AU6501594A - Bifunctional chelators and their use in radiopharmaceuticals - Google Patents
Bifunctional chelators and their use in radiopharmaceuticals Download PDFInfo
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- AU6501594A AU6501594A AU65015/94A AU6501594A AU6501594A AU 6501594 A AU6501594 A AU 6501594A AU 65015/94 A AU65015/94 A AU 65015/94A AU 6501594 A AU6501594 A AU 6501594A AU 6501594 A AU6501594 A AU 6501594A
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- cys
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- ile
- leu
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- 239000012217 radiopharmaceutical Substances 0.000 title claims description 20
- 229940121896 radiopharmaceutical Drugs 0.000 title claims description 20
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims description 20
- 239000002738 chelating agent Substances 0.000 title description 7
- 230000001588 bifunctional effect Effects 0.000 title description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 2
- 239000001433 sodium tartrate Substances 0.000 description 2
- 229960002167 sodium tartrate Drugs 0.000 description 2
- 235000011004 sodium tartrates Nutrition 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
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- VUMNOGGTHUAKKG-MFKWGIFDSA-N (8R,9S,10R,13S,14S)-13-(3-iodoprop-2-enyl)-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one Chemical compound IC=CC[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(CC[C@@H]3[C@H]1CC2)=O VUMNOGGTHUAKKG-MFKWGIFDSA-N 0.000 description 1
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- BQHFYSWNHZMMDO-UHFFFAOYSA-N 2-[2-[(1-carboxy-2-sulfanylethyl)amino]ethylamino]-3-sulfanylpropanoic acid Chemical compound OC(=O)C(CS)NCCNC(CS)C(O)=O BQHFYSWNHZMMDO-UHFFFAOYSA-N 0.000 description 1
- RXACEEPNTRHYBQ-UHFFFAOYSA-N 2-[[2-[[2-[(2-sulfanylacetyl)amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)CNC(=O)CNC(=O)CS RXACEEPNTRHYBQ-UHFFFAOYSA-N 0.000 description 1
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- LRZSAGKIMYFLHY-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;dihydrate Chemical compound O.O.OC(=O)CC(O)(C(O)=O)CC(O)=O LRZSAGKIMYFLHY-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- AUFACLFHBAGZEN-ZLUOBGJFSA-N Ala-Ser-Cys Chemical compound N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O AUFACLFHBAGZEN-ZLUOBGJFSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
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- 241000581444 Clinidae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 206010073306 Exposure to radiation Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 101100128278 Mus musculus Lins1 gene Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000000211 autoradiogram Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
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- 230000005251 gamma ray Effects 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005179 haloacetyl group Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- VCMGMSHEPQENPE-UHFFFAOYSA-N ketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1C1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 125000003473 lipid group Chemical group 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
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- 229920000656 polylysine Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- LKFCPWBGBPJDRC-UHFFFAOYSA-M potassium;thiobenzate Chemical compound [K+].[O-]C(=S)C1=CC=CC=C1 LKFCPWBGBPJDRC-UHFFFAOYSA-M 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 150000003281 rhenium Chemical class 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 229940069575 rompun Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1 Bifunctional chelating agents, their technetium and rhenium complexes, methods for their production, and radiopharma ceuticals containing these compounds. This invention relates to new technetium and rhenium 5 chelates, methods for their production, and radiopharmaceu ticals containing these compounds as well as to conjugates of these compounds with substances that accumulate selec tively in diseased tissue, in particular, peptides and proteins. This invention further relates to the production 10 of agents containing these compounds and their application in radiodiagnostics. Radioactive metal ions have been in use in medical diagnostics and for therapy for a longer period of time. For example, gamma-ray emitters such as the Tc-99m isotope 15 were used for detecting tumours. -ray emitters such as the Re-186, Re-188, and Re-189 isotopes were applied in tumour therapy. Technetium-99m is the most frequently applied radionuclide in nuclear medicine as it is particularly suitable as an isotope for in-vivo diagnostics due to its 20 favourable physical properties (no corpuscular radiation, physical half-life of 6 h, y-radiation 140 keV) and the low exposure to radiation resulting from them. Technetium-99m is easily gained from nuclide generators in the form of pertechnetate. It can be immediately used in this form to 25 produce kits for clinical routine applications. The efficiency of radionuclides in in-vivo diagnostics as well as for therapeutical purposes is dependent on the specificity and selectivity of the labelled chelates with regard to the target cell. An improvement of these 30 properties can be achieved by coupling the chelates with biomolecules according to the "drug targeting" principle. Antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are the obvious substances for use as biomolecules. For example, British 2 patent application GB 2,109,407 describes the use of radiolabelled monoclonal antibodies against tumour associated antigens for in-vivo tumour diagnostics. Direct labelling of protein using technetium-99m, either via donor 5 groups (amino, amide, thiol groups, etc.) of the protein (Rhodes, B.A. et al., J. Nucl. Med. 1986, 27, 685-693) or by introducing complexing agents (US Patent 4,479,930 and Fritzberg, A.R. et al., J. Nucl. Med. 1986, 27, 957) were described likewise. These experimental methods, however, 10 are not available for clinical application because their selectivity is too low and their background activity is too high to facilitate in-vivo imaging. The first receptor-binding radiopharmaceuticals were described by J.P. DiZio et al. (J. Nucl. Med. 1992, 33; 15 558-569 and Bioconjugate Chem. 1991, 2; 353-366). These compounds were not found suitable for in-vivo imaging. The fact that the compounds described have to be extracted from the labelling medium has proved to be a great disadvantage. These conditions are unsatisfactory as a user should be 20 exposed to as little radiation as possible when preparing the kit and because of the fact that only few clinics have suitable laboratories for carrying out such work. Cyclic amines as described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891-896) and Troutner et al. (J. Nucl. Med. 25 1980, 21; 443-448) as well as N 2
S
2 and N 3 S systems are per se of little use as tissue-specific radiopharmaceuticals as they lack reactive groups to combine with biomolecules or proteins (M. Borel et al., Appl.Radiat.Isot. 1992, 43, 425 436). 30 While pH values from 10 to 13 are required for labelling the above mentioned cyclic amines as well as N 2 0 2 systems known from literature (Pillai, M.R.A. et al.; Inorg. Chem. 1990, 29, 1850-1856),
N
2
S
2 and N 3 S systems can already be complexed, as a rule, at pH values from 9 to 11. But these 35 conditions are still too extreme for labelling unstable 3 conjugates of biomolecules and macromolecules. This is all the more true as some systems such as L,L-ethylene dicysteine (L,L-EC) can only be sufficiently labelled at pH values > 10 (Verbruggen, A.M. et al.; J. Nucl. Med. 1992, 5 33, 551-557). MAG 3 as it is known from literature even requires exposure for ten minutes to temperatures from 90 to 100 oC (Bannister, K.M. et al.; J. Nucl. Med. 1990, 31, 1568-1573) to be produced in a radiochemical purity that is sufficient for clinical applications. These conditions are 10 not satisfactory for everyday clinical routine.
N
2
S
2 and N 3 S systems as described by G. Bormans et al. (Nucl. Med. Biol. 1990, 17, 499-506) and in European Patent Specifications EP 0 173 424 and EP 0 250 013 meet the requirement of sufficient stability of the respective 15 technetium-99m complexes but are discharged too rapidly and without specific accumulation in the organism. Thus they are only used clinically, though to a limited extent, in renal function diagnostics. Their use is limited mainly because the demand has increased for substances that accu 20 mulate specifically in diseased tissues. To solve the refined problems of nuclear medicine, there is an increasing need for stable bifunctional complexing agents that do not show the disadvantages mentioned when complexing and are capable of forming conjugates with bio 25 molecules and macromolecules without considerably affecting the specificity and selectivity of the latter. At the same time, all requirements regarding radiation dose, stability, and solubility have to be met to use these compounds in human beings. 30 It is thus a problem of this invention to provide these compounds and conjugates, to create a fairly simple method for their production, and to provide a kit formulation for clinical application of these compounds/conjugates according to the invention. The present invention solves 35 this problem.
4 The compounds according to the invention are characterized by the general formula (I) R CH Y - Z CH III S N - R 8 (A') M
(A
3 ) R' 6(A 2 ) 5 wherein (Al) , (A 2 ) , and (A 3 ) are same or different and represent the general formula (CHR%) O (CHR 2 3
(CR
4
R
5 )k 10 X their free valences being linked arbitrarily with the respective nitrogen or sulfur atoms, and wherein 5
R
3 and R 5 are same or different and represent a hydrogen atom, or a methyl or ethyl group, and
R
4 is a hydrogen atom, a branched or unbranched alkyl group containing 1 to 4 carbon atoms, the C atoms of which may 5 optionally carry additional amino groups, N(RaRb) groups (with Ra and Rb being either same or different and repre senting branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, carboxy, or amino 10 group), hydroxy groups, thiol groups, halogens, carboxy groups, alkoxy carbonyl groups containing 1 to 20 carbon atoms, acyloxy groups containing 1 to 12 carbon atoms, amino carbonyl groups, sulfonyl groups, amino sulfonyl groups, or phosphorus residues, 15 R 2 and R 9 are same or different and represent the same as R4, k, 1, and m are same or different and stand for the numbers 0, 1, 2, 3, or 4, and X is a hydrogen atom, a carboxy group, an alkoxy group 20 containing 1 to 20 carbon atoms, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon atoms, an amino carbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethyl amino carbonyl group, a p-amino 25 phenyl group, a p-hydroxyphenyl group, a halogen atom, a hydroxy group, an amino group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally 30 carry one additional hydroxy, carboxy, or amino group), a hydrazine group, a hydrazide group, a cholesteryl oxycarbonyl methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl 6 oxycarbonyl group, another steroid or a derivative of an ethinyl or ethenyl steroid, a substituent of the formula Zl-Yl-(CH 2
)-Q-CO
5 where Q is an -NH- or -0-,
Z
1 has the same meaning as Z, Yl has the same meaning as Y, and i has the same meaning as m, 10 a substituent of the formula V - U - Q1 where
Q
1 is an -NH-, -CO-, or -0-, U is a bond, a group of the formula -(OCH 2 CO)h- with h=1-3, 15 or a suitable linker for coupling with bio- or macromole cules, and V is a hydrogen atom, a hydroxy group, an N(RaRb) group (with Ra and Rb being either same or different and repre senting branched or unbranched alkyl or acyl residues 20 containing 1 to 20 carbon atoms, the C atoms of which may optionally carry one additional hydroxy, carboxy, or amino group), a biomolecule, or a macromolecule, and Y is an unsaturated unbranched or branched chain of up to 12 carbon atoms containing at least one double and/or 25 triple bond which may, optionally, carry additional one or several and at any position in the chain, hydroxy, carboxy, alkoxy, amino, or substituted amido groups containing 1 to 20 carbon atoms in the alkyl and/or aryl residue, Z is a hydrogen atom, a halogen atom, a carboxy group, a 30 hydroxy group, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon 7 atoms, an alkoxy group containing 1 to 20 carbon atoms, a cholesteryl oxycarbonyl methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid or a derivative 5 of an ethinyl or ethenyl steroid, a substituent of the formula V - U - Q1 where
Q
1 is an -NH-, -CO-, or -0-, 10 U is a bond, a group of the formula -(OCH 2 C=O)h- with h=1 3, or a suitable linker for coupling with bio- or macro molecules, and V is a hydrogen atom, a hydroxy group, an N(RaRb) group (with Ra and Rb being either same or different and repre 15 senting branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry one additional hydroxy, carboxy, or amino group), a biomolecule, or a macromolecule, and M is an element having the atomic number 43 or 75, 20 R 1 has the same meaning as R4,
R
6 , R 7 , and R 8 are same or different and represent a hydro gen atom, an alkyl group containing 1 to 4 carbon atoms, the C atoms of which may carry additional hydroxy, carboxy, or amino groups, or a group of the formula -CH 2 -X in which 25 X has the above meaning and their hydrosoluble salts. Preferred compounds according to the invention of the general formula (I) are characterized in that the residue Z is a hydrogen atom, a steroid, an ethinyl steroid or an 30 ethenyl steroid.
