₄Alkyl radical, R⁵Is hydrogen or straight or branched C₁-C₄An alkyl group.

11. A compound according to any preceding claim, wherein

-A-is selected from the group consisting of a bond, -CO-, -SO₂-、-(CH₂)_d-CO-、-SO-、-C≡C-CO-、-[CH₂]_m-E-[CH₂]_n-CO-、-[CH₂]_m-E-[CH₂]_n-SO₂-、-C(＝O)-O-、-NR¹⁰-、-O-、-(S)_p-、-C(＝O)NR¹²-、-NR¹²-、-C(＝S)NR¹²-、-C(＝S)O-、C₁-C₆Cycloalkyl, alkenyl, heterocycloalkyl, unsubstituted and substituted aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, aryloxy, aralkoxy, -SO₂NR¹³-、-NR¹³SO₂-、-NR¹³C(＝O)O-、-NR¹³C(＝O)NR¹²-, -NH-and-NH-O-,

wherein

d is an integer of 1 to 6,

m and n are independently any integer from 0 to 5;

-E-is a bond, -S-, -O-or-NR⁹-，

Wherein R is⁹Is H, C₁-C₁₀Alkyl, aryl, heteroaryl or aralkyl,

p is any integer from 1 to 3;

R¹⁰and R¹²Independently is H, C₁-C₁₀Alkyl, aryl, heteroaryl or aralkyl, and

R¹³is H, substituted or unsubstituted straight or branched C₁-C₆Alkyl, aryl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

further:

-B-is-NH-or-NR' -,

wherein R' is a branched, cyclic or straight chain C₁-C₆An alkyl group; and

-D-is- (CH)₂)_p-CO-, wherein p is an integer from 1 to 10, or- (CH)₂-CH₂-O)_q-CH₂-CH₂-CO-, wherein q is an integer from 1 to 5,

or

-B-D-together is a bond, an amino acid residue, an amino acid sequence having two (2) to twenty (20) amino acid residues or a non-amino acid group.

12. A compound as claimed in any one of the preceding claims, wherein-a-is selected from-CO-, -SO ™₂-and-C ≡ C-CO-.

13. A compound according to any one of the preceding claims, wherein-a-is selected from-CO-and-SO₂-。

14. The compound of any one of the preceding claims, wherein B-D is a natural or non-natural amino acid sequence or a non-amino acid group.

15. The compound of any one of claim 14, wherein B-D is Arg-Ser, Arg-Ava, Lys (Me)2- β -ala, Lys (Me)2-Ser, Arg- β -ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S-S-alkyl), or

Wherein k and l are independently selected in the range of 0 to 4.

16. The compound of any one of claims 14-15, wherein B-D is

NH-(CH₂)_p-CO-, wherein p is an integer from 1 to 10,

-NH-(CH₂-CH₂-O)_q-CH₂-CH₂-CO-, wherein q is an integer from 1 to 5,

-NH-cycloalkyl-CO-, wherein cycloalkyl is selected from C₅-C₈Cycloalkyl radicals, or

-NH-heterocycloalkyl- (CH)₂)_v-CO-, wherein the heterocycloalkyl group is chosen from C containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms₅-C₈Heterocycloalkyl, and v is an integer from 1 to 4.

17. The compound of any one of the preceding claims, wherein P is a peptide, peptidomimetic, oligonucleotide, or small molecule.

18. The compound of any one of the preceding claims, wherein P is a peptide comprising 4 to 100 amino acids.

19. The compound of any of the preceding claims, wherein P is selected from bombesin, somatostatin receptor specific peptides, somatostatin, derivatives and related peptides thereof, neuropeptide Y₁Their derivatives and related peptides, gastrin-releasing peptide, their derivatives and related peptides, epidermal growth factor (EGF of various origins), Insulin Growth Factor (IGF) and IGF-1, integrins (alpha)₃β₁、α_vβ₃、α_vβ₅、αIIb₃) LHRH agonists and antagonists, transforming growth factors, especially TGF-alpha, angiotensin, cholecystokinin receptor peptides, cholecystokinin (CCK) and analogues thereof; neurotensin and analogs thereof, thyrotropin-releasing hormone, pituitary adenylate cyclase-activating peptide (PACAP) and related peptides, chemokines, substrates and inhibitors of cell surface matrix metalloproteinases, prolactin and analogs thereof, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, Vasoactive Intestinal Peptide (VIP) and related peptides.

