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WO2009109798A2 - Précurseurs du métabolisme lipidique pour le diagnostic et le traitement du cancer - Google Patents

Précurseurs du métabolisme lipidique pour le diagnostic et le traitement du cancer Download PDF

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Publication number
WO2009109798A2
WO2009109798A2 PCT/IB2008/000542 IB2008000542W WO2009109798A2 WO 2009109798 A2 WO2009109798 A2 WO 2009109798A2 IB 2008000542 W IB2008000542 W IB 2008000542W WO 2009109798 A2 WO2009109798 A2 WO 2009109798A2
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prodrug
cancer
treatment
residue
detectable label
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WO2009109798A3 (fr
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Sven Norbert Reske
Boris Zlatopolskiy
Christoph Solbach
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Universitaet Ulm
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Universitaet Ulm
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Priority to PCT/IB2008/000542 priority Critical patent/WO2009109798A2/fr
Priority to EP08737300A priority patent/EP2268319A2/fr
Publication of WO2009109798A2 publication Critical patent/WO2009109798A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds

Definitions

  • the present invention pertains to methods for the treatment and diagnosis of cancer employing prodrugs for targeting of lipid metabolism comprising either a detectable label or a therapeutic residue.
  • the invention is based on the finding that the present prodrugs are specifically enriched in tumor tissue, in which they may be detected by suitable imaging techniques.
  • a prodrug comprising a therapeutic residue such as a suitable radioactive residue, may be used for the treatment of cancer.
  • Cancer represents one of the leading causes of death, and if current trends continue, cancer is expected to be the leading cause within some years.
  • Lung and prostate cancer represent one of the most frequent cancer killers for men, while lung and breast cancer are the most frequent cancer killers for women.
  • Currently available cancer therapies include surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient.
  • advances in cancer therapy have led to employment of biological therapy and immunotherapy to treat cancer.
  • Surgery may be contraindicated due to the health of the patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue.
  • Hormonal therapy is rarely given as a single agent and although it can be effective, is often used only to prevent or delay recurrence of cancer after other treatments have removed the majority of the cancer cells.
  • Biological and immuno therapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions. Despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks.
  • chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, such as severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant to or develop resistance to the chemotherapeutic agents. In fact, cells resistant to a particular chemotherapeutic agent often prove to be resistant to other drugs, even drugs that act by wholly unrelated mechanisms; the so called pleiotropic drug or multidrug resistance. Thus, many cancers prove refractory to standard chemotherapeutic treatment protocols because of drug resistance.
  • Known assays base for example on the detection of nucleic acids, proteins or other biomarkers released from tumor cells in body fluids.
  • WO2006128192 discloses for example the use of free circulating DNA as a marker for diagnosis, prognosis, and treatment of cancer.
  • the diagnostic and prognostic tumor biomarkers in use today are not adequate in early identification of cancer due to their low sensitivity. Accordingly, there is still a need to develop more robust assays and genotypic markers that can be related to functional tumor biology. There is also a need in developing improved methods in the treatment of cancer.
  • the present invention seeks to overcome the problems associated with prior art methods.
  • the present invention provides particular prodrugs for targeting of lipid metabolism as well as their use for diagnosis and/or the treatment of cancer.
  • the present prodrugs for targeting of lipid metabolism are selected from
  • R represents an aliphatic, aromatic, heterocyclic, aralkylic, heteroaralkylic, or alicyclic substituent comprising a detectable label or a therapeutic residue.
  • the present invention is based on the finding that the present prodrugs for targeting of lipid metabolism are enriched in tumor cells. Labeling said prodrugs for targeting of lipid metabolism with a detectable label renders in vivo or in vitro diagnosis possible, whereas marking with a therapeutic residue permits the treatment of cancer.
  • the present prodrugs for targeting of lipid metabolism are esterified to the respective Acyl-CoA derivatives with coenzyme A (CoA) and enriched in tumor cells by specific interaction with enzymes, such as racemases, of lipid metabolism of the tumor. It has been surprisingly found that the activity said enzymes is highly upregulated in tumor cells giving the possibility to quantitatively, selectively and sensitively detect tumors. Another advantage resides in the possibility to treat tumors with non-invasive techniques, i.e. by administering the present prodrugs for targeting of lipid metabolism exhibiting therapeutic residues, which are almost exclusively incorporated in tumor tissue. Another advantage of the use of the present prodrugs for targeting of lipid metabolism resides is that they may be easily adapted to the changing requirements in the clinical field since the prodrug may be easily provided with another detectable label or therapeutic residue.