8 Furthermore, compounds according to the invention of general formula (I) are preferred that are characterized in that residue Z is a hydrogen atom, a steroid, an ethinyl steroid or an ethenyl steroid, and that residue X is a 5 hydrogen atom, a halogen atom, a carboxy group, an amino group, or an amido group containing 1 to 20 carbon atoms in their alkyl and/or aryl residue. In addition, compounds according to the invention of general formula (I) are preferred that are characterized in 10 that residue Z is a hydrogen atom, a steroid, an ethinyl steroid or an ethenyl steroid, and that residue X is a hydrogen atom, a halogen atom, a carboxy group, an amino group, or an amido group containing 1 to 20 carbon atoms in the alkyl and/or aryl residue, Y is an ethinylide group, 15 residues R 1 , R 3 , R 6 , R 7 , and R 8 represent hydrogen atoms, and k, 1, and m each represent the number 0. Another group of preferred compounds according to the invention of general formula (I) is characterized in that residue Z is a hydrogen atom, and residue X is a choles 20 teryl oxycarbonyl methyl amino carbonyl group, a choles teryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid or a derivative of an ethine or ethene steroid. Furthermore, preferred compounds according to the invention 25 of general formula (I) are characterized in that residue Z is a hydrogen atom, residue X is a cholesteryl oxycarbonyl methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid or a derivative of an ethine or ethene 30 steroid, residue Y is an ethinylide group, and that residues R 1 , R 3 , R 6 , R 7 , and R 8 represent hydrogen atoms, and k, 1, and m each represent the number 0. A third group of preferred compounds according to the invention of general formula (I) is characterized in that 9 residue Z is a hydrogen atom, residue X is a hydrogen atom, a carboxy group, or a substituent of the formula V - U - Q1 where 5 Q 1 is an -NH-, -CO-, or -0-, U is a bond, a group of the formula -(OCH 2 CO)h- with h=1-3, or a suitable linker for coupling with bio- or macromole cules, and V is a hydrogen atom, a hydroxy group, an N(RaRb) group 10 (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, carboxy, or amino group), a biomolecule, or a macromolecule. 15 Other preferred compounds according to the invention of general formula (I) are characterized in that residue Z is a hydrogen atom, residue X is a hydrogen atom, a carboxy group, or a substituent of the formula V - U - Q 20 where
Q
1 is an -NH-, -CO-, or -0-, U is a bond, a group of the formula -(OCH 2 CO)h- with h=1-3, or a suitable linker for coupling with bio- or macromole cules, and 25 V is a hydrogen atom, a hydroxy group, an N(RaRb) group (with Ra and Rb being either same or different and repre senting branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, carboxy, or amino 30 group), a biomolecule, or a macromolecule, that residue Y is an ethinylide group, and that residues R 1 , R 3 , R 6 , R 7 , and R 8 represent hydrogen atoms, and k, 1, and m each represent the number 0.
10 A fourth group of preferred compounds according to the invention of general formula (I) is characterized in that residue Z is a hydrogen atom, and residue X is a hydrogen atom, a carboxy group, an alkoxy group containing 1 to 20 5 carbon atoms, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon atoms, an amino carbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethyl amino carbonyl group, a p-aminophenyl group, a p-hydroxy 10 phenyl group, a halogen atom, a hydroxy group, an amino group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, 15 carboxy, or amino group), a hydrazine group, or a hydrazide group. In addition, compounds according to the invention of general formula (I) are characterized in that residue Z is a hydrogen atom, and residue X is a hydrogen atom, a 20 carboxy group, an alkoxy group containing 1 to 20 carbon atoms, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon atoms, an amino carbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethyl amino 25 carbonyl group, a p-aminophenyl group, a p-hydroxyphenyl group, a halogen atom, a hydroxy group, an amino group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms 30 of which may optionally carry an additional hydroxy, carboxy, or amino group), a hydrazine group, or a hydrazide group, that residue Y is an ethinylide group, and that residues R 1 , R 3 , R 6 , R 7 , and R 8 represent hydrogen atoms, and k, 1, and m each represent the number 0.
11 The present invention further relates to compounds of the general formula (II) R'Y-Z T CH S N R" (A') (A 3 ) \ / N6 N R (A 2 ) 5 wherein Al, A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y and Z have the meaning specified above and wherein T is a hydrogen atom, an acetate group, a benzoate group, a p-methoxybenzyl group, an acetamidomethyl group, a benzamidomethyl group, a 10 trimethyl acetamidomethyl group, a hydroxy acetyl group, or another suitable sulfur protective group. Another object of this invention are conjugates of com pounds according to the invention of general formulae (I) and (II) with substances that accumulate selectively in 15 tissues. The fragments are bonded amidically, imidically, or ester-like, depending on the kind of substances to be conjugated. If the substances that accumulate in the tissues are peptides, proteins, antibodies, or fragments thereof, they are bonded amidically through their amino 20 groups; if the substances that accumulate in the tissues contain hydroxy groups, they are bonded ester-like; and if the substances that accumulate in the tissues contain aldehyde groups, they are bonded imidically.
12 Such substances accumulating in tissues are preferred that accumulate in diseased tissues, above all in tissues that have atherosclerotic plaques. 5 Furthermore, conjugates according to the invention are preferred that are characterized in that the substances that accumulate in diseased tissue are peptides such as endothelines, partial endotheline sequences, endotheline 10 analogues, endotheline derivatives, or endotheline antagonists. Particularly preferred conjugates according to the invention are characterized in that the peptides comprise 15 the following sequences or parts thereof: cys-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr Li 20 phe-cys-his-leu-asp-ile-ile-trp, 25 phe-cys-his-leu-asp-ile-ile-trp, I -- I cys-thr-cys-phe-thr-tyr-lys-asp-lys-glu-cys-val-tyr 30 tyr-cys-his-leu-asp-ile-ile-trp, cys-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyr phe-cys-his-leu-asp-ile-ile-trp, 35 13 cys-ser-cys-asn-ser-trp-leu-asp-lys-glu-cys-val-tyr phe-cys-his-leu-asp-ile-ile-trp, 5 cys-ser-cys-lys-asp-met-thr-asp-lys-glu-cys-leu-asn phe-cys-his-gln-asp-val-ile-trp, 10 ala-ser-cys -r-ser-leu-met-asp-lys-glu-cys-val-tyr phe-ala-his-leu-asp-ile-ile-trp, 15 ala-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyr phe-ala-his-leu-asp-ile-ile-trp, cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-ala-val-tyr phe-ala-his-leu-asp-ile-ile-trp, 20 cys-val-tyr-phe-cys-his-leu-asp-ile-ile-trp, N-acetyl-leu-met-asp-lys-glu-ala-val-tyr-phe-ala-his-leu 25 asp-ile-ile-trp, or the partial sequence his-leu-asp-ile-ile-trp 30 or the cyclic amino acid sequences Cyclo-(Dtrp-Dasp-pro-Dval-leu), 35 Cyclo-(Dglu-ala-alloDile-leu-Dtrp).
14 The compounds according to the invention of the general formula (I) R C Y - Z CH S N - R" (A) M
(A
3 ) R"N NR7 RS (A 2 )R 5 are produced according to a method known to a person skilled in the art, for example, by reacting, in the presence of a reductant (such as Sn(II) chloride or dithionide) and, optionally, an auxiliary ligand (such as 10 sodium citrate or sodium tartrate), technetium-99m in the form of pertechnetate which is easily eluted from molyb denum-technetium generators, with a compound of the general formula (II) R Y--Z T CH S N--R"
(A
1 )
(A
3 ) 15 (A 2
)
15 wherein Al, A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y, Z, and T have the meaning specified above. The reaction is preferably carried out in an aqueous medium 5 at room temperature. The SH protective group is split off in situ or according to the methods known to a person skilled in the art from the relevant literature, e.g. basic hydrolysis, reductive decomposition, etc. (see, for example, "Protective Groups in Organic Synthesis", T.W. 10 Greene, John Wiley and Sons 1981). Another object of the present invention are methods for the production of compounds according to the invention of the general formula (II) R Y Z T CH S N R 8 (A')
(A
3 ) 15
(A
2 ) characterized in that, in a generally known way, a) a compound of the general formula (III) 16 R C Y Z CH Hal N R (A')
(A
3 ) RS 6 N (A 2 ) R wherein A', A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y and Z have the meaning 5 specified above and Hal represents a halogen, is reacted with a compound of the general formula T - S- M+ wherein M+ is an alkaline metal cation and T has the meaning specified above, 10 or, b) a compound of the general formula
HN(R
6 ) -A 2
-N(R
7 ) -A 3
-N(R
8 ) -Y-Z wherein A 2 , A 3 , R 6 , R 7 , and R 8 have the meaning specified above, are reacted with 15 a compound of the general formula T - S - Al - W wherein Al and T have the meaning given in Claim 11, and W represents a leaving group which enables Al to react with free amino acids. 20 The N-haloacetyl amides required as parent substances are produced according to methods known from the relevant literature by acylating an amino function using haloacetyl 17 halides (JACS, 1969, 90, 4508; Chem. Pharm. Bull. 1981, 29(1), 128). The required amines of the general formula
HN(R
6 ) -A 2
-N(R
7 ) -A 3
-N(R
8 ) -Y-Z 5 are synthesized according to methods of peptide synthesis known from the relevant literature (see, for example, "The Practice of Peptide Synthesis", M. Bodanszky and A. Bodanszky; Springer Verlag, 1984, and Fieser, Reagents for Organic Synthesis 10, 142). N-protected a- and $-amino 10 acids are coupled, according to methods known to a person skilled in the art such as a (primary or secondary) amine addition/ elimination reaction, with N-unprotected organic molecules using a carbonyl compound (such as acid chloride, mixed anhydride, activated ester). After separating the 15 amino protecting group according to methods known from literature (such as basic hydrolysis, hydrogenolysis, reductive decomposition using alkaline metals in liquid ammonium), the remaining amino acid is re-derivated in a second reaction using an N-protected a- and 1-amino acid 20 according to methods known from the relevant literature (e.g. the carbodiimide method). The amino protecting group is separated according to the above-mentioned methods described in the literature. The compounds of the general formula 25 T - S - Al - W that are also required are synthesized by converting the carboxy group(s) of respective carboxylic acids according to methods known to a person skilled in the art, for example, according to the diimide method (Fieser, Reagents 30 for Organic Synthesis 10, 142), via a mixed or cyclic anhydride (Org. Prep. Proc. Int. 1975, 7, 215), or using an activated ester (Adv. Org. Chem. Part B, 472).