20. The compound of any one of the preceding claims, wherein P is selected from bombesin, somatostatin, neuropeptide Y₁And their analogs.

21. A compound according to any preceding claim, wherein P is selected from bombesin analogues having the sequence of formula III or formula IV:

AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-AA₈-NT₁T₂(type a) III wherein:

T₁＝T₂h, or T₁＝H、T₂OH or T₁＝CH₃、T₂＝OH

AA₁＝Gln、Asn、Phe(4-CO-NH₂)

AA₂＝Trp、D-Trp

AA₃＝Ala、Ser、Val

AA₄＝Val、Ser、Thr

AA₅＝Gly、(N-Me)Gly

AA₆＝His、His(3-Me)、(N-Me)His、(N-Me)His(3-Me)

AA₇Sta, pepstatin analogs and isomers, 4-Am, 5-MeHpA, 4-Am, 5-MeHxA, gamma-substituted amino acids

AA₈Leu, Cpa, Cba, CpnA, Cha, t-buty, tBuAla, Met, Nle, iso-Bu-Gly

AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-AA₈-NT₁T₂(form B) IV wherein:

T₁＝T₂h, or T₁＝H、T₂OH or T₁＝CH₃、T₂＝OH

AA₁Gln, Asn or Phe (4-CO-NH)₂)

AA₂＝Trp、D-Trp

AA₃＝Ala、Ser、Val

AA₄＝Val、Ser.Thr

AA₅＝βAla、β²-and β³Amino acids, as shown below

Where SC represents the side chain found in protein amino acids and homologs of protein amino acids,

AA₆＝His、His(3-Me)、(N-Me)His、(N-Me)His(3-Me)

AA₇＝Phe、Tha、Nal，

AA₈＝Leu、Cpa、Cba、CpnA、Cha、t-buGly、tBuAla、Met、Nle、iso-Bu-Gly.

22. The compound of any one of the preceding claims, wherein P is-NR⁷-peptide, or- (CH)₂)_n-peptide, -O- (CH)₂)_n-peptide or-S- (CH)₂)_n-peptide, NR⁷-small molecule, or- (CH)₂)_n-small molecule, -O- (CH)₂)_n-small molecule or-S- (CH)₂)_n-small molecule, NR⁷-oligonucleotide, or- (CH)₂)_n-oligonucleotide, -O- (CH)₂)_n-oligonucleotide or-S- (CH)₂)_n-an oligonucleotide, wherein n is an integer from 1 to 6.

23. A compound according to any one of the preceding claims, wherein R⁷Is hydrogen or unbranched or branched C₁-C₆An alkyl group.

24. A compound according to any one of the preceding claims, wherein R⁷Is hydrogen or methyl.

25. A compound according to any preceding claim, wherein P is a small molecule having a molecular weight of from 200 to 800.

26. The compound of any one of the preceding claims, wherein P is an oligonucleotide.

27. A compound according to any one of the preceding claims selected from

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide,

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-valyl- β -alanyl-histidyl (π -Me) -glycinamide,

3-cyano-4- ([1, 2, 3] triazolo [4, 5-b ] pyridin-3-yloxy) -benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide,

4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide,

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

4- (benzotriazol-1-yloxy) -3-chloro-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

4- (benzotriazol-1-yloxy) -3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -FA4-Am, 5-MeHpA-Leu-NH₂，