  • Fig. 1 shows the synthesis of 11 -aminoundecylmalonic acid and of /?-[*I]-iodobenzoyl-l l- aminoundecylmalonic acid according to an embodiment of the present invention
  • Fig. 2 shows the synthesis of n C-dodecylmalonic acid according to an embodiment of the present invention
  • Fig. 3 shows the synthesis of 11-fluorododecylmalonic acid as well as 11-[ 18 F]- fluorododecylmalonic acid (FSU 01) according to an embodiment of the present invention
  • Fig. 4 shows the synthesis of 13-iodotridecen-12-ylmalonic acid as well as 13-[*Ij- iodotridecen-12-ylmalonic acid according to an embodiment of the present invention
  • Fig. 5 shows an uptake of FSU 01 in prostate carcinoma cells according to an embodiment of the present invention, wherein only a neglectable cellular retention of FSU 01 may be observed after 24 h incubation, suggesting that said compound is metabolically degraded and eliminated from the cell in a quantitative manner;
  • Fig. 6 shows the biodistribution of FSU 01 in the transgene TRAMP - prostate carcinoma - model of the mouse according to an embodiment of the present invention, wherein FSU 01 is fast and intensively enriched in the prostate carcinoma tissue of the primary tumor and in lymph nodes, wherein the remaining organs show only a minor and uniform uptake of FSU
  • FSU 01 with exception of the skeleton and liver and kidney as excretion organs, wherein the high activity of FSU 01 in the bladder is probably due to the degradation to low molecular excretion products and subsequent renal excretion, wherein further analysis has shown that partial enrichment of FSU 01 in lymph nodes and skeleton was due to the formation of metastasis.
  • a “prodrug” and a “prodrug for targeting of lipid metabolism”, i.e. a prodrug of lipid metabolism, as used herein pertains to a pharmacological substance, i.e. a free fatty acid (FFA), which is metabolized in vivo into an active metabolite.
  • FFA free fatty acid
  • Metabolisation is hereby performed inter alia by the action of racemases, i.e. enzymes which may catalyze the inversion around the asymmetric carbon atom in a substrate having one center of asymmetry. It will be, however, appreciated that the substrates of e.g. racemases do not necessarily exhibit a center of asymmetry.
  • the present inventors surprisingly found in cell culture experiments and in mouse model experiments a strong uptake of a radio labelled prodrug of lipid metabolism, such as 2-(l l- [ 18 F]fluoroundecyl)malonic acid (also termed [F18]-FSU 01), in tumor tissue giving raise not only to the detection and/or localisation of the tumor, but also permits treatment of the tumor by employing a suitable therapeutic residue instead of a therapeutic label.
  • a radio labelled prodrug of lipid metabolism such as 2-(l l- [ 18 F]fluoroundecyl)malonic acid (also termed [F18]-FSU 01)
  • detectable label refers to any atom or molecule that may be used to provide a detectable (preferably quantifiable) effect and that can be attached to the present prodrugs.
  • these labels comprise e.g. enzymes which produce a detectable signal, for example by colorimetry, fluorescence or luminescence, such as horseradish peroxidase, alkaline phosphatase, [beta]-galactosidase or glucose-6-phosphate dehydrogenase, chromophores, such as fluorescent, luminescent or dye compounds, groups with an electron density detectable by electron microscopy or by virtue of their electrical property, such as conductivity, amperometry, voltametry or impedance, detectable group, for example the molecules of which are sufficiently large to induce detectable modifications of their physical and/or chemical characteristics; this detection can be carried out by optical methods such as diffraction, surface plasmon resonance, surface variation or contact angle variation, or physical methods such as atomic force spectros
  • Indirect systems may be used as well, such as, for example, ligands capable of reacting with an anti-ligand.
  • the ligand/anti-ligand pairs are well known to those skilled in the art, which is the case, for example, of the following pairs: biotin/streptavidin, hapten/antibody, antigen/antibody, peptide/antibody, sugar/lectin, polynucleotide/sequence complementary to the polynucleotide.
  • the anti-ligand may be detected directly by the labels described above or can itself be detectable by another ligand/anti-ligand pair.
  • An imaging technique as used herein refers to any kind of apparatus or device, capable of producing a visual signal or an image upon detecting a detectable label.
  • the apparatus permits localization of the detectable label within a mammal.
  • These kinds of biological imaging include for example radiology.
  • Non-limiting examples include positron- emission-tomography (PET), which produces a three-dimensional image or map of functional processes in the body.
  • PET positron- emission-tomography
  • the system detects pairs of gamma rays emitted indirectly by a positron-emitting radioisotope, which is introduced into the body on a metabolically active molecule, i.e. a prodrug.
  • Images of metabolic activity in space are then reconstructed by computer analysis, which may be supported by a CT X-ray scan performed on the patient at the same time and in the same device in order to obtain a three dimensional image enabling localization of tissue in which the prodrug is enriched.
  • positron emission a proton is converted via the weak force to a neutron, a positron and a neutrino. Isotopes, which undergo this so called beta plus decay, and thereby emit positrons.
  • Suitable positron-emitting radionuclides for this purpose include 11 C, 13 N, 18 F, 62 Cu, 64 Cu, 68 Ga, 75 Br, 76 Br, 77 Br, 80m Br, 86 Y, 121 I, 124 I of which 11 C and 18 F may be preferred.
  • the present invention should not be assumed to be intended thereto; other radionuclides may be used.
  • the present prodrugs may be also labeled with technetium and rhenium isotopes using known chelating complexes. Methods for the generation of radionuclides as well as radio labeling of compounds are well known to the skilled person. US2007273308 and WO2007122488 pertain e.g.
  • PET is preferably coupled with a computer tomography (CT).
  • CT computer tomography
  • Such PET/CT devices enable quantitative detection and allocation of the signals detected to particular tissues, i.e. a localization of the radionuclides employed and hence of the prodrugs attached thereto.
