EP0571545A1 - Synthese in situ d'agents radiopharmaceutiques - Google Patents
Synthese in situ d'agents radiopharmaceutiquesInfo
- Publication number
- EP0571545A1 EP0571545A1 EP19920907162 EP92907162A EP0571545A1 EP 0571545 A1 EP0571545 A1 EP 0571545A1 EP 19920907162 EP19920907162 EP 19920907162 EP 92907162 A EP92907162 A EP 92907162A EP 0571545 A1 EP0571545 A1 EP 0571545A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- radionuclide
- ligand
- acid
- radiopharmaceutical agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000012217 radiopharmaceutical Substances 0.000 title claims abstract description 54
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 12
- 229940121896 radiopharmaceutical Drugs 0.000 title abstract description 24
- 230000002799 radiopharmaceutical effect Effects 0.000 title abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 125000002015 acyclic group Chemical group 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 49
- 229910052751 metal Inorganic materials 0.000 claims description 29
- 239000002184 metal Substances 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- -1 or optionally Chemical group 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 150000001723 carbon free-radicals Chemical class 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 230000002285 radioactive effect Effects 0.000 claims description 9
- 150000007513 acids Chemical class 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 239000002504 physiological saline solution Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229910052738 indium Inorganic materials 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- 229910052748 manganese Inorganic materials 0.000 claims description 3
- 229910052762 osmium Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 3
- 229910052702 rhenium Inorganic materials 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 229910052713 technetium Inorganic materials 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 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 claims description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 2
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- HRHYPQBQTBRCFK-UHFFFAOYSA-N diaminomethanedisulfinic acid Chemical compound OS(=O)C(N)(N)S(O)=O HRHYPQBQTBRCFK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 claims description 2
- 229960005219 gentisic acid Drugs 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 150000003018 phosphorus compounds Chemical class 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 238000001514 detection method Methods 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 239000000470 constituent Substances 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZHRZLXZJVUFLNY-XAMCCFCMSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]propanoyl]amino]propanoyl]amino]propanoic acid Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZHRZLXZJVUFLNY-XAMCCFCMSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 3
- 108010084094 alanyl-alanyl-alanyl-alanine Proteins 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000004696 coordination complex Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229940056501 technetium 99m Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 230000009918 complex formation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229940127042 diagnostic and therapeutic radiopharmaceutical Drugs 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical class OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 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 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003495 technetium Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the present invention relates to novel in situ synthesis methods of forming radiopharmaceuticals.
- radiopharmaceuticals are used as radiographic imaging agents for visualizing skeletal structures, organs, or tissues.
- imaging is accomplished by preparation of radioactive agents, which when introduced into the body of a patient, are localized in the specific structure which is to be studied. The localized agents may then be traced, plotted or scintiphotographed by radiation detectors, such as, traversing scanners or scintillation cameras.
- radiation detectors such as, traversing scanners or scintillation cameras.
- the distribution and relative intensity of the detected radioactive agents indicates the position of the structure in which the agent is localized, and also shows the presence of aberrations in structure or function, pathological conditions or the like.
- radiopharmaceuticals may be used as therapeutic agents, for providing radiation to a particular pathological condition which is to be treated.
- Such treatment may be accomplished by preparation of radioactive therapeutic agents which again are designed to localize in a particular structure, organ or tissue.
- radioactive therapeutic agents which again are designed to localize in a particular structure, organ or tissue.
- radiation may be delivered directly to the pathological condition requiring radiation treatment.
- both diagnostic and therapeutic radiopharmaceuticals are comprised of a radionuclide- labelled compound.
- the metal can exist in it's free state, as an ion, or in the form of a metal complex with a ligand or group of ligands.
- metal radionuclides that form complexes are Tc-99m and Re-186.
- the former is used in diagnostic work and the latter is used for therapy.
- the resultant radiopharmaceuticals further include appropriate carriers and auxiliary agents, such as delivery vehicles suitable for injection, aspiration or inges ion by the patient, as well as physiological buffers and salts, and the like.
- radiopharmaceuticals generally require initial synthesis of the ligand, followed by a separate synthesis of the radionuclide complex (i.e. a labelling procedure) .
- radiopharmaceuticals of the prior art are formed by first synthesizing the desired structure specific ligand, according to known methods for such a ligand.
- the prepared ligand generally in a lyophilized kit also containing one or more excipients is then reacted with a radionuclide- containing solution under radionuclide complex-forming reaction conditions.
- the prepared ligand may be reacted along with a reducing agent with a pertechnetate solution under technetium-99m complex-forming reaction conditions.
- the complexes are then administered to the patient via injection, inhalation or ingestion.
- the radionuclide-containing solutions can be obtained from a generator, as in the case of Tc-99m, or can be supplied in saline or water by a manufacturer, as with Re- 186. With Tc-99m the radionuclide solution is eluted from a Mo-99/Tc-99m generator system.
- the complex-forming reaction is carried out at complex-forming temperatures (e.g. 20°C to 100° C) for a few minutes to several hours when forming technetium complexes.
