JPH06505268A - In situ synthesis of radiopharmaceutical formulations - Google Patents
In situ synthesis of radiopharmaceutical formulationsInfo
- Publication number
- JPH06505268A JPH06505268A JP4506601A JP50660192A JPH06505268A JP H06505268 A JPH06505268 A JP H06505268A JP 4506601 A JP4506601 A JP 4506601A JP 50660192 A JP50660192 A JP 50660192A JP H06505268 A JPH06505268 A JP H06505268A
- Authority
- JP
- Japan
- Prior art keywords
- carbon atoms
- radionuclide
- ligand
- acid
- group
- 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.)
- Pending
Links
- 229940121896 radiopharmaceutical Drugs 0.000 title claims description 48
- 239000012217 radiopharmaceutical Substances 0.000 title claims description 48
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims description 48
- 239000000203 mixture Substances 0.000 title claims description 25
- 238000009472 formulation Methods 0.000 title claims description 22
- 238000011065 in-situ storage Methods 0.000 title claims description 10
- 230000015572 biosynthetic process Effects 0.000 title description 13
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 239000003446 ligand Substances 0.000 claims description 70
- 125000004432 carbon atom Chemical group C* 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 229910052751 metal Inorganic materials 0.000 claims description 31
- 239000002184 metal Substances 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 13
- 125000002015 acyclic group Chemical group 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 238000000034 method Methods 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
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 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
- 239000000126 substance Substances 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 230000002285 radioactive effect Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000005855 radiation Effects 0.000 claims description 6
- 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 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
- 239000003381 stabilizer Substances 0.000 claims description 5
- 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 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
- 239000008103 glucose Substances 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
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 229910052713 technetium Inorganic materials 0.000 claims description 4
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 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 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 238000003384 imaging method Methods 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
- 229910052759 nickel 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
- 229910052702 rhenium Inorganic materials 0.000 claims description 3
- 229910052703 rhodium 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
- NYYSPVRERVXMLJ-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-one Chemical compound FC1(F)CCC(=O)CC1 NYYSPVRERVXMLJ-UHFFFAOYSA-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
- 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
- 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- 239000003937 drug carrier Substances 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid 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
- 238000002156 mixing Methods 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 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
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
- 238000006462 rearrangement reaction Methods 0.000 claims 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 150000001260 acyclic compounds Chemical class 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 238000001514 detection method Methods 0.000 claims 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims 1
- 229960005219 gentisic acid Drugs 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 229960000367 inositol Drugs 0.000 claims 1
- 150000003018 phosphorus compounds Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- -1 Ca" Chemical class 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 230000009918 complex formation Effects 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 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
- 239000002671 adjuvant Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012857 radioactive material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- BYXHQQCXAJARLQ-ZLUOBGJFSA-N Ala-Ala-Ala Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O BYXHQQCXAJARLQ-ZLUOBGJFSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 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
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 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
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010017893 alanyl-alanyl-alanine Proteins 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229940127042 diagnostic and therapeutic radiopharmaceutical Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- HRHYPQBQTBRCFK-UHFFFAOYSA-N diaminomethanedisulfinic acid Chemical compound OS(=O)C(N)(N)S(O)=O HRHYPQBQTBRCFK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 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
- 238000012544 monitoring process Methods 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 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
- 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
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 放射性医薬製剤の現場合成 本発明は新規な放射性医薬製剤の現場合成法に関する。[Detailed description of the invention] In situ synthesis of radiopharmaceutical formulations The present invention relates to a novel method for the in situ synthesis of radiopharmaceutical formulations.