  • Function and operation of PET/CT as well as devices are well known to the skilled person (cf. Reske, S.N., Der Onkologe, 13(8) (2007) pp.
  • MRT magnetic resonance tomography
  • Spacers or “linkers” are molecules that are characterized in that they have a first end attached to the prodrug and a second end attached to the detectable label or therapeutic residue. Thus, the spacer molecule separates the prodrug and the detectable label or therapeutic residue, but is attached to both.
  • the spacers may be synthesized directly on or may be attached as a whole to the prodrug. Bindings within the spacer may include carbon- carbon single bonds, carbon-carbon double bonds, carbon-nitrogen single bonds, or carbon- oxygen single bonds. In addition, the spacer may have side chains or other substitutions.
  • the detectable label or therapeutic residue may be reacted by suitable means to form for example preferably a covalent bound between the spacer and prodrug.
  • Suitable linkers include alkyl, alkenyl, alkynyl chains, aromatic, polyaromatic, and heteroaromatic rings any of which may be optionally substituted for example with one or more ether, thiooether, ester, amine, sulphonamide, or amide functionality, monomers and polymers comprising ethylene glycol, amino acid, or carbohydrate subunits.
  • the linkers may be chosen to provide good in vivo pharmacokinetics, such as favorable excretion characteristics of the prodrug upon conversion in the mammal. The use of linkers with different lipophilicities and or charge can significantly change the in vivo pharmacokinetics of the prodrug to suit the diagnostic and /or therapeutic needs.
  • Linkers including a polyethylene glycol moiety have been found to slow blood clearance which may be desirable in some circumstances.
  • Spacers may be also in form of chelators capable of forming a complex with the detectable label or therapeutic residue.
  • aliphatic or "aromatic” substituent refers to residues composed of carbon and hydrogen. Aromatic substituents include ring structures, such as benzene, whereas aliphatic compounds do not. The present aliphatic or aromatic substituents may exhibit in addition to the detectable label or therapeutic residue one or more other residues, such as a hydroxy or amino group.
  • lower alkyl refers either to linear alley 1 residues of 1 - 8 C atoms or to branched alkyl residues of 3 - 8 C atoms.
  • Lower alkenyl designates residues exhibiting different numbers of double bounds; the length of said residues is in case linear alkenyl residues 3 - 8 C and branched alkenyl residues from 4 - 8 C atoms, respectively.
  • “Lower alkynyl” is directed to residues exhibiting different numbers of tripple bounds; the length of said residues is 3 - 8 C.
  • Said residues may also have one or more substituents, such as heteroatoms.
  • n is used to designate the number of C-atoms of lower alkyl, alkenyl and alkynyl residues. It will be appreciated that lower alkenyl residues may also contain single bonds, whereas lower alkynyl residues may contain single and/or double bonds.
  • therapeutic residue refers to an atom, such as 32 P, " 7 Cu 5 89 Sr, 88 Y, 90 Y, 123 I, 125 I, 131 I, 153 Sm, 165 Dy; 169 Er, 177 Lu, 178 Ta 5 186 Re, 188 Re, 195m Pt, 211 At, 213 Bi, 225 Ac or a complex containing such an atom in a coordinated form. It will be appreciated that respective radioactive therapeutic residues may be generated and attached to the present prodrugs for targeting of lipid metabolism in the same manner as detectable labels.
  • the use of the present prodrugs with therapeutic residues in cancer treatment combines the advantage of target selectivity with that of being systemic, as with chemotherapy, and it may be used as part of a therapeutic strategy with curative intent or for disease control and palliation.
  • therapeutic residue and detectable label are identical permitting diagnosis and treatment of cancer simultaneously.
  • sample is meant to include any specimen or culture of biological material from a mammal.
  • Biological samples may be human from human origin, fluid, such as blood or urine, solid or tissue.
  • the sample may be used as such in an assay or may be subjected to a preliminary isolation step prior to performing the assay.
  • the samples may be for example taken in order to follow elimination of radionuclides from the body and in order to assure that complete elimination has occurred.
  • room temperature refers to a temperature between 21 and 23 0 C.
  • reduced pressure designates any pressure below atmospheric pressure. A reduced pressure is preferably below 0.1 bar.
  • saturated saline refers to a saturated aqueous NaCl solution.
  • R represents an aliphatic, aromatic, heterocyclic, aralkylic, heteroaralkylic, or alicyclic substituent comprising a detectable label or a therapeutic residue.
  • Free fatty acids represent the substrates of lipid metabolism, lipid conversion and lipid storage particularly in the liver and adipose tissue and energy production in heart and skeletal muscles. FFA are therefore incorporated by heart and liver in great amounts after intravenous injection and dependent from work load and hormonal regulation of the skeletal muscles. FFA further represent important substrates for biosynthesis of cellular membranes, modification of proteins, transcriptional regulation and intracellular signal transduction (Berk, P. D. (1996). "How do long-chain free fatty acids cross cell membranes" Proc Soc Exp Biol Med 212(1): 1 - 4).
  • Energy demand of the tumor and energy metabolism, of, for example, the prostate carcinoma is very low due to a slow growth with a tumor cell growth fraction of around 1% and a very low division rate of tumor cells in comparison to energy demand of the heart muscle or skeletal muscles under workload.