18 The compounds according to the invention show the desired properties to a great extent. The radionuclides required for their application are stably bound in the complex. 5 The coupling options of the chelating agents according to the invention are of particular interest; these agents can be viewed as being trifunctional as they facilitate coupling via a multiple bond as well as via a carboxy or amino group besides metal complexing in Al, A 2 , or A 3 . 10 It is of particular relevance to the invention that labelling methods be provided which permit rapid and quantitative reaction of the compounds of the invention under more gentle conditions than those of known methods, and immediately before use of the radiopharmaceutical. 15 It is of great advantage to link the chelating agent with steroids via the multiple bond as this allows both coupling to a -CH 2 group of the steroid or bonding to the 17-ethinyl or 17-ethenyl group of steroids. Some technetium-99m labelled steroid derivatives have a 20 surprisingly strong affinity for their respective steroid hormone receptor. Thus, the technetium complex of 3,17@ dihydroxy-17a- (5- [2-benzoylthioacetyl-glycyl-glycyl] amino-pent- 1 - (E) -en-3-in) -1,3,5-estratriene (Example 13b) showed a similar receptor affinity as 17p-estradiol in an 25 in-vitro cytosol test (Carlson, K.E. et al. 1989, 32, 345 355). This makes these compounds excellently suited for re ceptor imaging using technetium-99m and for the diagnosis and therapy of steroid-dependent tumours. Another advantage of the present invention is the fact 30 that, due to the option of linking either via the carboxy group or via the multiple bond, it allows to control the solubility and pharmacokinetics of the complexes by chemi cal substitution at the level of complexing agents.
19 Biodegradable groups or linkers in X are of particular significance here. Compounds containing lipophilic substituents in X or Z show surprising properties, such as the compound of Example 9, 5 as they accumulate in atherosclerotic plaques and thus provide a way to visualize atherosclerotic modifications on vessel walls. Selection of appropriate bio- and macromolecules (e.g. monoclonal antibodies, steroids, ... ) in X or Z yields 10 complexes according to the invention that show a surpris ingly great extent of tissue and organ specificity and may therefore contribute excellently to solving a number of diagnostic and therapeutical problems. The complexing ligands obtained in this way of the general 15 formula (II) in which Z is a hydrogen atom and/or ligands of the general formula (II) containing an ethinyl function may be coupled with iodovinyl steroids according to methods known to a person skilled in the art (e.g. R. Rossi et al., Tetrahedron 1983, 39, 287). The iodovinyl steroids required 20 are synthesized according to methods known from the relevant literature (e.g. H. Hofmeister et al., Tetrahedron 1986, 42, 3575). The carboxy groups of compounds of the general formula (II) may be converted, for example, according to the diimide 25 method (Fieser, Reagents for Organic Synthesis 10, 142), via a mixed or cyclic anhydride (Org. Prep. Proc. Int. 1975, 7, 215), or using an activated ester (Adv. Org. Chem. Part B, 472). The chelating agents are coupled to bio- or macromolecules 30 according to methods known to a person skilled in the art by converting the carboxy group(s) at the chelating agent, for example, according to the diimide method (Fieser, Reagents for Organic Synthesis 10, 142), via a mixed or 20 cyclic anhydride (Org. Prep. Proc. Int. 1975, 7, 215), or using an activated ester (Adv. Org. Chem. Part B, 472), and subsequent formation of a covalent bond by reaction with a nucleophilic group of the bio- or macromolecule. 5 The chelating agents obtained in this way may also be linked with bio- or macromolecules that are known to accu mulate to a particularly great extent in the organ, organic part, or tissue to be examined. Among such molecules are, for example, enzymes, hormones, polysaccharides such as 10 dextrane or starches, porphyrins, bleomycins, insulin, prostaglandins, steroid hormones, amino sugar, amino acids, peptides such as polylysine, proteins (such as immoglobu lins, monoclonal antibodies, lectins), lipides (including liposomes), and nucleotides of the DNA and RNA types. 15 Conjugates with albumins such as human serum albumin, with antibodies such as monoclonal antibodies, antibodies spe cific to tumour-associated antigens, or antimyosin are of particular significance here. Suitable synthetic polymers such as polyethylene imines, polyamides, etc. may be linked 20 instead of biological macromolecules. The pharmaceuticals produced from these conjugates are suited for application in tumour diagnostics and tumour therapy, diagnosis of atherosclerosis, or receptor imaging. Bonding affinity and specificity of the produced pharmaceu 25 tical to the target organ, target organ part, or target tissue should be impaired only slightly, or not at all, by forming the conjugate. The radiopharmaceuticals of the invention are also produced in a generally known way by dissolving or suspending the 30 complexing agents according to the invention and their conjugates in an aqueous medium, optionally by adding the adjuvants common in galenics, and subsequent optional lyophilization of the solution or suspension. Among the suitable additives are physiologically tolerable buffers 35 (such as tromethamine), auxiliary ligands (such as sodium 21 citrate or sodium tartrate), reductants (such as tin (II) chloride) or, if required, electrolytes such as sodium chloride, or, if required, (one of) the adjuvants common in galenics (such as lactose, mannite) and/or surfactant(s) 5 (such as lecithine, Tween@, Myrj®). The composition of additives used should facilitate the production of the compounds according to the invention. Another object of the present invention is a kit for pro ducing radiopharmaceuticals consisting of a compound of the 10 general formula (II), a reductant and, optionally, an auxiliary ligand, said substances being either dry or in solution, instructions for use including instructions for reacting the compounds described with technetium-99m or rhenium in the form of a pertechnetate or perrhenate 15 solution. The radiopharmaceuticals according to the invention are applied at doses from 0.1 mCi to 50 mCi, preferably at a dose between 0.5 mCi and 30 mCi, per 70 kg of a patient's body weight. Details of application and dosage are de 20 scribed, for example, in "Radiotracers for Medical Applica tions" CRC Press, Boca Raton, Florida. The radiopharmaceu ticals are designed for intravenous administration. For radiodiagnostic and radiotherapeutic purposes, the complex compounds/conjugates are used in the form of complexes with 25 radionuclides of elements having the atomic numbers 43 or 75. The radiopharmaceuticals according to the invention meet the various requirements to be appropriate for use as radiopharmaceuticals in radiodiagnostics and radiotherapy. 30 They are excellently suited for accumulating in target tissues after i.v. administration, thus permitting a non invasive diagnosis of the respective tissues. Solubility in water of the radiopharmaceuticals according to the invention is ensured, if required, by adjuvants common in 35 galenics as described above. In addition, the radiopharma- 22 ceuticals according to the invention do not only have great in-vitro stability but also a surprisingly great in-vivo stability; therefore, there is no, or at least no clini cally relevant, release or exchange of the radionuclide 5 bound in the complex. The preferred radiopharmaceuticals according to the inven tion are furthermore characterized in that they contain the compounds according to the invention of the general formu lae (I) or (II) in the form of liposomes, and that the 10 compound according to the invention of general formula (I) is optionally prepared in a kit using technetium or rhenium in the form of their permetallates. The radiopharmaceuticals according to the invention may also be used in radioimmuno- or radiation therapy. These 15 differ from radiodiagnostics only in the type and quantity of radionuclide used. Its objective is to destroy tumour cells using short-wave rays of a fairly short range. Among the suitable -ray emitting isotopes are rhenium-186 and rhenium-188. 20 The radiopharmaceuticals according to the invention are suited for non-invasive in-vivo imaging of tissues containing steroid receptors, for example, steroid hormone dependent tumours. The radiopharmaceuticals according to the invention are 25 suited for non-invasive in-vivo imaging of atherosclerotic vessel changes, for example, of plaques. All in all, new complexing agents and metal complexes have been successfully synthesized that open up new ways for 30 diagnostic and therapeutic medicine. This is desirable mainly with a view to the development of novel imaging procedures for nuclear diagnostics.
23 The invention shall now be explained in more detail by the following examples.
24 Example 1 a) S-benzoyl thioacetyl glycyl glycyl propargyl amide [la] A solution of 215.1 mg (1.22 mmol) of potassium thiobenzoate in anhydrous DMF is added by dropping, and in a nitrogen 5 atmosphere, to a solution of 150 mg (0.61 mmol) of chloro acetyl glycyl glycyl propargyl amide in anhydrous DMF. Then, catalytic quantities of sodium iodide are added, and the batch is heated for 2 hours to 110 OC. After cooling down to room temperature, the reaction mixture is stirred into 1 N 10 HCl and extracted with acetic ester until the product is no longer contained in the aqueous phase. The organic phases are evaporated to dryness under reduced pressure, again taken up in acetic ester, washed with water, and dried above Mg 2
SO
4 . After drawing off the solvent under reduced pres 15 sure, the product is recrystallized from methanol or, if re quired, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). Yield: 76% of the title compound [la]
C
16
H
17
N
3 0 4 S (MW: 347.39) 20 1 H NMR (d 6 -DMSO): 6 = 3.11 (t; 1H, -CECH) 3.69 (d; 2H, -NH(CH 2 )CO-) 3.78 (d; 2H, -NH(CH 2 )CO-) 3.84 - 3.88 (m; 2H, -NH(CH 2 )-C=CH) 25 3.90 (s; 2H, -SCH 2 CO-) 7.55 - 7.61 (m; 2H, ArH) 7.69 - 7.74 (m; 1H, ArH) 7.93 - 7.97 (m; 2H, ArH) 8.20 (t; 1H, -NH-) 30 8.27 (t; 1H, -NH-) 8.50 (t; 1H, -NH-) 25 b) Technetium-99m complex [1b] of S-benzoyl thioacetyl glycyl glycyl propargyl amide A solution of 0.5 mg (1.44 ymol) of S-benzoyl thioacetyl glycyl glycyl propargyl amide [la] in 50 pl of 1 N soda lye 5 is diluted with 250 pl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/l, pH 8.5). Afterwards, 50 yl of 0.15 molar trisodium citrate dihydrate solution and 2.5 pl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution 10 (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; 15 gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na2HPO4; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na 2
HPO
4 ; 0.01 mol; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 20 95%. Example 2 a) 2-acetyl thiosuccinyl glycyl glycyl propargyl amide 25 [2a] 5.89 g of (37.5 mmol) of glycyl glycyl propargyl amide are dissolved in a nitrogen atmosphere in 60 ml of anhydrous DMF, mixed with 8.50 g (48.7 mmol) of acetyl mercaptosuc cinic anhydride and kept agitated overnight at room 30 temperature. The reaction mixture is then evaporated to dryness under reduced pressure. The residue is suspended in methanol, filtered off by suction, and recrystallized from water. Yield: 61% of the title compound [2a] 35 C 1 3
H
1 7
N
3 0 6 S (MW: 343.36) 26 1 H NMR (d 6 -DMSO): 6 = 2.35 (s; 3H, -COCH 3 ) 2.66; 2.83 (2x dd; 2H, -(CH 2 )COOH) 2.99 (t; 1H, -CECH) 5 3.70 - 3.77 (m; 4H, 2x -NH(CH 2 )-CO) 3.88 (dd; 2H, -NH(CH 2 )-C=CH) 4.35 (t; 1H, S-CH(CH 2
COOH)-CH
2 -) 8.07 (t; 1H, -NH-) 8.12 (t; 1H, -NH-) 10 8.26 (t; 1H, -NH-) b) Technetium- 9 9 m complex [1b] of 2-acetyl thiosuccinyl glycyl glycyl propargyl amide A solution of 0.5 mg (1.45 ymol) of 2-acetyl thiosuccinyl 15 glycyl glycyl propargyl amide [2a] in 50 yl of 0.1 N soda lye is diluted with 250 pl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/1, pH 8.5). Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 2.5 yl of 0.2 molar tin(II) chloride dihydrate solution are added. The 20 reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: 25 MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na2HPO4; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na2HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. 30 Radiochemical purity of the Tc-99m complex is more than 95%.