- a large excess (e.g. greater than one hundred fold excess to metal radionuclide) of the prepared ligand is used and a sufficient amount of reducing agent is present, if needed, to insure reduction of the radionuclide to facilitate complexation by the ligand.
- Radiopharmaceutical agents are then prepared by combining the radionuclide complex, in an amount sufficient for the desired diagnostic or therapeutic purpose, with a pharmaceutically acceptable radiological vehicle.
- the radiological vehicle should be acceptable for injection, aspiration or ingestion.
- examples of such vehicles are human serum albumin; aqueous buffer solutions, e.g. tris(hydromethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc.; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal plasma cations such as Ca +2 , Na + , K + , and Mg +2 .
- agents known as “stabilizers” can be included. These hold the radionuclide in a stable form until it can be reacted with the ligand.
- stabilizers can include agents known as "transfer ligands" which are particularly useful in holding the metal stable in a reduced oxidation state until the ligand can capture it. Examples of transfer ligands include salts of glucoheptonic acid, tartaric acid, and citric acid, or other suitable ligands as will be discussed in more detail below.
- the ligand in a standard metal radionuclide radiopharmaceutical the ligand must be completely presynthesized and reacted with the metal radionuclide to give a complex in which the ligand is essentially unchanged after complex formation with the exception of removal of hydrogen ions or protecting groups. Removal of these groups facilitates coordination of the ligand to the metal radionuclide.
- the ligand cyclization reaction was facilitated by the presence of the nickel, which held the ends of the acyclic ligand in place and allowed the formation, in good yield, of the product ligand through closure of the ring.
- the metal provided a "template” for the ring closure of the reaction and from this effect the term “template syntheses” has been coined for this process. This has also been found in syntheses involving cyclic tetrapeptides as described in a number of references. In these cases the ligand was the desired product with the metal being removed at the end by standard means.
- the ultimate ligand- etal complex is the target.
- the template reaction yields a metal complex that has unique physicochemical properties because the metal is "locked in” and is not easily removed from the ligand.
- An example of such a reaction is shown below:
- radiopharmaceuticals may be produced in situ by reacting a non-radioactive acyclic ligand with a radionuclide, wherein the acyclic ligand is capable of forming a cyclic ligand upon simple chemical conversion.
- the acyclic ligand first binds to the radionuclide, and then undergoes conversion to the cyclic ligand by reaction with itself, reaction with components in the reaction solution, or by simple rearrangement of the manner in which it bonds to the radionuclide, to form the final radiopharmaceutical.
- radionuclide including a metal radionuclide, selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm.
- a metal radionuclide selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm.
- the radionuclide is Tc-99m, Re-186 or Re-188.
- Acyclic ligands which may be used in the process according the present invention include any known ligands which are suitable for the formation of radionuclide complexes.
- ligands such as, acyclic tetra- and penta- peptides and, also, tri- and di- peptides that have auxiliary groups attached so that they can undergo ring closure reactions may be used.
- the acyclic ligand may be any ligand having the general formula: W ⁇ A'" ⁇ "' ⁇ B
- the acyclic ligand includes at least three and at most ive amino acid groups and has the formula:
- R t to Rg are the same or different and are selected from the group consisting of hydrogen or substituents of any natural or synthetic amino acid;
- X is OH or HH—-c-—cooH .
- the radiopharmaceutical forming reaction will take place in situ over a period of time by reaction of the radionuclide and ligand complex with constituents already present from the complex formation.
- constituents such as water, H + , OH " , chloride, or ethanol may be available to yield the radiopharmaceutical agent in final administratable form.
- the complex may simply react with itself to yield the radiopharmaceutical agent.
- the reaction according to the present invention may follow the general reaction:
- M represents a metal radionuclide optionally having one or more additional ligands attached to the metal
- A, B, C, D, W, X, Y, and Z have the same definitions as given above in formula (I) .
- the process according to the present invention further provides a means for forming radiopharmaceuticals which were previously unobtainable because of problems associated with synthesis of the ligand, or with formation of the radionuclide complex.
- radiopharmaceuticals which were previously unobtainable because of problems associated with synthesis of the ligand, or with formation of the radionuclide complex.
- such previously unobtainable radiopharmaceuticals may now be formed because the ligand does not have to be presynthesized nor does the metal have to be complexed with the final form of the ligand, both of which may be chemically and radiopharmaceutically unfavorable processes.
- a radiopharmaceutical agent according to the present invention is generally used in the form of a composition which is suitable for diagnostic or therapeutic functions.
- a radiopharmaceutical composition will usually comprise a liquid, pharmaceutically acceptable carrier material, preferably a physiological saline solution.
- a radiodiagnostic examination can be performed with such a composition by administering the composition to the patient and then recording the radioactive radiation emitted from the patient by means of, for example, a gamma camera.
- the present invention further relates to a method of preparing a radiopharmaceutical agent according to the present invention by reacting a radionuclide in the form of a radionuclide solution in the presence of a reducing agent and optionally a suitable chelator with an appropriate compound.
- the reducing agent serves to reduce the metal radionuclide in the solution which is obtained from a generator or supplied from a manufacturer.