  • the contribution to lipid metabolism is insignificant in comparison to e.g. the liver and membrane biosynthesis of the slow growing tumor cells is notably reduced in comparison to fast proliferating tissue, such as hematopoietic bone marrow or mucosa of the small intestine.
  • tumors comprise inter alia prostate carcinoma, colorectal carcinoma, breast cancer, lung tumors, tumors of the male or female genitourinary system, malignant melanoma, head and neck cancer, malignant lymphoma, neoplasia of the hematopoietic system and musculoskeletal tumors.
  • Characteristic for some of the faster growing tumors is also that they supply their energy demand by highly increased glucose consumption.
  • the cancer is characterized by increased consumption of substrates of tumoral lipid metabolism.
  • cancers/tumors include prostate carcinoma, colorectal carcinoma, breast cancer, lung tumors, tumors of the male or female genitourinary system, malignant melanoma, head and neck cancers, malignant lymphomas, neoplasias of the hematopoietic system and musculoskeletal tumors.
  • PCa prostate carcinoma
  • the prodrug further comprises a linker arranged between said prodrug and said detectable label, in that one end of the linker or spacer is attached to the prodrug, whereas the other end is attached to the detectable label.
  • the linker is preferably selected in a manner to provide good in vivo pharmacokinetics, inter alia by enabling rapid uptake of the prodrug in tumor tissue.
  • said detectable label is a radioactive label.
  • a suitable radioactive label detection with PET preferably PET/CT
  • PET/CT is enabled thus facilitating the localization of tumors in healthy tissue.
  • the radioactive label may be for example of 11 C, 13 N, 18 F, 62 Cu, 64 Cu, 68 Ga, 75 Br, 76 Br, 77 Br, 8Om Br, 86 Y or 124 I.
  • radioactive halogens are employed. More preferably, 11 C and 18 F are used due to their minor influence on the interaction between enzyme and prodrug.
  • said imaging technique is selected from positron-emission- tomography (PET), and positron-emission-tomography/computer tomography (PET/CT).
  • PET/CT is preferred due to the improved possibilities of visualizing/indicating the position and dimensions of a tumor in healthy tissue.
  • Another advantage resides in that even metastasis comprising few tumor cells may be detected and localized.
  • the metastasis comprise preferably less than 10 5 tumor cells, more preferably less than 10 4 tumor cells and most preferably less than 10 2 tumor cells.
  • a prodrug of lipid metabolism wherein said prodrug is selected from
  • R represents an aliphatic, aromatic, heterocyclic, aralkylic, heteroaralkylic, or alicyclic substituent comprising a detectable label or a therapeutic residue.
  • Preferred prodrugs comprise malonic, alpha - methyl - substituted carboxylic acid derivatives with a single substituent, malonic acid monomethylester and malonic acid monoamide. It will be appreciated that the synthesis of appropriate prodrugs for targeting of lipid metabolism is well within the knowledge of the skilled person and that the skilled artisan is not restricted to a particular route of synthesis.
  • P-Iodbenzoyl-l l-aminodecylmalonic acid (standard) and 11-Aminoundecylmalonic acid (precursor) may be produced starting from DMUSM in three steps as outlined in figure 1.
  • the corresponding radio labelled malonic acid derivate may be obtained by acetylating e.g. 11 -aminodecylmalonic acid with p- I-benzene-N-hydroxysuccinate. It will be appreciated that other radio labels or therapeutic residues may be attached in a similar manner.
  • u C-dodecylmalonic acid may be produced (cf. fig. 2).
  • LDA lithium diisopropylamide
  • HMPT hexamethylphosphortriamide
  • the precursor is generated in situ.
  • 11 CO 2 followed by hydrolysis, the 11 C marked product is obtained.
  • the corresponding standard is obtained by hydro lysing of the dimethylester, which is obtained by alcylation of sodium dimethylmalonate with dodecylbromide.
  • 2-Methyl-13-(methylsulfonyloxy)methyltridecanoate serving as precursor for the preparation of 13-[ i8 F]fluoro-2-methyItridecanic acid, is synthesised starting from 2-methyldimethyl- malonate. In the same manner 13-fluoro-2-methyltridecanic acid may be obtained. Synthesis of 3-Hydroxy-(2S)-methylmethylpropionate is known in the state of the art.
  • a synthesis of 13-iodotridecen-12-ylmalonic acid as well as 13- [*I]-iodotridecen-12-ylmalonic acid are synthesized are exemplary outlined in fig.4.
  • Quality control of the compounds may be easily checked by high performance liquid chiOmatographie (HPLC) or in case of e.g. 18 F labelling or another labelling with a halogen by comparison of the retention times of the radio labelled products with those of the respective "cold" standard compounds.
  • HPLC high performance liquid chiOmatographie
  • the prodrug preferably comprises a linker arranged between said prodrug and said detectable label.
  • the linker may be selected in a manner bestowing the present prodrug advantageous properties, such as good in vivo pharmacokinetics.
  • the detectable label preferably comprises a chemoluminescent, fluorescent, bioluminescent, radioactive label or a label detectable by PET, CT or MRT.
  • chemoluminescent, fluorescent, bioluminescent or radioactive labels also in vitro approaches may be used.
  • In vitro assay for the diagnosis of cancer may for example based on interaction with enzymes, e.g. racemases, characteristic for the presence of a tumor from the body.