27 Example 3 a) S-acetyl thioacetyl glutaminyl glycyl propargyl amide [3a] A solution/suspension of 2.0 g (8.3 mmol) of glutaminyl 5 glycyl propargyl amide in 80 ml of anhydrous DMF is slowly mixed with a solution of 5.3 g (8.4 mmol) of S-acetyl mercaptoacetic N-hydroxysuccinimide ester in anhydrous THF. The mixture is hydrolyzed after 4 hours of stirring at room temperature. Then the solvent is removed under reduced 10 pressure, and the residue recrystallized from methanol/water. Yield: 45% of the title compound [3a]
C
1 4
H
1 9
N
3 0 6 S (MW: 357.36) 1 H NMR (d 6 -DMSO): 15 6 = 1.64 - 1.92 (m; 2H, -CHCH 2
CH
2 COOH) 2.31 (s; 3H, -COCH 3 ) 2.36 (t; 2H, -CHCH 2
CH
2 COOH) 3.02 (t; 1H, -C=-CH) 3.70 (s; 2H, -NH(CH29-CO) 20 3.73 - 3.80 (m; 1H, -CHCH 2
CH
2 COOH) 3.89 (dd; 2H, -NH(CH 2 )-C=CH) 8.09 (m; 1H, -NH-) 8.19 (m; 1H, -NH-) 8.26 (m; 1H, -NH-) 25 b) Technetium-99m complex [3b] of S-acetyl thioacetyl glutaminyl glycyl propargyl amide A solution of 0.5 mg (1.40 ymol) of S-acetyl thioacetyl glutaminyl glycyl propargyl amide [3a] in 50 pl of 0.1 N soda lye is diluted with 250 yl of phosphate buffer 30 (Na 2
HPO
4 , 0.5 mol/l, pH 8.5). Afterwards, 50 yl of 0.15 molar trisodium citrate dihydrate solution and 2.5 pl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated 28 at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 pm; 5 gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na2HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 10 Example 4 a) S-acetyl thioacetyl glycyl glutaminyl propargyl amide [4a] A solution/suspension of 2.0 g (8.3 mmol) of glycyl 15 glutaminyl propargyl amide in 80 ml of anhydrous DMF is slowly mixed with a solution of 5.3 g (8.4 mmol) of S acetyl mercaptoacetic N-hydroxysuccinimide ester in anhydrous THF. The mixture is hydrolyzed after 4 hours of stirring at room temperature. Then the solvent is removed 20 under reduced pressure, and the residue recrystallized from methanol/water. Yield: 61% of the title compound [4a]
C
1 4
H
1 9
N
3 0 6 S (MW: 357.36) 1 H NMR (d 6 -DMSO): 25 6 = 1.60 - 1.88 (m; 2H, -CHCH 2
CH
2 COOH) 2.30 (s; 3H, -COCH 3 ) 2.28 (t; 2H, -CHCH 2
CH
2 COOH) 3.04 (t; 1H, -C=-CH) 3.68 (s; 2H, -NH(CH2)-CO) 30 3.70 - 3.77 (m; 1H, -CHCH 2
CH
2 COOH) 3.88 (dd; 2H, -NH(CH 2 )-C=CH) 4.19 (s; 2H, -SCH 2 CO-) 8.11 (m; 1H, -NH-) 8.23 (m; 1H, -NH-) 29 8.35 (m; 1H, -NH-) b) Technetium-99m complex [4b] of S-acetyl thioacetyl glycyl glutaminyl propargyl aide A solution of 0.5 mg (1.40 pmol) of S-acetyl thioacetyl 5 glycyl glutaminyl propargyl amide [4a] in 50 pl of 0.1 N soda lye is diluted with 250 pl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/l, pH 7.5). Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 2.5 yl of 0.2 molar tin(II) chloride dihydrate solution are added. 10 The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 pm filter). Labelling is analyzed using HPLC: 15 MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. 20 Radiochemical purity of the Tc-99m complex is more than 95%. Example 5 a) S-(p-methoxybenzyl) cysteinyl glycyl glycyl propargyl amide [5a] 25 9.8 g (0.02 mol) of N-tert.-butoxycarbonyl-S-(p-methoxyben zyl) cysteinyl glycyl glycyl propargyl amide are dissolved at OOC in trifluoroacetic acid and stirred in an ice bath for 4 hours. Then the solution is evaporated to dryness under reduced pressure, the residue is mixed with ethanol 30 and evaporated once again. The residue is purified by column chromatography above silica gel [CH 2 Cl 2
/CH
3 0H (5:1)]. The product crystallizes after evaporating. Yield: 93% of the title compound [5a] 30
C
1 8
H
2 4
N
4 0 4 S (MW: 392.48) 1 H NMR (CD 3 0D): 6 = 2.54 (t; 1H, -C=CH) 2.63 - 2.86 (m; 2H, -CHCH 2 S-) 5 3.48 - 3.52 (m; 1H, -CHCH 2 S-) 3.71 (s; 2H, -NH(CH 2 )CO-) 3.77 (s; 3H, -OCH 3 ) 3.85 (s; 2H, -NH(CH 2 )CO-) 3.92 (s; 2H, -CH 2 Ar) 10 3.97 (dd; 2H, -NH(CH2)-C=CH) 6.86; 7.25 (AA'BB'; 4H, ArH) b) Technetium-99m complex of cysteinyl glycyl glycyl propargyl amide [5b] A solution of 0.5 mg (1.27 ymol) of S-(p-methoxybenzyl) 15 cysteinyl glycyl glycyl propargyl amide [5a] in liquid HF is stirred for 15 minutes at 0 0 C. After evaporating the solvent at room temperature, the residue is taken up in 50 pl of 1 N soda lye and diluted with 250 yl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/l, pH 7.5) . Afterwards, 50 pl of 20 0.15 molar trisodium citrate dihydrate solution and 2.5 pl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 ym 25 filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0); 30 eluent B: acetonitrile/phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%.
31 Example 6 a) N-[2-acetylthio-3-cholesteryl oxycarbonyl propionyl] glycyl glycyl propargyl amide [6a] A solution of 5.0 g (8.9 mmol) of 3-acetylthio cholesterol 5 succinate in anhydrous THF is cooled in an ice bath and mixed in excess with dry triethyl amine. Afterwards, 1.9 g (17.8 mmol) of ethyl chloroformate are added by dropping. The batch is allowed to warm up to 0*C, then mixed with 3.0 g (18.0 mmol) of glycyl glycyl propargyl amide and 10 stirred at room temperature for 3 hours. The reaction mixture is hydrolyzed with water and extracted with acetic ester until the product is no longer contained in the aqueous phase. The organic phases are evaporated to dryness under reduced pressure, again taken up in acetic ester, 15 washed with water, and dried above Mg 2
SO
4 . After drawing off the solvent under reduced pressure, the product is recrystallized from methanol or, if required, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). Yield: 67% of the title compound (6a] 20
C
4 0
H
6 1
N
3 0 6 S (MW: 712.01) 1H NMR (CDCl 3 ) = 0.68 - 2.08 (m; 41H, steroidal) 2.30 (d; 2H, -C=CHCH 2 - steroidal) 2.32 (s; 3H, -COCH 3 ) 25 2.76 - 3.00 (m; 2H, -(CH 2 )COO-) 3.10 (t; 1H, -C=CH) 3.66 - 3.73 (m; 4H, 2x -NH(CH 2 )CO-) 3.84 (d; 2H, -NH(CH 2 )-C=CH) 4.39 (t; 1H, -S-CH(CH 2
COOH)-CH
2 -) 30 4.52 - 4.63 (m; 1H, -(CH)O steroidal) 5.48 (d; 1H, -C=CH- steroidal) 8.05 (t; 1H, -NH-) 8.11 (t; 1H, -NH-) 8.23 (t; 1H, -NH-) 32 b) Technetium-99m complex [6b] of N-[2-acetylthio-3 cholesteryl oxycarbonyl propionyl]-glycyl glycyl propargyl amide A solution of 0.5 mg (0.7 pmol) of N-[2-acetylthio-3 5 cholesteryl oxycarbonyl propionyll-glycyl glycyl propargyl amide [6a] in 300 pl of DMSO is mixed with 30 pl of 1 N soda lye. Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc-99m generator are added. The 10 reaction mixture is mixed in portions with 10 pl of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and filtered (0.2 pm filter). Labelling is analyzed using HPLC: 15 MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 30 min; eluent A: acetonitrile/water 50:50 (V/V); eluent B: acetonitrile; flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 20 95%. Example 7 a) Cholesterol-[N-(2-acetylthio succinyl glycyl glycyl propargyl amide-4-yl)glycine] ester (7a] 25 A solution of 2.0 mg (5.8 mmol) of 2-acetylthio succinyl glycyl glycyl propargyl amide [2a] in anhydrous THF is cooled in an ice bath and mixed in excess with dry triethyl amine. Afterwards, 1.3 g (11.6 mmol) of ethyl chloroformate are added by dropping. The batch is allowed to warm up to 30 OoC, then mixed with 5.0 g (12.0 mmol) of glycine cholesterol ester and stirred at room temperature for 3 hours. The reaction mixture is hydrolyzed with water and extracted with acetic ester until the product is no longer 33 contained in the aqueous phase. The organic phases are evaporated to dryness under reduced pressure, again taken up in acetic ester, washed with water, and dried above Mg 2
SO
4 . After drawing off the solvent under reduced pressure, the 5 product is recrystallized from methanol or, if required, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). Yield: 41% of the title compound [7a]
C
4 2
H
6 4
N
3 0 6 S (MW: 769.06) 1 H NMR (CD 3 0D): 10 S = 0.68 - 2.10 (m; 41H, steroidal) 2.32 (d; 2H, -C=CHCH 2 - steroidal) 2.33 (s; 3H, -COCH 3 ) 2.81 - 3.10 (m; 2H, -CH(CH 2 )COO-) 3.08 (t; 1H, -C=CH) 15 3.41 (d; 2H, -NH(CH 2 )CO-) 3.64 - 3.71 (m; 4H, 2x -NH(CH 2 )CO-) 3.83 (d; 2H, -NH(CH 2 )-C=CH) 4.35 (t; 1H, -S-CH(CH 2
COOH)-CH
2 -) 4.61 - 4.72 (m; 1H, -(CH)O- steroidal) 20 5.38 (d; 1H, -C=CH- steroidal) 8.05 (t; 1H, -NH-) 8.09 (t; 1H, -NH-) 8.13 (t; 1H, -NH-) 8.25 (t; 1H, -NH-) 25 b) Technetium-99m complex [7b] of cholesterol-[N-(2 acetylthio-succinyl glycyl glycyl propargyl amide-4 yl)glycine] ester A solution of 0.5 mg (0.65 pmol) of cholesterol-N-[2 30 acetylthio-succinyl glycyl glycyl propargyl amide-4 yl)glycine] ester [7a] in 300 pl of DMSO is mixed with 30 pl of 0.1 N soda lye. Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc-99m generator are 35 added. The reaction mixture is mixed in portions with 10 pl 34 of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and filtered (0.2 sm filter). Labelling is analyzed using HPLC: 5 MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 30 min; eluent A: acetonitrile/water 50:50 (V/V); eluent B: acetonitrile; flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 10 95%. Example 8 a) N-dodecanoyl-S-(p-methoxybenzyl) cysteinyl glycyl glycyl propargyl amide [8a] 15 2.0 g (5.1 mmol) of S-(p-methoxybenzyl) cysteinyl glycyl glycyl propargyl amide [5a] are dissolved in CH 2 Cl 2 and mixed with a small amount of NEt 3 . Afterwards, 1.2 g (5.5 mmol) of dodecanoic acid chloride in CH 2 Cl 2 are added by dropping and stirred at room temperature for 2 hours. The 20 mixture is hydrolyzed with water and extracted with CH 2 Cl 2 After drying, the product is evaporated under reduced pressure and the residue chromatographed using
CH
2 Cl 2 /MeOH (9:1) above silica gel. Yield: 80% of the title compound [8a] 25
C
3 0
H
4 6
N
4 0 5 S (MW: 574.79) 1 H NMR (d 6 -DMSO): 8 = 0.85 (t; 3H, -(CH 2
)
8
CH
3 ) 1.19 - 1.30 (m; 16H, -(CH2) 8
CH
3 ) 1.46 - 1.54 (m; 2H, -CH 2
-CH
2 CONH) 30 2.08 - 2.20 (m; 2H, -CH 2
-CH
2 CONH) 2.51 - 2.79 (m; 2H, -CHCH 2 S) 3.08 (t; 1H, -C=CH) 3.74 (s; 3H, OCH 3 ) 3.67 - 3.78 (m; 4H, 2x -NH(CH 2
)CO-)
35 3.76 (d; 2H, -CH 2 Ar) 3.85 - 3.88 (m; 2H, -NH(CH 2 )-C=CH) 4.49 - 4.55 (m; 1H, -CHCH 2 S-) 6.85; 7.23 (AA'BB'; 4H, ArH) 5 8.04 - 8.09 (m; 2H, 2x -NH-) 8.22 (m; 1H, -NH-) 8.33 (m; 1H, -NH-) b) Technetium-99m complex [8b] of N-dodecanoyl cysteinyl glycyl glycyl propargyl amide 10 A solution of 0.5 mg (0.9 ymol) of N-dodecanoyl cysteinyl glycyl glycyl propargyl amide [8a] in liquid HF is stirred for 15 minutes at 04C. After evaporating the solvent at room temperature, the residue is dissolved in 300 pl of DMSO and mixed with 30 pl of 1 N soda lye. Afterwards, 50 15 pl of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc 99m generator are added. The reaction mixture is mixed in portions with 10 pl of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and 20 filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0); 25 eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%.