3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

3-chloro-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

3-chloro-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

3-cyano-4- (2, 5-dioxo-pyrrolidin-1-yloxy) -N- (thymidyl-propyl) -benzamide:

or

3-cyano-4- (benzotriazol-1-yloxy) -N- (thymidyl-propyl) -benzamide:

28. the compound of any one of claims 1-26, comprising

·A-a-1：4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·A-a-2：4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (Me) -Sta-Leu-NH₂，

·A-a-3：4-[18]fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·A-a-4：4-[18]Fluoro-3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-5：4-[18]fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-6：4-[18]fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-7：4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

·A-a-8：4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -FA4-Am, 5-MeHpA-Leu-NH₂，

·A-a-9：4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-10：4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-11：4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-12：4-[18]fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·A-a-13：4-[18]fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·A-a-14：4-[18]fluoro-3-cyano-benzoyl-Lys (Me)2-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·A-a-15：4-[18]fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-16：4-[18]fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·A-a-17：4-[18]fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am, 5-MeHpA-Leu-NH₂，

·A-a-18：4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-LeuNH₂，

·A-a-19：4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·A-a-20：4-[18]Fluoro-3-trifluoromethyl-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-21：4-[18]fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·A-a-22：4-[18]fluoro-3-trifluoromethyl-benzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-23 4-[18]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

·IIB-a-24 4-[18]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-25 4-[18]-fluoro-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-263，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·IIB-a-27 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-FA 02010-Cpa-NH₂，

·IIB-a-28 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

·IIB-a-29 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-30 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-tBuGly-NH₂，

·IIB-a-31 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-32 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-33 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

·IIB-a-34 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂，

·IIB-a-35 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

·IIB-a-36 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂，

·IIB-a-37 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·IIB-a-38 3，4-[18]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-39 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-40 3，4-[18]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-41 3，4-[18]-difluorobenzoyl-Arg-beta Ala-Arg-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-42 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Cpa-NH₂，

·IIB-a-43 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-tBuGly-NH₂，

·IIB-a-44 3，4-[18]-difluorobenzoyl-Arg-Arg-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-45 3，4-[18]-difluorobenzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·IIB-a-46 3，4-[18]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-47 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

·IIB-a-48 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-49 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Cpa-NH₂，

·IIB-a-49 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-50 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Leu-NH₂，

·IIB-a-51 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂，

·IIB-a-52 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-Cpa-NH₂，

·IIB-a-53 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Cpa-NH₂，

·IIB-a-54 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Leu-NH₂，

·IIB-a-55 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-DHis-Phe-Leu-NH₂，

·IIB-a-56 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-Leu-NH₂，

·IIB-a-57 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-Leu-NH₂，

·IIB-a-58 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-tbuGly-NH₂，

·IIB-a-59 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Tha-NH₂，

·IIB-a-60 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Nle-NH₂，

·IIB-a-61 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-tbuGly-NH₂，

·IIB-a-62 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-tbu Gly-NH₂，

·IIB-a-633 ，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Tha-tbuGly-NH₂，

·IIB-a-64 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Cpa-NH₂，

·IIB-a-65 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-NMeVal-beta Ala-His-Phe-Leu-NH₂，

·IIB-a-66 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-NMePhe-Leu-NH₂，

·IIB-a-67 3，4-[18]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-beta Ala-His-Phe-Leu-NH₂，

·IIB-a-68 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-DAla-Val-beta Ala-His-Phe-Leu-NH₂，

·IIB-a-69 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-DVal-beta Ala-His-Phe-Leu-NH₂，

·IIB-a-70 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-DPhe-Leu-NH₂，

·IIB-a-71 3，4-[18]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-tbuGly-NH₂，