  • a method is envisaged comprising the steps of providing a sample from a mammal, optionally purifying the sample, adding a present prodrug exhibiting one of the above mentioned markers and detecting the degradation products caused by the activity of enzymes characteristic for the presence of a tumor. It will be appreciated that such methods are well known to the skilled person.
  • prodrug may be alpha - methyl - carboxylic or malonic acids and their derivatives.
  • the prodrug is 2-[l l-[ 18 F]fluoroundecyl]malonic acid (designated [F18]- FSU 01), which has been found to be incorporated in tumor tissue, such as prostate tumor tissue, fast and in high amounts.
  • the aliphatic substituent may be selected from C8 - C20 linear alkyl or C8 - C20 branched alkyl. Instead of an aliphatic substituent also an aromatic substituent may be employed. According to another embodiment of the present invention, the aliphatic substituent may be C9, CI l, C13, C15, C17 or C19 linear alkyl. According to a further embodiment of the present invention, the aliphatic substituent may be Cl 1 linear alkyl.
  • the detectable marker may be selected from the group consisting of 11 C, 13 N, 18 F, 32 P 5 35 S 5 64 Cu, 62 Cu, 67 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, S0m Br, S6 Y, 89 Sr, 88 Y 5 90 Y, 99m Tc, 111 In, 121 I, 123 I, 124 I, 125 I, 127 I, 131 I, 153 Sm, 165 Dy; 169 Er, 1 77 Lu, 178 Ta, 186 Re, ISS Re 295m Pt, 211 At, 213 Bi, 225 Ac.
  • the diagnostic residue may be 11 C, 18 F or 123 I.
  • the therapeutic residue may be preferably selected from the group consisting Of 32 P, 67 Cu, 89 Sr, 88 Y, 90 Y, 123 1, 125 1, 131 I, 153 Sm, 1 65 Dy; 169 Er, 177 Lu, 178 Ta, 186 Re, 188 Re, 195m Pt, 211 At, 213 Bi, 225 Ac.
  • the therapeutic residue may be 90 Y.
  • the detectable marker may be 18 F, 11 C or 123 I. According to an embodiment of the present invention, the detectable marker may be 1 8 F and 123 I.
  • Rl and R2 may be independently selected from H, Cl - C8 linear alkyl, C2 - C8 branched alkyl, C3 - C8 linear alkenyl, C4 - C8 branched alkenyl, C3 - C8 linear alkynyl, or C4 - C8 branched alkynyl.
  • Rl and/or R2 may be H or Cl - C2 linear alkyl, since these residues may easily react with enzymes in tumor tissue due to a reduced steric hindrance. According to another embodiment of the present invention, Rl and/or R2 may be H.
  • a method for the treatment of cancer comprises the steps of providing a prodrug for targeting of lipid metabolism to a mammal, wherein said prodrug comprises a therapeutic residue, administering said prodrug to a mammal.
  • the prodrug may be selected from
  • R represents an aliphatic, aromatic, heterocyclic, aralkylic, heteroaralkylic, or alicyclic substituent comprising a detectable label or a therapeutic residue.
  • the neoplastic tissue i.e. the tumor tissue
  • the therapeutic residue may be selected in order to correspond to a suitable detectable label, in that upon administering of the present prodrug not only enrichment in the target tissue and elimination from the body, but also the activity of the therapeutic residue on the tumor tissue may be observed.
  • the pharmacokinetics may be further influenced by choice of a suitable linker.
  • said therapeutic residue may be selected from the group consisting Of 32 P, 67 Cu, 89 Sr, 88 Y, 90 Y 5 123 I, 125 I 5 131 I, 153 Sm, 165 Dy, 169 Er 5 177 Lu, 178 Ta 5 186 Re 5 188 Re, 195m Pt, 211 At 5 213 Bi, and 225 Ac, According to an embodiment of the present invention, the therapeutic residue may be identical with a detectable label.
  • prodrug may be alpha - methyl - carboxylic or malonic acids and their derivatives.
  • the aliphatic substituent may be selected from C4 - C25 linear alkyl or C4 - C25 branched alkyl.
  • an aromatic substituent may be employed.
  • the aliphatic substituent may be CI l 5 C13 or Cl 5 linear alkyl.
  • the aliphatic substituent may be CI l linear alkyl.
  • Rl and R2 may be independently selected from Cl - C8 linear alkyl, C3 - C8 branched alkyl, C3 - C8 linear alkenyl, C4 - C8 branched alkenyl, C3 - C8 linear alkynyl, and C4 - C8 branched alkynyl.
  • Rl and/or R2 may be H or Cl - C2 linear alkyl, since these residues may easily react with enzymes in tumor tissue due to a reduced steric hindrance.
  • Rl and/or R2 may be H.
  • a cancer to be treated is selected from prostate carcinoma, colorectal carcinoma, breast cancer, lung tumors, tumors of the male or female genitourinary system, malignant melanoma, head and neck cancers, malignant lymphomas, neoplasias of the hematopoietic system and musculoskeletal tumors.
  • the prodrug is administered by intravenous, subcutaneous, intramuscular or intracavitary injection.
  • the prodrug is contained in a pharmaceutical composition.
  • Said composition may be in the form of a parenteral formulation since due to the lipophilic nature of said compound administration via injection is advisable.