36 Example 9 a) N-(3-hexadecyl aminocarbonyl-2-acetylthio-propionyl) glycyl glycyl propargyl amide [9a] A solution of 2.0 g (5.8 mmol) of 2-acetylthio succinyl 5 glycyl glycyl propargyl amide [2a] in anhydrous THF is cooled in an ice bath and mixed with 1.7 g (7.0 mmol) of hexadecylamine. Afterwards, 1.47 g (7.0 mmol) of dicyclo hexyl carbodiimide in anhydrous THF mixed with 2 ml of triethyl amine are added by dropping at 0CC. The batch is 10 allowed to warm up to room temperature and stirred for 3 hours at this temperature. The reaction mixture is mixed with a few drops of acetic acid, hydrolyzed with water and extracted with acetic ester until the product is no longer contained in the aqueous phase. The organic phases are 15 evaporated to dryness under reduced pressure, again taken up in acetic ester, washed with water, and dried above Mg 2
SO
4 . After drawing off the solvent under reduced pressure, the product is recrystallized from methanol or, if required, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). 20 Yield: 69% of the title compound [9a]
C
2 9
H
5 0
N
4 0 5 S (MW: 566.81) 1 H NMR (d 6 -DMSO): 3 = 0.87 (t; 3H, -CH 2
CH
3 ) 1.16 - 1.35 (m; 28H, -(CH 2
)
1 4
CH
3 ) 25 2.33 (s; 3H, -COCH 3 ) 2.73 - 3.10 (m; 4H, -(CH 2 )-) 3.07 (t; 1H, -C=-CH) 3.67 - 3.76 (m; 4H, 2x -NH(CH 2 )CO-) 3.85 - 3.89 (m; 2H, -NH(CH 2 )-C=CH) 30 4.29 - 4.35 (m; 1H, -S-CH(CH 2
COOH)-CH
2 -) 7.99 (t; 1H, -NH-) 8.07 (t; 1H, -NH-) 8.15 - 8.23 (m; 2H, 2x -NH-) 37 b) Technetium-9 9 m complex [9b] of N-(3-hexadecyl aminocarbonyl- 2 -acetylthio-propionyl) glycyl glycyl propargyl amide A solution of 0.5 mg (0.9 ymol) of N-(3-hexadecyl 5 aminocarbonyl-2-acetylthio-propionyl) glycyl glycyl propargyl amide[9a] in 300 pl of DMSO is mixed with 30 pl of 1 N soda lye. Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechne tate solution from a Mo-99/Tc-99m generator are added. The 10 reaction mixture is mixed in portions with 10 pl of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: 15 MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. 20 Radiochemical purity of the Tc-99m complex is more than 95%. Example 10 a) N-dodecanoyl homocysteinyl glycyl glycyl propargyl amide [10a] 25 A solution of 2.0 g (6.7 mmol) of N-dodecanoyl homocysteinyl thiolactone in anhydrous THF is mixed with a solution of 1.2 g (7.0 mmol) glycyl glycyl propargyl amide in DMF. After adding 1 ml of triethyl amine, the batch is refluxed for 3 hours. It is then evaporated under reduced 30 pressure, the residue is taken up in CH 2 Cl 2 and washed with diluted HCl. The organic phases are washed neutrally with water and dried above Mg 2
SO
4 . After evaporating the solvent under reduced pressure, the product is recrystallized from 38 methanol and, optionally, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). Yield: 58% of the title compound [10a]
C
23
H
40
N
4 0 4 S (MW: 468.66) 5 1 H NMR (d 6 -DMSO): = 0.86 (t; 3H, -(CH 2
)
8
CH
3 ) 1.20 - 1.33 (m; 16H, -(CH 2
)
8
CH
3 ) 1.48 - 1.57 (m; 2H, -CH 2
-CH
2 CONH-) 2.10 - 2.19 (m; 2H, -CH 2
-CH
2 CONH-) 10 2.56 - 2.73 (m; 2H, -CHCH 2
CH
2 SH) 3.10 (t; 1H, -C=CH) 3.38 - 3.44 (m; 2H, -CHCH 2
CH
2 SH) 3.52 (s; 1H, -SH) 3.65 - 3.73 (m; 4H, 2x -NH(CH 2 )CO-) 15 3.86 - 3.90 (m; 2H, -NH(CH 2 )-C=CH) 4.48 - 4.54 (m; 1H, -CHCH 2
CH
2 SH) 8.05 - 8.10 (m; 2H, 2x -NH-) 8.24 (t; 1H, -NH-) 8.35 (t; 1H, -NH-) 20 b) Technetium-99m complex [10b] of N-dodecanoyl homocysteinyl glycyl glycyl propargyl amide A solution of 0.5 mg (1.06 pmol) of N-dodecanoyl homocys teinyl glycyl glycyl propargyl amide [10a] in 300 pl of DMSO is mixed with 30 pl of 1 N soda lye. Afterwards, 50 pl 25 of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc-99m generator are added. The reaction mixture is mixed in portions with 10 pl of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and 30 filtered (0.2 pm filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0); 39 eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 5 Example 11 a) N-decanoyl homocysteinyl glycyl glycyl propargyl amide [11a] A solution of 2.0 g (7.4 mmol) of N-decanoyl homocysteinyl 10 thiolactone in anhydrous THF is mixed with a solution of 1.35 g (8.0 mmol) of glycyl glycyl propargyl amide in DMF. After adding 1 ml of triethyl amine, the batch is refluxed for 3 hours. It is then evaporated under reduced pressure, the residue is taken up in CH 2 Cl 2 and washed with diluted 15 HCl. The organic phases are washed neutrally with water and dried above Mg 2
SO
4 . After evaporating the solvent under reduced pressure, the product is recrystallized from methanol and, optionally, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). 20 Yield: 67% of the title compound [11a]
C
2 1
H
3 6
N
4 0 4 S (MW: 440.61) 1 H NMR (d 6 -DMSO): = 0.85 (t; 3H, -(CH 2
)
6
CH
3 ) 1.18 - 1.30 (m; 12H, -(CH 2
)
6
CH
3 ) 25 1.45 - 1.53 (m; 2H, -CH 2
-CH
2 CONH-) 2.11 - 2.22 (m; 2H, -CH 2
-CH
2 CONH-) 2.55 - 2.70 (m; 2H, -CHCH 2
CH
2 SH) 3.09 (t; 1H, -C=-CH) 3.37 - 3.42 (m; 2H, -CHCH 2
CH
2 SH) 30 3.50 (s; 1H, -SH) 3.65 - 3.75 (m; 4H, 2x -NH(CH 2 )CO-) 3.87 - 3.92 (m; 2H, -NH(CH 2 )-C=CH) 4.48 - 4.53 (m; 1H, -CHCH 2
CH
2 SH) 8.08 - 8.12 (m; 2H, 2x -NH-) 40 8.22 (t; 1H, -NH-) 8.32 (t; 1H, -NH-) b) Technetium-99m complex [llb] of N-decanoyl homocysteinyl glycyl glycyl propargyl amide 5 A solution of 0.5 mg (1.1 pmol) of N-decanoyl homocysteinyl glycyl glycyl propargyl amide [11a] in 300 pl of DMSO is mixed with 30 pl of 1 N soda lye. Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc-99m generator 10 are added. The reaction mixture is mixed in portions with 10 pl of 0.2 molar tin(II) chloride dihydrate solution, incubated at room temperature for 10 minutes, and filtered (0.2 pm filter). Labelling is analyzed using HPLC: 15 MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. 20 Radiochemical purity of the Tc-99m complex is more than 95%. Example 12 a) N-hexanoyl homocysteinyl glycyl glycyl propargyl aide 25 [12a] A solution of 2.0 g (9.3 mmol) of N-hexanoyl homocysteinyl thiolactone in anhydrous THF is mixed with a solution of 1.7 g (10.0 mmol) of glycyl glycyl propargyl amide in DMF. After adding 1 ml of triethyl amine, the batch is refluxed 30 for 3 hours. It is then evaporated under reduced pressure, the residue is taken up in CH 2 Cl 2 and washed with diluted HCl. The organic phases are washed neutrally with water and dried above Mg 2
SO
4 . After evaporating the solvent under 41 reduced pressure, the product is recrystallized from methanol and, optionally, purified by column chromatography using CH 2 Cl 2 /MeOH (9:1). Yield: 60% of the title compound [12a] 5 C 1 7
H
2 8
N
4 0 4 S (MW: 384.50) 1H NMR (d 6 -DMSO): 6 = 0.86 (t; 3H, -(CH 2
)
2
CH
3 ) 1.20 - 1.31 (m; 12H, -(CH 2
)
2
CH
3 ) 1.47 - 1.54 (m; 2H, -CH 2
-CH
2 CONH-) 10 2.10 - 2.19 (m; 2H, -CH 2
-CH
2 CONH-) 2.56 - 2.68 (m; 2H, -CHCH 2
CH
2 SH) 3.11 (t; 1H, -CsCH) 3.36 - 3.40 (m; 2H, -CHCH 2
CH
2 SH) 3.51 (s; 1H, -SH) 15 3.67 - 3.76 (m; 4H, 2x -NH(CH 2 )CO-) 3.85 - 3.89 (m; 2H, -NH(CH2)-C=CH) 4.47 - 4.54 (m; 1H, -CHCH 2
CH