·IIB-a-72 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-Cpa-NH₂，

·IIB-a-73 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂，

·IIB-a-74 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂，

·IIB-a-75 4-[18]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuAla-NH₂，

·4-[18]Fluoro-3-cyano-benzoyl- (piperidinyl-4-carbonyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·4-[18]Fluoro-3-cyano-benzoyl- (piperazin-1-yl-acetyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·4-[18]Fluoro-3-cyano-benzoyl-1, 4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·B-a-1：4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·B-a--2：4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-His (Me) -Sta-Leu-NH₂，

·B-a-3：4-[19]-fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-4：4-[19]-fluoro-3-cyano-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-5：4-[19]-fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-6：4-[19]-fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-7：4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

·B-a-8：4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-9：4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-10：4-[19]-fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-11：4-[19]-fluoro-3-cyano-benzoyl-Lys (Me) 2-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-12：4-[19]-fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-13：4-[19]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-14：4-[19]-fluoro-3-cyano-benzoyl-Lys (Me)2-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-15：4-[19]-fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-16：4-[19]-fluoro-3-cyano-benzoyl-Lys (Me)2- β Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-17：4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am, 5-MeHpA-Leu-NH₂，

·B-a-18：4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-19：4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-20：4-[19]-fluoro-3-trifluoromethyl-benzoyl-1, 4-cis-Achc-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-21：4-[19]-fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-22：4-[19]-fluoro-3-trifluoromethyl-benzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-23：4-[19]-fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

·B-a-24：4-[19]-fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-25：4-[19]-fluoro-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-26：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·B-a-27：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-FA 02010-Cpa-NH₂，

·B-a-28：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

·B-a-29：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-30：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-tBuGly-NH₂，

·B-a-31：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-32：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-33：3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am, 5-MeHpA-tbuGly-NH₂，

·B-a-34：3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHXA-Cpa-NH₂，

·B-a-35：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Cpa-NH₂，

·B-a-36：3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂，

·B-a-37：3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

·B-a-38：3，4-[19]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-39：3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-40：3，4-[19]-difluorobenzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-41：3，4-[19]-difluorobenzoyl-Arg-beta Ala-Arg-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·B-a-42：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Cpa-NH₂，

·B-a-43：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-tBuGly-NH₂，

·B-a-44：3，4-[19]-difluorobenzoyl-Arg-Arg-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-45：3，4-[19]-difluorobenzoyl-Arg-beta Ala-Gln-Trp-Ala-Val-NMeGly-His (3Me) -Sta-Leu-NH₂，

·B-a-46：3，4-[19]-difluorobenzoyl-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-47：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am, 5-MeHpA-Cpa-NH₂，

·B-a-48：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-49：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Cpa-NH₂，

·B-a-49：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis (3Me) -4-Am, 5-MeHpA-Leu-NH₂，

·B-a-50：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-Gly-NMeHis-4-Am, 5-MeHpA-Leu-NH₂，

·B-a-51：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂，

·B-a-52：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-Cpa-NH₂，

·B-a-53：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Cpa-NH₂，

·B-a-54：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-Leu-NH₂，

·B-a-55：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-DHis-Phe-Leu-NH₂，

·B-a-56：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-Leu-NH₂，

·B-a-57：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-Leu-NH₂，

·B-a-58：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hLeu-tbuGly-NH₂，

·B-a-59：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Tha-NH₂，

·B-a-60：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Nle-NH₂，

·B-a-61：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Phe-tbuGly-NH₂，

·B-a-62：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-NMeHis-Tha-tbuGly-NH₂，

·B-a-63：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Tha-tbuGly-NH₂，

·B-a-64：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His (3Me) -Phe-Cpa-NH₂，

·B-a-65：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-NMeVal-beta Ala-His-Phe-Leu-NH₂，

·B-a-66：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-NMePhe-Leu-NH₂，

·B-a-67：3，4-[19]-difluorobenzoyl-Ava-Gln-DTrp-Ala-Val-beta Ala-His-Phe-Leu-NH₂，

·B-a-68：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-DAla-Val-beta Ala-His-Phe-Leu-NH₂，

·B-a-69：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-DVal-beta Ala-His-Phe-Leu-NH₂，