  • other kind of formulations such as oral formulations, may be envisaged as well.
  • the methods of preparation may include the step of bringing the active compound into association with a carrier, which constitutes of one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulations.
  • compositions for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non- aqueous liquid; or as an oil-in- water or water-in-oil emulsion.
  • Such compositions may be prepared by any suitable method of pharmacy, which includes the step of bringing into association the active compound and a suitable carrier.
  • the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a power or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispensing agent(s).
  • Molded tablets may be prepared by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose to which may also be added any accessoiy ingredient(s).
  • compositions for oral administration may optionally include enteric coatings known in the art to prevent degradation of the compositions in the stomach and provide release of the drug in the small intestine.
  • compositions suitable for buccal or sub-lingual administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth and pastilles comprising the compound in an inert base such as gelation and glycerin or sucrose and acacia.
  • compositions suitable for parenteral administration comprise sterile aqueous and nonaqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient.
  • compositions may contain anti-oxidants, buffers, bacteriostats and solutes, which render the compositions isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried or a lyophilized condition requiring only the addition of the sterile liquid carrier, for example, saline or water- for- injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the use of the present prodrugs for targeting of lipid metabolism for the treatment and/or prevention of cancer is envisaged.
  • PCa-cell lines were used: LNCaP (human prostate carcinoma, DSMZ Cat.-No. ACC 256) and TRAMP (murine prostate adenocarcinoma, obtainable from LGC Cat. No. CRL-2730; Greenberg, N.M. et al., Proc Natl Acad Sci U S A, 92(8) (1995) pp. 3439-43).
  • PC3 DSMZ Cat.-No. ACC 465) was used as reference.
  • Human colon adenocarcinoma CX-I were obtained from DSMZ Cat.-No. ACC 129.
  • PC3 was cultivated/maintained in 50% Ham's F12 with 50% RPMI, 10% FKS, 1% penicillin + streptomycin, 1% L-glutamate.
  • LNCaP was cultivated/maintained in RPMI with 10% FKS, 1% penicillin + streptomycin, 1% L-glutamate, 1% sodium pyruvate, 1% not essential amino acids.
  • TRAMP cells were cultivated/maintained in DMEM (high glucose), 5% Nu-serum IV, 5 % FKS; 1% penicillin + streptomycin, 10 "s M dihydrotestosterone, 5 ⁇ g/ml insuline.
  • CX-I cells were cultivated/maintained in DMEM (high glucose), 10% FKS.
  • Radioactivity was measured according to manufactures instructions with a ⁇ -counter (Cobra 2, GR Healthcare / Packard Instruments, Palo Alto, USA).
  • THF was distilled under reduced pressure.
  • the residue was diluted with 1 M HCl (10 ml) and water (200 ml).
  • the resulting emulsion was extracted with pentane (100 ml).
  • the pentane solution was washed with 1 M HCl (50 ml), water (10 * 50 ml) and a saturated saline solution (50 ml) and afterwards dried over magnesium sulfate.
  • the target compound (0.43 g, 81%) was obtained as colourless liquid.
  • GE remote controlled synthesis unit of Nuclear Interface
  • [ 18 F]fluoride produced by the cyclotron was fixed on a conditioned (10 ml 1 M NaHCO 3 , 10 ml water) anion exchange cartridge (Sep-Pak light, Accell Plus QMA 5 Waters) and thereby separated from the [ 18 O]water-matrix.
  • [ ] S F]fluoride was eluted with 360 ⁇ L 0,066 M KOH and subsequently 20 mg Kryptofix 2.2.2. in 1 ml acetonitrile was added to a [ 18 F] fluoride solution.
  • the radionuclide was activated for the radiolabeling by means of subsequent azeotropic distillation for 6 min. under vacuum (approx. 6 mbar) until dryness at first 95 0 C and later 100°C.
  • the radiolabeling was conducted by addition of compound (9 mg, 23.65 ⁇ mol) obtained in example 4 in acetonitrile (1 ml) and heating at 85 0 C for 10 min.
  • Not converted [ 18 F] fluoride was removed from the neutralized and diluted reaction mixture by means of a Al 2 ⁇ 3 -carti ⁇ dge (Sep-Pak light, Alumina N 5 Waters) and purified by semipreparative HPLC (stationaiy phase: LiChrospher Select B 5 ⁇ , 250x10 mm, Chromatographic Service; mobile phase: CH 3 CN/H 2 O 60/40 v/v, 0,1 % TFA; flow: 5 ml/min; radioactivity detector and UV- detector (210 nm)) by means of an automated injection unit (flow-detector). The product fraction was isolated after approx. 7 min. by valve switching and was diluted with 50 ml water.
  • Quality control of the produced fluorine- 18 labelled fatty acids was performed by an analytical Radio-HPLC-system (stationary phase: LiChrospher Select B 5 ⁇ , 250x4,6 mm, Chromatographic Service; mobile CH 3 CN/H 2 O 50/50 v/v, 0,1 % TFA; flow: 2 ml/min; radio activity detector und UV-detector (210 nm)).
  • Product identification was performed by comparison of the retention times of the products with those of the respective "cold" standard compounds (the compounds obtained in example 3).