- Suitable reducing agents are, for example, dithionite, formamidine sulphinic acid, diaminomethane disulphinate or suitable metallic reducing agents, for example, reducing metals such as tin metal, or reducing ions such as Sn(II) , Fe(II), Cu(I), Ti(III) or Sb(III) ; wherein Sn(II) has proved to be particularly suitable.
- the radionuclide solution is reacted with a ligand having the general formula (I) above directly, or in a two step reaction in which the metal is first bound to a transfer ligand and then displaced by the ligand of choice.
- suitable transfer ligands for the radionuclide are dicarboxylic acids, polycarboxylic acids or hydroxy car oxylie acids, such as oxalic acid, malonic acid, succinic acid, aleic acid, orthophthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; phosphorus compounds such as pyrophosphates; or enolates.
- Citric acid, tartaric acid, ascorbic acid, glucoheptonic acid or a derivative thereof are particularly suitable transfer ligands when the radionuclide is technetium-99m.
- the present invention also relates to a kit, comprising:
- a ligand according to the general formula (I) preferably being in a dry condition, and also preferably having an inert, pharmaceutically acceptable carrier and/or auxiliary substances added thereto;
- ingredients (1) and (2) may optionally be combined; and further wherein instructions for use with a prescription for carrying out the above-described method by reacting ingredients (1) and (2) with a radionuclide solution may be optionally included.
- the radionuclide solution can be obtained simply by the user himself from a generator which is available to him, or as the solution is supplied from a manufacturer.
- the ingredients (1) and (2) may be combined, provided they are compatible.
- Such a monocomponent kit, in which the combined ingredients are preferably lyophilized, is excellently suitable to be reacted by the user with the radionuclide solution in a simple manner.
- the ingredient (1) of the above kits may be delivered as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, but is preferably present in a dry condition, for example in a lyophilized condition.
- ingredient (1) When used as a component for an injection liquid, it should be sterile, and, if the ingredient (1) is present in a dry condition, the user should use a sterile physiological saline solution as a solvent.
- ingredient (1) may be stabilized in a usual manner with suitable stabilizers such as ascorbic acid, gentisic acid or salts of these acids, or it may be provided with other auxiliary means such as fillers, e.g. glucose, lactose, mannitol, inositol, and the like.
- the HPLC-chromatogram shows the presence of mainly one radioactive species (peak A) and a small amount of another compound (peak B) .
- Electrophoresis experiments with isolated peak A and peak B show that peak A has a free corboxyl group (migration distance is larger at higher pH) whereas the migration distance of peak B doew not increase with increasing pH, indicating the absence of a free carboxyl group.
- Coinjection of peak B with 99Tc-cyclo- tetra-L-alanine shows that peak B is 99mTc-cyclotetra-alanine as indicated in Scheme I. Peak A is assumed to be non-cyclisized 99mTc-tetra-L- alanine as represented in Scheme I.
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Abstract
Procédé de production d'agents radiopharmaceutiques in situ, c'est-à-dire dans lequel un radionuclide et un ligand acyclique réagissent avec des constituants de la solution de réaction formant un complexe afin de produire un agent radiopharmaceutique administrable. La formation d'agents radiopharmaceutiques selon l'invention permet d'obtenir des agents radiopharmaceutiques auparavant impossible à obtenir à cause de problèmes associés à la sythèse du ligand ou à la réaction de formation du complexe.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US65634691A | 1991-02-14 | 1991-02-14 | |
US656346 | 1991-02-14 |
Publications (1)
Publication Number | Publication Date |
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EP0571545A1 true EP0571545A1 (fr) | 1993-12-01 |
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ID=24632654
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP19920907162 Withdrawn EP0571545A1 (fr) | 1991-02-14 | 1992-01-27 | Synthese in situ d'agents radiopharmaceutiques |
Country Status (5)
Country | Link |
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EP (1) | EP0571545A1 (fr) |
JP (1) | JPH06505268A (fr) |
AU (1) | AU1429392A (fr) |
CA (1) | CA2101642A1 (fr) |
WO (1) | WO1992014492A1 (fr) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US4615876A (en) * | 1983-04-25 | 1986-10-07 | Curators Of The University Of Missouri | Macrocyclic complexes of technetium-99m for use as diagnostic radionuclides |
EP0250013B1 (fr) * | 1986-05-28 | 1990-05-09 | MALLINCKRODT, INC.(a Missouri corporation) | Chélates de technétium pour la détermination de la fonction rénale |
-
1992
- 1992-01-27 JP JP4506601A patent/JPH06505268A/ja active Pending
- 1992-01-27 CA CA002101642A patent/CA2101642A1/fr not_active Abandoned
- 1992-01-27 WO PCT/US1992/000630 patent/WO1992014492A1/fr not_active Application Discontinuation
- 1992-01-27 EP EP19920907162 patent/EP0571545A1/fr not_active Withdrawn
- 1992-01-27 AU AU14293/92A patent/AU1429392A/en not_active Abandoned
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Publication number | Publication date |
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WO1992014492A1 (fr) | 1992-09-03 |
CA2101642A1 (fr) | 1992-08-15 |
AU1429392A (en) | 1992-09-15 |
JPH06505268A (ja) | 1994-06-16 |
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