2 SH) 8.03 - 8.10 (m; 2H, 2x -NH-) 8.20 (t; 1H, -NH-) 20 8.29 (t; 1H, -NH-) b) Technetium-99m complex (12b] of N-hexanoyl homocysteinyl glycyl glycyl propargyl aide A solution of 0.5 mg (1.3 ymol) of N-decanoyl homocysteinyl glycyl glycyl propargyl amide [11a] in 300 pl of DMSO is 25 mixed with 30 pl of 1 N soda lye. Afterwards, 50 Al of 0.15 molar trisodium citrate dihydrate solution and 0.4 to 0.9 mCi of pertechnetate solution from a Mo-99/Tc-99m generator are added. The reaction mixture is mixed in portions with 10 y1 of 0.2 molar tin(II) chloride dihydrate solution, 30 incubated at room temperature for 10 minutes, and filtered (0.2 pm filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 pm; gradient from 100% A to 100% B within 7.5 min; 35 eluent A: phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0); 42 eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 5 Example 13 a) 3,170-dihydroxy-17a-[5-(2-benzoyl thioacetyl glycyl glycyl) amino pent-i-(E)-en-3-in]-1,3,5-estratriene [13a] 10 A suspension of 120.0 mg (0.24 mmol) of 17p-hydroxy-17a iodovinyl-1,3,5-estratriene-3-tetrahydropyranyl ether, 0.3 g (0.85 mmol) of S-benzoyl thioacetyl glycyl glycyl propargyl amide [la], 10.0 mg (0.044 mmol) of benzyl triethyl ammonium chloride, 10.6 mg (9.2 pmol) of 15 tetrakis(triphenyl phosphine)palladium(0), and 8.15 mg (0.043 mmol) of copper(I) iodide in 4 ml of toluene is stirred at room temperature for 72 hours. Then the mixture is mixed with water, extracted twice with toluene, and dried above Mg 2
SO
4 . After evaporating the solvent under 20 reduced pressure, the residue is taken up in 5 ml of THF, mixed with 150 mg (0.6 mmol) of pyridine toluene-p-sulfonic acid in 5 ml of ethanol, and refluxed for 3 hours. Then the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography using 25 CH 2 Cl 2 /MeOH (8:1). Yield: 41% of the title compound [13a]
C
3 6
H
4 1
N
3 0 6 S (MW: 643.80) 1 H NMR (d 6 -DMSO): 6 = 0.86 (t; 3H, -CH 3 steroidal) 30 1.15 - 2.30 (m; 13H, steroidal) 2.65 - 2.74 (m; 2H, -CH 2 - steroidal) 3.72 (d; 2H, -NH(CH 2 )CO-) 3.81 (d; 2H, -NH(CH2)CO-) 3.90 (s; 2H, -SCH 2
CO-)
43 4.02 (d; 2H, -NH(CH 2 )-C=C-) 5.65; 6.35 (AB; 2H, -CH=CH-) 6.43 (d; 1H, steroidal) 6.50 (dd; 1H, steroidal) 5 7.00 (d; 1H, steroidal) 7.44 - 7.49 (m; 2H, ArH) 7.51 - 7.56 (m; 2H, ArH) 7.90 - 7.96 (m; 2H, ArH) 8.23 (t; 1H, -NH-) 10 8.27 (t; 1H, -NH-) 8.80 (t; 1H, -NH-) b) Technetium-99m complex [13b] of 3,17f-dihydroxy-17a-[5 (2-benzoyl thioacetyl glycyl glycyl) amino pent-i-(E) 15 en-3-in]-1,3,5-estratriene A solution of 0.5 mg (0.8 ymol) of 3,17-dihydroxy-17a-[5 (2-benzoyl thioacetyl glycyl glycyl) amino pent-l-(E)-en-3 in]-1,3,5-estratriene [13a] in 250 pl of ethanol is mixed with 50 pl of 1 N soda lye and incubated at room 20 temperature for 15 minutes. Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 2.5 pl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated 25 at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: HAMILTON PRP-1 column, 125 x 4.6 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; 30 eluent A: acetonitrile; eluent B: acetonitrile/phosphate buffer (Na 2
HPO
4 ; 0.001 mol; pH 7.4) 50:50 (V/V); flow rate: 2.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 35 44 Example 14 a) 170-hydroxy-17a-[5-(2-benzoyl thioacetyl glycyl glycyl) amino pent-1-(E,Z)-en-3-inl]-1,3,5-estrene- 3 -on [14a] A suspension of 120.0 mg (0.28 mmol) of 170-hydroxy-17a 5 iodovinyl-4-estrene-3-on, 0.3 g (0.85 mmol) of S-benzoyl thioacetyl glycyl glycyl propargyl amide [la], 10.0 mg (0.044 mmol) of benzyl triethyl ammonium chloride, 10.6 mg (9.2 pmol) of tetrakis(triphenyl phosphine)palladium(0), and 8.15 mg (0.043 mmol) of copper(I) iodide in 4 ml of 10 toluene is stirred at room temperature for 72 hours. Then the mixture is mixed with water, extracted twice with toluene, and dried above Mg 2
SO
4 . After evaporating the solvent under reduced pressure, the residue is taken up in 5 ml of THF, mixed with 150 mg (0.6 mmol) of pyridine 15 toluene-p-sulfonic acid in 5 ml of ethanol, and refluxed for 3 hours. Then the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography using CH 2 Cl 2 /MeOH (8:1). Yield: 39% of the title compound [14a] 20
C
3 6
H
4 3
N
3 0 6 S (MW: 645.80) 1 H NMR (d 6 -DMSO): = 0.95 (t; 3H, -CH 3 steroidal) 0.82 - 2.50 (m; 20H, steroidal) 3.68 (d; 2H, -NH(CH 2 )CO-) 25 3.80 (d; 2H, -NH(CH 2 )CO-) 3.87 (s; 2H, -SCH 2 CO-) 3.94 - 3.98 (m; 2H, -NH(CH 2 )-C=C-) 5.60; 5.95 (AB; 2H, -CH=CH-) 5.82 (s; 1H, steroidal) 30 7.41 - 7.45 (m; 2H, ArH) 7.49 - 7.54 (m; 2H, ArH) 7.85 - 7.90 (m; 2H, ArH) 8.24 (t; 1H, -NH-) 8.29 (t; 1H, -NH-) 35 8.78 (t; 1H, -NH-) 45 b) Technetium-99m complex [14b] of 17P-hydroxy-17a-[5-(2 benzoyl thioacetyl glycyl glycyl) amino pent-i-(E,Z) en-3-in]-4-estrene-3-on 5 A solution of 0.5 mg (0.8 ymol) of 17-hydroxy-17a-[5-(2 benzoyl thioacetyl glycyl glycyl) amino pent-l-(E,Z)-en-3 in]-4-estrene-3-on [14a] in 250 pl of ethanol is mixed with 50 pl of 1N soda lye and incubated at room temperature for 15 minutes. Afterwards, 50 yl of 0.15 molar trisodium 10 citrate dihydrate solution and 2.5 pl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 sm filter). 15 Labelling is analyzed using HPLC: HAMILTON PRP-1 column, 125 x 4.6 mm, 5 pm; gradient from 100% A to 100% B within 7.5 min; eluent A: acetonitrile; eluent B: acetonitrile/phosphate buffer (Na2HPO 4 ; 0.001 20 mol; pH 7.4) 50:50 (V/V); flow rate: 2.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. Example 15 25 a) S-acetyl thioacetyl sarcosyl glycyl propargyl amide [15a] A solution of 1.54 g (8.4 mmol) of sarcosyl glycyl propargyl amide in 30 ml of anhydrous THF is slowly mixed with a solution of 5.3 g (8.4 mmol) of S-acetyl 30 mercaptoacetic acid N-hydroxy succinimide ester in anhydrous THF. The mixture is stirred at room temperature for 4 hours and then heated for 30 minutes to 40 0 C. After cooling, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography above 46 silica gel [CH 2 Cl 2
/CH
3 0H (9:1)]. The product crystallizes from ethanol. Yield: 88% of the title compound [15a]
C
1 2
H
1 7
N
3 0 4 S (MW: 299.35) 5 1 H NMR (d 6 -DMSO): = 2.34 (s; 3H, -COCH 3 ) 2.81 (s; 3H, -N-CH 3 ) 3.07 (t; 1H, -CHCH) 3.70 (d; 2H, -NH(CH 2 )CO-) 10 3.82 (s; 2H, -NH(CH2)CO-) 3.86 - 3.90 (m; 2H, -NH(CH 2 )-C=CH) 3.93 (s; 2H, SCH 2 CO-) 8.13 (t; 1H, -NH-) 8.22 (t; 1H, -NH-) 15 b) Technetium-99m complex (15b] of S-acetyl thioacetyl sarcosyl glycyl propargyl amide A solution of 0.5 mg (1.67 pmol) of S-acetyl thioacetyl sarcosyl glycyl propargyl amide [15a] in 50 pl of 0.1 N soda lye is diluted with 250 pl of phosphate buffer 20 (Na 2
HPO
4 , 0.5 mol/l, pH 8.5). Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 2.5 yl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated 25 at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; 30 eluent A: phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na2HPO 4 ; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 35 47 Example 16 a) 2-(S-acetylthio)succinyl sarcosyl glycyl propargyl amide [16a] 8.89 g (48.5 mmol) of sarcosyl glycyl propargyl amide are 5 dissolved in a nitrogen atmosphere in 60 ml of anhydrous DMF, mixed with 8.5 g (48.7 mmol) of acetyl mercaptosuccin anhydride and stirred for 1 hour at 40 0 C. The product is precipitated with ether after cooling and centrifuged off. The crystalline product is recrystallized from THF. 10 Yield: 90% of the title compound [16a] C1 4 H1 9
N
3 0 6 S (MW: 357.39) 1H NMR (d 6 -DMSO): 6 = 2.34 (s; 3H, -COCH 3 ) 2.78 (s; 3H, -N-CH 3 ) 15 2.70 - 3.04 (m; 2H, -(CH 2 )COOH) 3.07 (t; 1H, -C=-CH) 3.68 - 3.73 (m; 4H, 2x -NH(CH 2 )CO-) 3.85 - 3.89 (m; 2H, -NH(CH 2 )-C=CH) 4.33 - 4.38 (m; 1H, -S-CH(CH 2
COOH)-CH
2 -) 20 8.12 (t; 1H, -NH-) 8.23 (t; 1H, -NH-) 12.68 (broad; 1H, -COOH) b) Technetium-99m complex [16b] of 2-(S-acetylthio) succinyl sarcosyl glycyl propargyl amide 25 A solution of 0.5 mg (1.4 ymol) of 2-(S-acetylthio) succinyl sarcosyl glycyl propargyl amide [16a] in 50 pl of 0.1 N soda lye is diluted with 250 pl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/l, pH 8.5). Afterwards, 50 pl of 0.15 molar trisodium citrate dihydrate solution and 2.5 pl of 30 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, and filtered (0.2 pm filter).