  • Tridecynyl- 12-01-1 (4.95 g, 29.71 mmol), Ph 3 P (11.69 g, 44.57 mmol) and imidazole (3.034 g, 44.57 mmol) were dissolved in THF (50 ml) under argon atmosphere and ice cooling. Iodine (10.406 g 5 41.0 mmol) in THF (20 ml) was added drop wise within 20 min. The reaction mixture was stirred for 2 hours at room temperature. Afterwards saturated Na 2 S 2 O 3 solution (3 ml) was added drop wise within 2 min. The reaction mixture was dried over magnesium sulfate. The obtained residue was extracted with pentane (20 x 50 ml).
  • the pentane solution was washed successively with 1 M KHSO 4 (50 ml), water (5 x 100 ml) and saturated saline (50 ml).
  • the target compound (3.25 g, 80%) was obtained as colourless oil, which crystallizes slowly as colourless solid.
  • the target compound was obtained as a mixture Z/E isomers (30:70), containing less than 5 mol% of the elimination product (tridecyn-12-ylmalonic acid) (0.175 g, > 89%) as colourless solid.
  • Trifluoroacetic acid/acetoniti ⁇ le 10/90 v/v (50 ⁇ l) was added.
  • the reaction mixture was diluted with acetonitrile/water (0.1 % TFA) 33/67 v/v (750 ⁇ l) and separated by a semipreparative HPLC(stationary phase: LiChrospher 60 Select B 5 ⁇ RP C-8; 250 x 10 mm, Chromatographic Service; mobile phase gradient: CH 3 CN with 0,1% TFA and 0.1% TFA 5 0.5 min. 50% CH 3 CN with 0.1% TFA 5 5 - 10 min. 50 - 80% CH 3 CN with 0.1% TFA 5 10 - 50 min.
  • Quality control of the produced radio iodine labelled fatty acid was carried out by analytical radio HPLC (stationary phase: LiChrospher Select B 5 ⁇ , 250x4,6 mm, Chromatographic Service; mobile phase: CH 3 CN/H 2 O 80/20 v/v; flow: 1 ml/min; radio activity detector and TJV-detector (220 nm)).
  • Product identification was carried out by comparison of the retention times of the radio labelled products with that of the respective "cold" standard compound. The radio chemical purity of the product was >95%.
  • PC3 cells serve hereby as androgen independent negative control, whereas LNCap and TRAMP (Greenberg, N.M. et al., Proc Natl Acad Sci U S A 5 92(8) (1995) p. 3439-43) cell lines are both androgen dependent, i.e. exhibiting an enzyme expression profile essentially corresponding to that of human prostate cancer cells in vivo.
  • the cells were incubated for 24 h in the respective media according to the instructions provided by the German Collection of Microorganisms and Cell Cultures.
  • Values at 1 h were determined by removing 100 ⁇ l from each well and adding 900 ⁇ l PBS (activity per well: x ⁇ 10 MBq).
  • Values at 20 h were determined by removing 200 ⁇ l from the original solution and adding directly to each well (200 ⁇ l per well).
  • Tissue/organ uptake of FSU 01 was calculated 30 and 60 min after intravenous application of FSU 01 in a caudal vein (cf. fig. 6).
  • a high uptake of [F-IS]FSU 01 in prostate primary tumors and lymph node metastasis of the prostate carcinoma may be derived therefrom.
  • the 18 F labeled alkylmalonic acid was enriched in the transgene TRAMP mouse model, for example, in prostate carcinoma and its metastasis in lymph nodes more than 10 -
  • control tissue such as periprostatic soft tissues, intestinal tissue, skeletal muscles or normal prostate tissue.

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Abstract

La présente invention porte sur des procédés pour le traitement et le diagnostic d'un cancer à l'aide de promédicaments pour cibler le métabolisme lipidique, comprenant soit un marqueur détectable, soit un résidu thérapeutique. L'invention est basée sur la découverte du fait que les présents promédicaments sont spécifiquement enrichis dans un tissu de tumeur, dans lequel ils peuvent être détectés par des techniques d'imagerie appropriées. En variante, un promédicament comprenant un résidu thérapeutique, tel qu'un résidu radioactif approprié, peut être utilisé pour le traitement du cancer.