·B-a-70：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-DPhe-Leu-NH₂，

·B-a-71：3，4-[19]-difluorobenzoyl-Ava-Gln-Trp-Ala-Val-beta Ala-His-beta hIle-tbuGly-NH₂，

·B-a-72：4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-Cpa-NH₂，

·B-a-73：4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂，

·B-a-74：4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂，

·B-a-75：4-[19]-fluoro-3-cyano-benzenesulfonyl-Ava-Gln-Trp-Ala-Val-NMeGly-His-4-Am, 5-MeHpA-tbuAla-NH₂。

29. The compound of any one of claims 1-26, comprising

IIA-a-76: 4- [18] fluoro-3-cyano-benzoyl-Ava- ε -c [ Lys- (NMe) Phe-1Nal-D-Trp-Lys-Thr ],

IIA-a-77: 4- [18] fluoro-3-cyano-benzoyl-Ava- β -c [ Dpr-Met- (NMe) Phe-Tyr-D-Trp-Lys ],

IIB-a-76: 4- [19] fluoro-3-cyano-benzoyl-Ava- ε -c [ Lys- (NMe) Phe-1Nal-D-Trp-Lys-Thr ],

IIB-a-77: 4- [19] fluoro-3-cyano-benzoyl-Ava- β -c [ Dpr-Met- (NMe) Phe-Tyr-D-Trp-Lys ],

·IIA-a-78：4-[18]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH₂，

·IIA-a-79：4-[18]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH₂，

·IIA-a-78：4-[19]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH₂，

·IIA-a-79：4-[19]fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH₂，

·4-[19]Fluoro-3-cyano-benzoyl- (piperidinyl-4-carbonyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·4-[19]Fluoro-3-cyano-benzoyl- (piperazin-1-yl-acetyl) -Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH₂，

·4-[19]Fluoro-3-cyano-benzoyl-1, 4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂，

3-cyano-4-fluoro-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide [ alpha ], [ beta ] -alanyl-phenylalanyl-glycinamide¹⁹F]，

3-cyano-4-fluoro-benzoyl-valyl- β -alanyl-phenylalanyl-glycinamide [ alpha ], [ beta ] -alanyl-phenylalanyl-glycinamide¹⁸F]，

3-cyano-4-fluoro-benzoyl-valyl- β -alanyl-histidyl (π -Me) -glycinamide [2 ]¹⁹F]，

3-cyano-4-fluoro-benzoyl-valyl- β -alanyl-histidyl (π -Me) -glycinamide [2 ]¹⁸F]，

3-cyano-4-fluoro-benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucinamide [2 ]¹⁹F]，

3-cyano-4-fluoro-benzoyl- (5-aminopentanoyl) -phenylalanyl- (4(S) -amino-3 (S) -hydroxy-6-methyl) heptanoyl-leucine amide [2 ]¹⁸F]，

3-cyano-4- [ F-19] fluoro-N- (thymidyl-propyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-propyl) -benzamide,

3-cyano-4- [ F-19] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide,

3-cyano-4- [ F-19] fluoro-N- (thymidyl-hexyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-hexyl) -benzamide,

3-cyano-4- [19F ] fluoro-N- (thymidyl-butyl) benzamide,

3-cyano-4- [19F ] fluoro-N- (thymidyl-butyl) benzamide,

3-cyano-4-fluoro-N- (trifluoromethylthymidylyl-hexyl) benzamide,

3-cyano-4-fluoro-N- (trifluoromethylthymidylyl-hexyl) benzamide,

3-cyano-4-fluoro [ F-18] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide,

3-cyano-4-fluoro [ F-19] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide,

3-cyano-4- [ F-19] fluoro-N- (thymidylyl-propyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-propyl) -benzamide;

3-cyano-4- [ F-19] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (2- [ 2-thymidyl-ethoxy ] -ethyl) -benzamide;