診断および治療のために放射性医薬製剤を使用することは生物学的および医学的 研究の分野においてよく知られている。特に、放射性医薬製剤は骨格構造、臓器 または組織を映像化するための放射線写真用造影剤として使用される。このよう な画像化は、患者の体内に導入されると研究対象の特定の構造に局在する放射性 薬剤を製造することにより達成される。次に、局在した薬剤を横行スキャナーま たはシンチレーションカメラのような放射線検出器により追跡し、プロットし、 またはシンチ写真を撮ることができる。検出された放射性薬剤の分布および相対 強度は薬剤が局在する構造の位置を指し示し、そして構造または機能の異常の存 在、病状などもまた示す。同様に、放射性医薬製剤は治療対象の特定の病状に放 射線を与えるための治療剤として使用することができる。このような治療は特定 の構造、臓器または組織に局在するように設計された放射性治療剤を製造するこ とにより達成される。The use of radiopharmaceutical preparations for diagnosis and treatment is a biological and medical Well known in the field of research. In particular, radiopharmaceutical preparations are used to treat skeletal structures and organs. or as a radiographic contrast agent for imaging tissues. like this Imaging involves the use of radioactive materials that, when introduced into a patient's body, localize to specific structures being studied. This is achieved by manufacturing drugs. Next, the localized drug is transferred to a transverse scanner. tracked and plotted by a radiation detector such as a scintillation camera, Or you can take cinch photos. Distribution and relative of detected radiopharmaceuticals Intensity indicates the location of the structure where the drug is localized and indicates the presence of structural or functional abnormalities. Also indicates current status, medical condition, etc. Similarly, radiopharmaceutical preparations are released to target the specific disease state being treated. It can be used as a therapeutic agent for administering radiation. This type of treatment is manufacturing radiotherapeutic agents designed to localize to structures, organs, or tissues of This is achieved by
このような薬剤が局在すると、放射線を放射線治療の必要な病気の場所に直接施 すことができる。When these drugs are localized, radiation can be delivered directly to the diseased area requiring radiotherapy. can be done.
一般に、診断および治療用放射性医薬製剤は放射性核種で標識された化合物から なる。金属ベースの放射性核種である場合、金属はイオンのようにその自由な状 態で、またはリガンドもしくはりガントグループとの金属錯体の形態で存在しう る。錯体を形成する金属放射性核種の例はＴｃ−９９ｍおよびＲｅ−１８６であ る。前者は診断用に、そして後者は治療のために使用される。得られる放射性医 薬製剤はさらに適当な担体および補助剤、例えば注射、吸引または患者による摂 取に適したデリバリ−ビヒクル、並びに生理的緩衝剤および塩などを含有する。In general, diagnostic and therapeutic radiopharmaceutical preparations are made from compounds labeled with radionuclides. Become. In the case of metal-based radionuclides, the metal is in its free form like an ion. or in the form of metal complexes with ligands or Gantt groups. Ru. Examples of metal radionuclides that form complexes are Tc-99m and Re-186. Ru. The former is used for diagnosis and the latter for treatment. radiologist obtained The pharmaceutical formulation may further include suitable carriers and adjuvants, such as injection, inhalation or ingestion by the patient. and a suitable delivery vehicle, as well as physiological buffers, salts, and the like.
従来の放射性医薬製剤の製造法は一般に最初にリガンドの合成、次いで、放射性 核種錐体の合成（すなわち標識付は工程）を特徴とする特に、従来の放射性医薬 製剤は最初に所望の構造の特定のリガンドをこのようなリガンドについて知られ ている方法に従って合成することにより製造される。一般に、１種以上の賦形剤 もまた含有する凍結乾燥キットで製造されたリガンドは次に放射性核種錯体を生 成する反応条件下で、放射性核種を含有する溶液と反応させられる。例えば、テ クネチウム−９９ｍ放射性医薬製剤を製造することが望ましい場合、製造された リガンドはテクネチウム−９９ｍ錯体を生成する反応条件下で還元剤と共にペル テクネテートと反応させることができる。錯体は次に注射、吸入または摂取によ り患者に投与される。Conventional methods for producing radiopharmaceutical formulations generally involve first synthesizing the ligand, followed by radioactive In particular, conventional radiopharmaceuticals characterized by the synthesis of nuclide cones (i.e. labeling is a step) The formulation is first carried out using a specific ligand of the desired structure, which is known for such a ligand. It is manufactured by synthesizing according to the method. Generally one or more excipients The ligand produced in the lyophilization kit, which also contains The radionuclide is reacted with a solution containing the radionuclide under reaction conditions. For example, If it is desired to produce a Cnetium-99m radiopharmaceutical formulation, the produced The ligand is perfused with a reducing agent under reaction conditions to form a technetium-99m complex. Can be reacted with technetate. The complex can then be injected, inhaled or ingested. administered to patients.