PCT/IB2008/000542 2008-03-07 2008-03-07 Précurseurs du métabolisme lipidique pour le diagnostic et le traitement du cancer Ceased WO2009109798A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010010666A1 (de) 2010-03-01 2011-09-01 Sven Reske Diagnose und Therapie von Krebserkrankungen mittels Fettsäuren
WO2013150534A1 (fr) * 2012-04-03 2013-10-10 Aposense Ltd. Nouveaux agents de ciblage pour indications diagnostiques et thérapeutiques
JP2019156796A (ja) * 2018-03-15 2019-09-19 国立大学法人大阪大学 ホウ素クラスター脂質への放射線同位元素標識化法と標識化ホウ素クラスター脂質のウイルス粒子への導入法
KR20220004730A (ko) * 2019-05-10 2022-01-11 샤먼 비보헬쓰 테크놀로지 씨오., 엘티디. 치환된 불소-함유 이미다졸 염 화합물, 이의 제조 방법, 이의 약학적 조성물 및 이의 용도

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128192A2 (fr) 2005-05-27 2006-11-30 John Wayne Cancer Institute Utilisation d'adn en circulation libre pour le diagnostic, le pronostic et le traitement du cancer
WO2007122488A2 (fr) 2006-04-20 2007-11-01 Hammersmith Imanet Limited Composés radiofluorés et leur préparation
US20070273308A1 (en) 2005-12-22 2007-11-29 Sven Fritzler Method for producing radioactive isotopes for positron emission tomography
WO2007148083A2 (fr) 2006-06-21 2007-12-27 Ge Healthcare As Stabilisation de précurseurs radiopharmaceutiques
WO2007148089A2 (fr) 2006-06-21 2007-12-27 Hammersmith Imanet Limited Méthodes de radiomarquage

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6592847B1 (en) * 1998-05-14 2003-07-15 The General Hospital Corporation Intramolecularly-quenched near infrared flourescent probes
US7270799B2 (en) * 2004-01-15 2007-09-18 Nst Neurosurvival Technologies Ltd. Perturbed membrane-binding compounds and methods of using the same
CA2662655A1 (fr) * 2006-09-19 2008-03-27 Metabolon, Inc. Biomarqueurs du cancer de la prostate et procedes les utilisant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128192A2 (fr) 2005-05-27 2006-11-30 John Wayne Cancer Institute Utilisation d'adn en circulation libre pour le diagnostic, le pronostic et le traitement du cancer
US20070273308A1 (en) 2005-12-22 2007-11-29 Sven Fritzler Method for producing radioactive isotopes for positron emission tomography
WO2007122488A2 (fr) 2006-04-20 2007-11-01 Hammersmith Imanet Limited Composés radiofluorés et leur préparation
WO2007148083A2 (fr) 2006-06-21 2007-12-27 Ge Healthcare As Stabilisation de précurseurs radiopharmaceutiques
WO2007148089A2 (fr) 2006-06-21 2007-12-27 Hammersmith Imanet Limited Méthodes de radiomarquage

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
BERK, P. D.: "How do long-chain free fatty acids cross cell membranes", PROC SOC EXP BIOL MED, vol. 212, no. 1, 1996, pages 1 - 4
CZERNIN, J.; M.-E. PHELPS, ANNU REV MED, vol. 53, 2001, pages 89 - 112
GATENBY, R. A.; R. J. GILLIES, NATURE CANCER 4, November 2004 (2004-11-01), pages 891 - 899
GREENBERG, N.M. ET AL., PROC NATL ACAD SCI U S A, vol. 92, no. 8, 1995, pages 3439 - 43
HOYO, N. ET AL., BIOSCI REP, vol. 10, no. 1, 1990, pages 105 - 12
IOZZO, P. ET AL., EUR J NUCL MED MOL IMAGING, vol. 30, no. 8, 2003, pages 1160 - 4
MORRIS, M.J.; H.I., SCHER, EUR. J. NUCL. MED. MOL. IMAGING, vol. 34, no. 2, 2007, pages 181 - 4
RESKE, S. N. ET AL., AM J PHYSIOL IMAGING, vol. 1, no. 4, 1986, pages 214 - 229
RESKE, S. N., J. KOTZERKE, EUR J NUCL MED, vol. 28, no. 11, 2001, pages 1707 - 23
RESKE, S.N ET AL., UROLOGE A, vol. 45, no. 10, 2006, pages 1240 - 1250
RESKE, S.N. ET AL., UROLOGE A, vol. 45, no. 6, 2006, pages 707 - 714
RESKE, S.N., DER ONKOLOGE, vol. 13, no. 8, 2007, pages 677 - 690
SCH6DER, H.; S.M. LARSON, SEMIN NUCL MED, vol. 34, no. 4, 2004, pages 274 - 292
TOGHROL, F. ET AL., TOGHROL, vol. 25, no. 6, 1980, pages 371 - 6

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010010666A1 (de) 2010-03-01 2011-09-01 Sven Reske Diagnose und Therapie von Krebserkrankungen mittels Fettsäuren
WO2013150534A1 (fr) * 2012-04-03 2013-10-10 Aposense Ltd. Nouveaux agents de ciblage pour indications diagnostiques et thérapeutiques
JP2019156796A (ja) * 2018-03-15 2019-09-19 国立大学法人大阪大学 ホウ素クラスター脂質への放射線同位元素標識化法と標識化ホウ素クラスター脂質のウイルス粒子への導入法
KR20220004730A (ko) * 2019-05-10 2022-01-11 샤먼 비보헬쓰 테크놀로지 씨오., 엘티디. 치환된 불소-함유 이미다졸 염 화합물, 이의 제조 방법, 이의 약학적 조성물 및 이의 용도
JP2022532006A (ja) * 2019-05-10 2022-07-13 厦門華綽生物医薬科技有限公司 フッ素含有置換イミダゾール塩系化合物、その製造方法、医薬組成物及びその使用
KR102683706B1 (ko) * 2019-05-10 2024-07-11 샤먼 비보헬쓰 테크놀로지 씨오., 엘티디. 치환된 불소-함유 이미다졸 염 화합물, 이의 제조 방법, 이의 약학적 조성물 및 이의 용도
JP7765811B2 (ja) 2019-05-10 2025-11-07 厦門華綽生物医薬科技有限公司 フッ素含有置換イミダゾール塩系化合物、その製造方法、医薬組成物及びその使用

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