3-cyano-4- [ F-19] fluoro-N- (thymidyl-hexyl) -benzamide,

3-cyano-4- [ F-18] fluoro-N- (thymidyl-hexyl) -benzamide;

3-cyano-4- [19F ] fluoro-N- (thymidyl-butyl) benzamide,

3-cyano-4- [18F ] fluoro-N- (thymidyl-butyl) benzamide;

wherein F is¹⁸F or¹⁹F，

3-cyano-4-fluoro-N- (trifluoromethylthymidylyl-hexyl) benzamide,

3-cyano-4-fluoro-N- (trifluoromethyl-thymidylyl-hexyl) benzamide;

wherein F is¹⁸F or¹⁹F，

3-cyano-4-fluoro [ F-18] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide;

3-cyano-4-fluoro [ F-19] -N- {6- [3- ((2R, 4S, 5R) -4-hydroxy-5-hydroxymethyl-tetrahydro-thiophen-2-yl) 5-methyl-2, 6, dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -hexyl } -benzamide;

3-CN，4-F-Bz-Ava-Gln-Trp-Ala-Val-Gly-His-FA01010-Leu-NH2，

4F，3CN-Bnz-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2，

3-CF3, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2,

3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His (3Me) -Sta-Leu-NH2,

3-CN, 4-F-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2, wherein F is¹⁸F or¹⁹F。

30. The compound of claims 1-26, wherein P is selected from

Seq ID 1 Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂

Seq ID 2 Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH₂

Seq ID 3 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH₂

Seq ID 4 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH₂

Seq ID 7 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

Seq ID 8 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 12 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 17 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

Seq ID 23 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Cpa-NH₂

Seq ID 27 Gln-Trp-Ala-Val-NMeGly-His-FA02010-Cpa-NH₂

Seq ID 28 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuGly-NH₂

Seq ID 30 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-tBuGly-NH₂

Seq ID 32 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 33 Gln-DTrp-Ala-Val-Gly-His-4-Am，5-MeHpA-tbuGly-NH₂

Seq ID 34 Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂

Seq ID 35 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

Seq ID 36 Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂

Seq ID 42 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Cpa-NH₂

Seq ID 43 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-tBuGly-NH₂

Seq ID 46 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 48 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Cpa-NH₂

Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 50 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Leu-NH₂

Seq ID 51 Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂

Seq ID 52 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-Cpa-NH₂

Seq ID 53 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Cpa-NH₂

Seq ID 54 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Leu-NH₂

Seq ID 55 Gln-Trp-Ala-Val-βAla-DHis-Phe-Leu-NH₂

Seq ID 56 Gln-Trp-Ala-Val-βAla-His-βhLeu-Leu-NH₂

Seq ID 57 Gln-Trp-Ala-Val-βAla-His-βhIle-Leu-NH₂

Seq ID 58 Gln-Trp-Ala-Val-βAla-His-βhLeu-tbuGly-NH₂

Seq ID 59 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Tha-NH₂

Seq ID 60 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Nle-NH₂

Seq ID 61 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-tbuGly-NH₂

Seq ID 62 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-tbuGly-NH₂

Seq ID 63 Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-tbuGly-NH₂

Seq ID 64 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Cpa-NH₂

Seq ID 65 Gln-Trp-Ala-NMeVal-βAla-His-Phe-Leu-NH₂

Seq ID 66 Gln-Trp-Ala-Val-βAla-His-NMePhe-Leu-NH₂

Seq ID 67 Gln-DTrp-Ala-Val-βAla-His-Phe-Leu-NH₂

Seq ID 68 Gln-Trp-DAla-Val-βAla-His-Phe-Leu-NH₂

Seq ID 69 Gln-Trp-Ala-DVal-βAla-His-Phe-Leu-NH₂

Seq ID 70 Gln-Trp-Ala-Val-βAla-His-DPhe-Leu-NH₂

Seq ID 71 Gln-Trp-Ala-Val-βAla-His-βhIle-tbuGly-NH₂

Seq ID 72 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-Cpa-NH₂

Seq ID 73 Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂

Seq ID 74 Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂

Seq ID 75 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuAla-NH₂

Seq ID 77 Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH₂

Seq ID 82 Gln-Trp-Ala-Val-Gly-His(3Me)-FA4-Am，5-MeHpA-Leu-NH₂

Seq ID 90 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

Seq ID 91 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

Seq ID 101 Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am-5-MeHpA-4-amino-5-methylheptyl