48 Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na2HPO 4 ; 0.01 M; pH 2.0); 5 eluent B: acetonitrile/phosphate buffer (Na 2
HPO
4 ; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 95%. 10 Example 17 a) (2-(S-acetylthio)succinyl sarcosyl glycyl propargyl amide-4-yl)-cys-ser-cys-ser-ser-leu-met-asp-lys-glu cys-val-tyr-phe-cys-his-leu-asp-ile-ile-trp [17a] A solution of 50 mg of 2-(S-acetylthio)succinyl sarcosyl 15 glycyl propargyl amide [16a] and 15 mg of N-hydroxy suc cinimide in anhydrous, freshly distilled DMF is cooled down to -15*C and mixed with 28 mg of dicyclohexyl carbodiimide in anhydrous DMF. The reaction mixture is stirred for 2 hours at -5 0 C, then 2 hours at room temperature, and then 20 cooled down to -15*C. Precipitated N,N'-dicyclohexyl urea is filtered off. The filtrate is mixed with a solution of 1 mg of cys-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr phe-cys-his-leu-asp-ile-ile-trp (endotheline 1) in anhydrous DMF and stirred for 20 hours at room temperature. 25 The reaction mixture is evaporated under reduced pressure at room temperature. A flocculent precipitate emerges after adding diethyl ether by dropping. The precipitate is cen trifuged and purified by preparative HPLC (gradient: aceto nitrile/phosphate buffer). When the buffered eluate is neu 30 tralized, the organic solvent portion is blown off using nitrogen, and the residue is lyophilized. The crystalline product is kept in a protective gas atmosphere (Ar). MW: calc.: 2831.3 det.: 2831.6 (FAB-MS) 49 b) Technetium-99m complex [17b] of (2-(S-acetylthio) succinyl sarcosyl glycyl propargyl amide-4-yl)-cys-ser cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr-phe-cys his-leu-asp-ile-ile-trp 5 A solution of 0.5 mg of 2-(S-acetylthio) succinyl sarcosyl glycyl propargyl amide-4-yl)-cys-ser-cys-ser-ser-leu-met asp-lys-glu-cys-val-tyr-phe-cys-his-leu-asp-ile-ile-trp [17a] in 50 pl of 0.1 N soda lye is diluted with 250 yl of phosphate buffer (Na 2
HPO
4 , 0.5 mol/l, pH 8.5). Afterwards, 10 50 yl of 0.15 molar trisodium citrate dihydrate solution and 2.5 y1 of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated at room temperature for 10 minutes, 15 and filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; eluent A: phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0); 20 eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 80%. 25 Example 18 a) Cyclo(trp-leu-val-pro-asp)-cys-gly-gly-propargyl amide [18a] A solution of 133.0 mg of cyclo(trp-leu-val-pro-asp) and 41.3 mg of hydroxy benzotriazole in 6 ml of anhydrous, 30 freshly distilled DMF is cooled down to -15 0 C and mixed with a solution of 51.7 mg of 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride in 8 ml of DMF. The reaction mixture is stirred for 2 hours at -50C and another 50 2 hours at room temperature. Then, a solution of 134.0 mg of S-(p-methoxybenzyl) cysteinyl glycyl glycyl propargyl amide [5a] in anhydrous DMF is slowly added by dropping. After 7 more hours of stirring, the solution is evaporated 5 under reduced pressure, and the peptide precipitated with ether. The protecting groups present are split off by stirring in liquid HF. After evaporating the HF, the residue is purified by preparative HPLC (gradient: acetonitrile/phosphate buffer). When the buffered eluate is 10 neutralized, the organic solvent portion is blown off using nitrogen, and the residue is lyophilized. The crystalline product is kept in a protective gas atmosphere (Ar). MW: calc.: 865.0 det.: 865.2 (FAB-MS) 15 b) Technetium-99m complex [18b] of cyclo(trp-leu-val-pro asp)-cys-gly-gly-propargyl amide A solution of 0.5 mg of cyclo(trp-leu-val-pro-asp)-cys-gly gly-propargyl amide[18a] in 300 yl of phosphate buffer 20 (Na 2
HPO
4 , 0.5 mol/l, pH 8.5) is mixed with 50 sl of 0.15 molar trisodium citrate dihydrate solution and 2.5 yl of 0.2 molar tin(II) chloride dihydrate solution are added. The reaction mixture is mixed with a pertechnetate solution (0.4 to 0.9 mCi) from a Mo-99/Tc-99m generator, incubated 25 at room temperature for 10 minutes, and filtered (0.2 ym filter). Labelling is analyzed using HPLC: MERCK nucleosile column, 125 x 4 mm, 5 ym; gradient from 100% A to 100% B within 7.5 min; 30 eluent A: phosphate buffer (Na2HPO4; 0.01 M; pH 2.0); eluent B: acetonitrile/phosphate buffer (Na 2 HPO4; 0.01 M; pH 2.0) 50:50 (V/V); flow rate: 1.0 ml/min. Radiochemical purity of the Tc-99m complex is more than 90%.
51 Example 19 Accumulation of N-(3-hexadecyl aminocarbonyl-2-acetyl thiopropionyl) glycyl glycyl propargyl amide, technetium 5 99m complex, in atherosclerotic vascular lesions of WHHL rabbits N-(3-hexadecyl aminocarbonyl-2-acetyl thiopropionyl) glycyl glycyl propargyl amide (produced according to Example 9a) is labelled as described in Example 9b. 10 99.9 GBq (2.7 mCi) of the substance labelled according to Example 9b were diluted to 1 ml with phosphor-buffered saline and administered via the ear vein to a narcotized WHHL rabbit, Rompun/Ketavet (1:2). The rabbit was killed 5 hours after the application, and an autoradiogram as well 15 as a Sudan(III) staining were carried out to visualize the atherosclerotic plaques (Figure 1). The accumulation factor between normal and atherosclerotic walls was between 3 and 8 depending on the thickness of the plaques (Sudan(III) staining).
Claims (19)
1. Compounds of the general formula (I) R1 C Y -- z CH (I (A) M (A 3 ) \N N/ RS (A 2 ) 5 wherein (Al) , (A 2 ) , and (A 3 ) are same or different and represent the general formula (CHR 9 )m 0 (CHR 2 ) (CR 4 R 5 )k 10 X their free valences being linked arbitrarily with the respective nitrogen or sulfur atoms, and wherein R 3 and R 5 are same or different and represent a 15 hydrogen atom, or a methyl or ethyl group, and 2 R 4 is a hydrogen atom, a branched or unbranched alkyl group containing 1 to 4 carbon atoms, the C atoms of which may optionally carry additional amino groups, N(RaRb) groups (with Ra and Rb being either same or 5 different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atomsthe C atoms of which may optionally carry one additional hydroxy, carboxy, or amino group), hydroxy groups, thiol groups, halogens, carboxy groups, alkoxy carbonyl 10 groups containing 1 to 20 carbon atoms, acyloxy groups containing 1 to 12 carbon atoms, amino carbonyl groups, sulfonyl groups, amino sulfonyl groups, or phosphoric acid residues, R 2 and R 9 are same or different and represent the same 15 as R4, k, 1, and m are same or different and stand for the numbers 0, 1, 2, 3, or 4, and X is a hydrogen atom, a carboxy group, an alkoxy group containing 1 to 20 carbon atoms, an alkoxy carbonyl 20 group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon atoms, an amino carbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethyl amino carbonyl group, a p-aminophenyl group, a p-hydroxyphenyl group, 25 a halogen atom, a hydroxy group, an amino group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atomsIthe C atoms of which may optionally carry one additional 30 hydroxy, carboxy, or amino group), a hydrazine group, a hydrazide group, a cholesteryl oxycarbonyl methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid or a derivative of an ethinyl or 35 ethenyl steroid, 3 a substituent of the formula Zl-Yl-(CH 2 )-Q-CO where Q is an -NH- or -0-, 5 Z 1 has the same meaning as Z, Yl has the same meaning as Y, and i has the same meaning as m, a substituent of the formula V - U - Q1 10 where Q 1 is an -NH-, -CO-, or -0-, U is a bond, a group of the formula -(OCH 2 CO)h- with h=1-3, or a suitable linker for coupling with bio- or macromolecules, and 15 V is a hydrogen atom, a hydroxy group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry one additional hydroxy, 20 carboxy, or amino group), a biomolecule, or a macromolecule, and Y is an unsaturated unbranched or branched chain of up to 12 carbon atoms containing at least one double and/or triple bond which may, optionally, carry 25 additional one or several and at any position in the chain, hydroxy, carboxy, alkoxy, amino, or substituted amido groups containing 1 to 20 carbon atoms in the alkyl and/or aryl residue, Z is a hydrogen atom, a halogen atom, a carboxy group, 30 a hydroxy group, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 4 carbon atoms, an alkoxy group containing 1 to 20 carbon atoms, a cholesteryl oxycarbonyl methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid 5 or a derivative of an ethinyl or ethenyl steroid, a substituent of the formula V - U - Q1 where Q 1 is an -NH-, -CO-, or -0-, 10 U is a bond, a group of the formula -(OCH 2 CO)h- with h=1-3, or a suitable linker for coupling with bio- or macromolecules, and V is a hydrogen atom, a hydroxy group, an N(RaRb) group (with Ra and Rb being either same or different and 15 representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, carboxy, or amino group), a biomolecule, or a macromolecule, and 20 M is an element having the atomic number 43 or 75, R 1 has the same meaning as R4, R 6 , R 7 , and R 8 are same or different and represent a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms, the C atoms of which may carry additional 25 hydroxy, carboxy, or amino groups, or a group of the formula -CH 2 -X in which X has the above meaning and their hydrosoluble salts.
2. Compounds according to Claim 1, characterized in that Z is a hydrogen atom, a steroid, an ethinyl steroid, or 30 an ethenyl steroid. 5
3. Compounds according to Claim 2, characterized in that X is a hydrogen atom, a halogen atom, a carboxy group, an amino group or an amido group containing 1 to 20 carbon atoms in their alkyl and/or aryl residue. 5
4. Compounds according to Claim 3, characterized in that Y is an ethinyliden group, R 1 , R 3 , R 6 , R 7 , and R 8 are hydrogen atoms, and k, 1, and m represent the number 0.
5. Compounds according to Claim 1, characterized in that Z is a hydrogen atom and X is a cholesteryl oxycarbonyl 10 methyl amino carbonyl group, a cholesteryl oxycarbonyl group, a cholesteryl oxycarbonyl methyl oxycarbonyl group, another steroid or a derivative of an ethinyl or ethenyl steroid.
6. Compounds according to Claim 5, characterized in that Y 15 is an ethinyliden group, that R 1 , R 3 , R 6 , R 7 , and R 8 are hydrogen atoms, and k, 1, and m represent the number 0 or 1.
7. Compounds according to Claim 1, characterized in that residue Z is a hydrogen atom, residue X is a hydrogen 20 atom, a carboxy group, or a substituent of the formula V - U - Q 1 where Q 1 is an -NH-, -CO-, or -0-, U is a bond, a group of the formula -(OCH 2 CO)h- with 25 h=1-3, or a suitable linker for coupling with bio- or macromolecules, and V is a hydrogen atom, a hydroxy group, an N(Rajb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl 30 residues containing 1 to 20 carbon atoms, the C atoms of which may optionally carry an additional hydroxy, 6 carboxy, or amino group), a biomolecule, or a macromolecule.
8. Compounds according to Claim 7, characterized in that Y is an ethinyliden group, that R 1 , R 3 , R 6 , R 7 , and R 8 are 5 hydrogen atoms, and k, 1, and m represent the numbers 0, 1, or 2.