acid-Leu-NH₂

Seq ID 102 Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am-5-MeHpA-4-amino-5-A

Cycloheptanoic acid-Cpa-NH₂。

31. A process for the preparation of a compound of formula II wherein K ═ W according to any one of claims 1 to 30, in which process a compound of formula a wherein K ═ LG-O is labelled with a fluorine isotope.

32. The method of claim 31, comprising the steps of: coupling a compound of formula a wherein K ═ LG-O according to any one of claims 1 to 30 with a fluorine isotope to form a compound of formula a wherein K ═ W, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

33. The method of claims 31 and 32, wherein W is a fluorine isotope, more preferably¹⁸F。

34. A composition comprising a compound of general chemical formula a according to any one of claims 1 to 30 wherein K ═ LG-O or W, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

35. A method of imaging a disease comprising introducing into a patient a detectable amount of a labeled compound of formula a as claimed in any one of claims 1-30 wherein K ═ W or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof.

36. The method of claim 35, wherein W is¹⁸F。

37. A kit comprising a sealed vial containing a predetermined amount of a compound of formula a wherein K ═ LG-O as defined in any one of claims 1 to 30, or pharmaceutically acceptable salts, hydrates, esters, amides, solvates and prodrugs thereof.

38. A compound of formula a wherein K ═ LG-O or W as claimed in any one of claims 1 to 30, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate and prodrug thereof, for use as a medicament.

39. A compound of general formula a according to any one of claims 1 to 30, wherein K ═ W, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, for use as a diagnostic imaging agent.

40. A compound of general formula a, or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, as claimed in any one of claims 1-30, wherein K ═ W, for use as a Positron Emission Tomography (PET) imaging agent.

41. The compound of claims 38 to 40, wherein W is a fluorine isotope, and more preferably¹⁸F。

42. Use of a compound of formula a or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, wherein K ═ LG-O or W, as claimed in any one of claims 1 to 30, in the manufacture of a medicament.

43. Use of a compound of general formula a or a pharmaceutically acceptable salt, hydrate, ester, amide, solvate or prodrug thereof, as claimed in any one of claims 1 to 30, wherein K ═ LG-O or W, in the manufacture of a diagnostic imaging agent.

44. The use of claim 43, wherein the diagnostic imaging agent is prepared for imaging tissue at a target site using the imaging agent.

45. The use of claim 44, wherein the imaging agent is a Positron Emission Tomography (PET) imaging agent.

46. A compound having the general chemical formula V:

wherein N is⁺(R¹)(R²)(R³)、X^--G and-Q have the same meanings as described above for the compound of formula A, and

R⁶selected from-S (O)₂-N(H)-CH₂-C(O)OH、-S(O)₂-N(Me)-CH₂-C (O) OH and C (O) OH.

47. A process for the preparation of a compound of formula a wherein K ═ LG-O by reacting a compound of formula V with a targeting agent.

48. The method of claim 47, wherein a compound of formula A, wherein K ═ LG-O, is reacted with the targeting agent, optionally with a condensing agent.

49. Peptide sequence selected from

·Seq ID 1 Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH₂

·Seq ID 2 Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH₂

·Seq ID 3 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH₂

·Seq ID 4 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH₂

·Seq ID 7 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

·Seq ID 8 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 12 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 17 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 23 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Cpa-NH₂

·Seq ID 27 Gln-Trp-Ala-Val-NMeGly-His-FA02010-Cpa-NH₂

·Seq ID 28 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuGly-NH₂

·Seq ID 30 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-tBuGly-NH₂

·Seq ID 32 Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 33 Gln-DTrp-Ala-Val-Gly-His-4-Am，5-MeHpA-tbuGly-NH₂

·Seq ID 34 Gln-DTrp-Ala-Val-Gly-His-4-Am-5-MeHxA-Cpa-NH₂

·Seq ID 35 Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH₂

·Seq ID 36 Gln-DTrp-Ala-Val-Gly-His-Sta-tbuAla-NH₂

·Seq ID 42 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Cpa-NH₂

·Seq ID 43 Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-tBuGly-NH₂

·Seq ID 46 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 48 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Cpa-NH₂

·Seq ID 49 Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 50 Gln-Trp-Ala-Val-Gly-NMeHis-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 51 Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-Leu-NH₂

·Seq ID 52 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-Cpa-NH₂

·Seq ID 53 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Cpa-NH₂

·Seq ID 54 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-Leu-NH₂

·Seq ID 55 Gln-Trp-Ala-Val-βAla-DHis-Phe-Leu-NH₂

·Seq ID 56 Gln-Trp-Ala-Val-βAla-His-βhLeu-Leu-NH₂

·Seq ID 57 Gln-Trp-Ala-Val-βAla-His-βhIle-Leu-NH₂

·Seq ID 58 Gln-Trp-Ala-Val-βAla-His-βhLeu-tbuGly-NH₂

·Seq ID 59 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Tha-NH₂

·Seq ID 60 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Nle-NH₂

·Seq ID 61 Gln-Trp-Ala-Val-βAla-NMeHis-Phe-tbuGly-NH₂

·Seq ID 62 Gln-Trp-Ala-Val-βAla-NMeHis-Tha-tbuGly-NH₂

·Seq ID 63 Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-tbuGly-NH₂

·Seq ID 64 Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-Cpa-NH₂

·Seq ID 65 Gln-Trp-Ala-NMeVal-βAla-His-Phe-Leu-NH₂

·Seq ID 66 Gln-Trp-Ala-Val-βAla-His-NMePhe-Leu-NH₂

·Seq ID 67 Gln-DTrp-Ala-Val-βAla-His-Phe-Leu-NH₂

·Seq ID 68 Gln-Trp-DAla-Val-βAla-His-Phe-Leu-NH₂

·Seq ID 69 Gln-Trp-Ala-DVal-βAla-His-Phe-Leu-NH₂

·Seq ID 70 Gln-Trp-Ala-Val-βAla-His-DPhe-Leu-NH₂

·Seq ID 71 Gln-Trp-Ala-Val-βAla-His-βhIle-tbuGly-NH₂

·Seq ID 72 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-Cpa-NH₂

·Seq ID 73 Gln-Trp-Ala-Val-NMeGly-His-Sta-Cpa-NH₂

·Seq ID 74 Gln-Trp-Ala-Val-NMeGly-His-Sta-tbuAla-NH₂

·Seq ID 75 Gln-Trp-Ala-Val-NMeGly-His-4-Am，5-MeHpA-tbuAla-NH₂

·Seq ID 77 Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH₂

·Seq ID 82 Gln-Trp-Ala-Val-Gly-His(3Me)-FA4-Am，5-MeHpA-Leu-NH₂

·Seq ID 90 Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am，5-MeHpA-Leu-NH₂

·Seq ID 91 Gln-Trp-Ala-Val-Gly-His-4-Am，5-MeHpA-Leu-NH₂

Seq ID 101 Gln-Trp-Ala-Val-Gly-His (3Me) -4-Am-5-MeHpA-4-amino-5-methyl

Heptanoic acid-Leu-NH₂

Seq ID 102 Gln-Trp-Ala-Val-NMeGly-His (3Me) -4-Am-5-MeHpA-4-amino-5-

Methylheptanoic acid-Cpa-NH₂。