9. Compounds according to Claim 1, characterized in that Z is a hydrogen atom, and residue X is a hydrogen atom, a carboxy group, an alkoxy group containing 1 to 20 10 carbon atoms, an alkoxy carbonyl group containing 1 to 20 carbon atoms, an acyloxy group containing 1 to 20 carbon atoms, an amino carbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethyl amino carbonyl group, a p 15 aminophenyl group, a p-hydroxyphenyl group, a halogen atom, a hydroxy group, an amino group, an N(RaRb) group (with Ra and Rb being either same or different and representing branched or unbranched alkyl or acyl residues containing 1 to 20 carbon atoms, the C atoms 20 of which may optionally carry an additional hydroxy, carboxy, or amino group), a hydrazine group, or a hydrazide group.
10. Compounds according to Claim 9, characterized in that Y is an ethinyliden group, that R 1 , R 3 , R 6 , R 7 , and R 8 are 25 hydrogen atoms, and k, 1, and m represent the numbers 0, 1, or 2.
11. Compounds of the general formula 7 R Y Z T CH S N -R (A') (A 3 ) \ / R 6, N (A 2 ) N R7 wherein Al, A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y and Z have the meaning specified in Claim 1, and where 5 T is a hydrogen atom, an acetate group, a benzoate group, a p-methoxybenzyl group, an acetamidomethyl group, a benzamidomethyl group, a trimethyl acetamidomethyl group, a hydroxy acetyl group, or another suitable sulfur protecting group. 10
12. Conjugates containing compounds of the general formulae (I) and/or (II) and substances that accumulate selectively in diseased tissues, with a covalent bond existing between these substances, said bond being amidic if the substances are amino groups such as 15 peptides, proteins, antibodies, or their fragments, ester-like if the substances contain hydroxy groups, such as fatty alcohols, and imidic if the substances contain aldehyde groups. 20
13. Conjugates according to Claim 12, characterized in that the substances that accumulate in diseased tissue are peptides, in particular, endothelines, partial endo theline sequences, endotheline analogues, endotheline derivatives, or endotheline antagonists. 8
14. Conjugates according to Claim 12, characterized in that the peptides contain the following sequences or parts thereof: 5 cys-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr phe-cys-his-leu-asp-ile-ile-trp, 10 cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-cys-val-tyr Li phe-cys-his-leu-asp-ile-ile-trp, 15 cys-thr-cys-phe-thr-tyr-lys-asp-lys-glu-cys-val-tyr L--7 tyr-cys-his-leu-asp-ile-ile-trp, 20 cys-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyr Li phe-cys-his-leu-asp-ile-ile-trp, 1 1 25 cys-ser-cys-asn-ser-trp-leu-asp-lys-glu-cys-val-tyr phe-cys-his-leu-asp-ile-ile-trp, 30 cys-ser-cys-lys-asp-met-thr-asp-lys-glu-cys-leu-asn phe-cys-his-gln-asp-val-ile-trp, 1 1 35 ala-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr phe-ala-his-leu-asp-ile-ile-trp, 9 ala-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyr phe-ala-his-leu-asp-ile-ile-trp, 5 cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-ala-val-tyr phe-ala-his-leu-asp-ile-ile-trp, cys-val-tyr-phe-cys-his-leu-asp-ile-ile-trp, 10 N-acetyl-leu-met-asp-lys-glu-ala-val-tyr-phe-ala-his leu-asp-ile-ile-trp, or the partial sequence 15 his-leu-asp-ile-ile-trp or the cyclic amino acid sequences 20 Cyclo-(Dtrp-Dasp-pro-Dval-leu), Cyclo-(Dglu-ala-alloDile-leu-Dtrp).
15. Method for the production of compounds of the general formula (I), characterized in that technetium-99m or 25 rhenium in the form of pertechnetate or perrhenate are reacted, in the presence of a reductant and, optionally, an auxiliary ligand, with a compound of the general formula (II) 10 R Y --- Z T CH S N - R 8 (A') (A 3 ) R JN NR7 RS (A 2 ) where Al, A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y and Z have the meaning 5 specified in Claim 1 and T has the meaning specified in Claim 11.
16. Method for the production of compounds of the general formula (II) 10 T 1 CH y -Z T CH S N -R (A') (A 3 ) 6 N N RS (A 2 ) characterized in that a) a compound of the general formula (III) 15 11 RY Z CH Hal N RI (A') (A 3 ) R 6' N\ (A 2 ) R wherein Al, A 2 , A 3 , RI, R 6 , R 7 , R 8 , Y and Z have the meaning 5 specified in claim 1 and Hal represents a halogen, is reacted with a compound of the general formula T - S- M+ wherein M+ is an alkaline metal cation and T has the meaning specified in claim 11, 10 or, b) a compound of the general formula HN(R 6 )-A 2 -N(R 7 )-A 3 -N(R 8 )-Y-Z wherein A 2 , A 3 , R 6 , R 7 , and R 8 have the meaning specified in Claim 1, are reacted with 15 a compound of the general formula T - S - Al - W wherein Al and T have the meaning given in Claim 11, and W represents a leaving group which enables Al to react with free amino acids. 20
17. Kit for producing radiopharmaceuticals consisting of a compound of the general formula (II) according to Claim 12 11, a reductant and, optionally, an auxiliary ligand, said substances being either dry or in solution, instructions for use including instructions for reacting the compounds described with technetium-99m or 5 rhenium in the form of a pertechnetate or perrhenate solution.
18. Radiopharmaceutical formulation for non-invasive in vivo visualization of receptors and tissue containing receptors and/or atherosclerotic plaques, characterized 10 in that it contains a compound according to Claim 1, optionally with the adjuvants common in galenics, and that the compound according to Claim 1 is prepared in a kit according to Claim 17 using technetium-99m or rhenium in the form of a pertechnetate or perrhenate 15 solution.
19. Radiopharmaceutical formulation according to Claim 18, characterized in that it contains a compound according to Claim 1 in the form of liposomes, and that the 20 compound according to Claim 1 is prepared in a kit according to Claim 17 using technetium-99m or rhenium in the form of a pertechnetate or perrhenate solution.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4311021A DE4311021A1 (en) | 1993-03-31 | 1993-03-31 | Bifunctional chelating agents, their technetium and rhenium complexes, processes for their preparation and radiopharmaceutical compositions containing these compounds |
DE4311021 | 1993-03-31 | ||
PCT/DE1994/000369 WO1994022491A1 (en) | 1993-03-31 | 1994-03-29 | Bifunctional chelators and their use in radiopharmaceuticals |
Publications (1)
Publication Number | Publication Date |
---|---|
AU6501594A true AU6501594A (en) | 1994-10-24 |
Family
ID=6484685
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU65015/94A Abandoned AU6501594A (en) | 1993-03-31 | 1994-03-29 | Bifunctional chelators and their use in radiopharmaceuticals |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0692979A1 (en) |
JP (1) | JPH08508261A (en) |
KR (1) | KR960701667A (en) |
AU (1) | AU6501594A (en) |
CA (1) | CA2156618A1 (en) |
DE (1) | DE4311021A1 (en) |
HU (1) | HUT72733A (en) |
NO (1) | NO953865L (en) |
NZ (1) | NZ263792A (en) |
WO (1) | WO1994022491A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU692153B2 (en) * | 1993-03-31 | 1998-06-04 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Type S3N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use |
AU692154B2 (en) * | 1993-03-31 | 1998-06-04 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Chelators of type XN1S1X' for radioactive isotopes, their metal complexes and their diagnostic and therapeutical uses |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4337600A1 (en) * | 1993-11-01 | 1995-05-04 | Diagnostikforschung Inst | N-alkyl peptide chelating agents, their metal complexes with radionuclides, processes for their preparation and radiopharmaceutical compositions containing these compounds |
US5632969A (en) * | 1994-10-13 | 1997-05-27 | Merck & Co., Inc. | N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications |
EP0826000B1 (en) * | 1995-05-10 | 2002-10-23 | Darwin Discovery Limited | Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses |
IL123430A (en) * | 1995-10-05 | 2001-04-30 | Darwin Discovery Ltd | Thio-substituted peptides as inhibitors for metalloproteinases and tnf liberation |
DE19652374A1 (en) * | 1996-12-04 | 1998-06-10 | Schering Ag | Use of endothelin conjugates in therapy, new endothelin conjugates, agents containing them, and processes for their preparation |
NZ511705A (en) * | 2001-05-14 | 2004-03-26 | Horticulture & Food Res Inst | Methods and rapid immunoassay device for detecting progesterone and other steroids |
EP1469875A1 (en) | 2002-01-29 | 2004-10-27 | Wyeth | Compositions and methods for modulating connexin hemichannels |
CN101648028B (en) * | 2002-05-06 | 2012-11-21 | 恩多塞特公司 | Vitamin-targeted imaging agents |
WO2014007632A1 (en) * | 2012-07-06 | 2014-01-09 | Stichting Het Nederlands Kanker Instituut | Cysteine protease capturing agents |
CN116731101A (en) | 2016-06-01 | 2023-09-12 | 雅斯娜 | Derivatives of N-caproic acid-L-tyrosine-L-isoleucine- (6) -aminocaproamide for the treatment of various diseases |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3855239T2 (en) * | 1987-07-16 | 1996-10-31 | Nycomed Imaging As | Aminocarboxylic acid and derivatives |
WO1992019274A1 (en) * | 1991-05-08 | 1992-11-12 | Mallinckrodt Medical, Inc. | Technetium chelates to be used for determining the renal function |
JPH0570484A (en) * | 1991-09-12 | 1993-03-23 | Hitachi Chem Co Ltd | Peptide and its salt |
DE69332470D1 (en) * | 1992-02-06 | 2002-12-12 | Biosynthema Inc | LIGANDS TO IMPROVE METAL CHELATE-GENERATION KINETICS |
-
1993
- 1993-03-31 DE DE4311021A patent/DE4311021A1/en not_active Withdrawn
-
1994
- 1994-03-29 EP EP94912439A patent/EP0692979A1/en not_active Withdrawn
- 1994-03-29 CA CA002156618A patent/CA2156618A1/en not_active Abandoned
- 1994-03-29 KR KR1019950704236A patent/KR960701667A/en not_active Application Discontinuation
- 1994-03-29 JP JP6521540A patent/JPH08508261A/en active Pending
- 1994-03-29 NZ NZ263792A patent/NZ263792A/en unknown
- 1994-03-29 WO PCT/DE1994/000369 patent/WO1994022491A1/en not_active Application Discontinuation
- 1994-03-29 AU AU65015/94A patent/AU6501594A/en not_active Abandoned
- 1994-03-29 HU HU9502858A patent/HUT72733A/en unknown
-
1995
- 1995-09-29 NO NO953865A patent/NO953865L/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU692153B2 (en) * | 1993-03-31 | 1998-06-04 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Type S3N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use |
AU692154B2 (en) * | 1993-03-31 | 1998-06-04 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Chelators of type XN1S1X' for radioactive isotopes, their metal complexes and their diagnostic and therapeutical uses |
Also Published As
Publication number | Publication date |
---|---|
KR960701667A (en) | 1996-03-28 |
NO953865L (en) | 1995-11-23 |
HU9502858D0 (en) | 1995-11-28 |
NO953865D0 (en) | 1995-09-29 |
CA2156618A1 (en) | 1994-10-13 |
HUT72733A (en) | 1996-05-28 |
EP0692979A1 (en) | 1996-01-24 |
DE4311021A1 (en) | 1994-10-27 |
JPH08508261A (en) | 1996-09-03 |
NZ263792A (en) | 1997-02-24 |
WO1994022491A1 (en) | 1994-10-13 |
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