放射性各種を含有する溶液はＴｃ−９９ｍの場合のように発生器から得ることが でき、またはＲｅ−１８６の場合のように製造業者により塩水または水の溶液と して供給されつる。。Ｔｃ−９９ｍの場合、放射性核種溶液はＭｏ−９９／Ｔｅ −９９ｍ発生器系から溶離される。錯体生成反応は、テクネチウム錯体を生成す る時に錯体生成温度（例えば２０℃〜１００℃）で数分〜数時間行なわれる。リ ガンドによる錯体化を容易にするため、かなり過剰量（例えば金属放射性核種に 対して１００倍以上の過剰量）の製造されたリガンドが使用され、必要に応じて 放射性核種を確実に還元するのに十分な量の還元剤が存在する。Solutions containing radioactive species can be obtained from generators, as in the case of Tc-99m. or, as in the case of Re-186, by the manufacturer with a solution of salt water or water. Vine supplied with. . In the case of Tc-99m, the radionuclide solution is Mo-99/Te -99m eluted from the generator system. The complex formation reaction produces a technetium complex. The reaction is carried out at a complex formation temperature (for example, 20° C. to 100° C.) for several minutes to several hours. Li Significant excess (e.g. for metal radionuclides) may be used to facilitate complexation by the (more than 100-fold excess) is used, and if necessary A sufficient amount of reducing agent is present to ensure reduction of the radionuclide.
放射性医薬製剤は所望の診断または治療のために十分な量の放射性核種錯体を薬 学的に許容しうる放射線学的ビヒクルと混合することにより製造される。放射線 学的ビヒクルは注射、吸引または摂取に適したものであるべきである。このよう なビヒクルの例はヒトの血清アルブミン：緩衝水溶液、例えばトリス（ヒドロメ チル）アミノメタン（およびその塩）、リン酸塩、クエン酸塩、重炭酸塩など； 滅菌水：生理的食塩水；並びに塩化物および／または重炭酸塩または通常の血漿 カチオン例えばＣａ”、Ｎａ” 。A radiopharmaceutical preparation contains a sufficient amount of radionuclide complex for the desired diagnosis or treatment. manufactured by mixing with a medically acceptable radiological vehicle. radiation The medical vehicle should be suitable for injection, inhalation, or ingestion. like this An example of a suitable vehicle is human serum albumin: buffered aqueous solutions such as Tris (hydrometal). aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; Sterile water: physiological saline; and chloride and/or bicarbonate or normal plasma Cations such as Ca", Na".
Ｋ＋およびＭｇ２＋を含有する平衡イオン溶液である。A balanced ionic solution containing K+ and Mg2+.
“安定剤“として知られている薬剤もまた含有することができる。これらはリガ ンドと反応させるまで放射性核種を安定な形態に維持する。これらの安定剤はリ ガンドが金属を捕獲するまでそれを還元された酸化状態で安定させるのに特に有 用である“トランスファーリガンド（ｔｒａｎｓｆｅｒ ｌｉｇａｎｄｓ）”と して知られている薬剤を包含しうる。トランスファーリガンドの例にはグルコヘ プトン酸、酒石酸およびクエン酸の塩、または下記でより詳細に説明されるよう な他の適当なリガンドが含まれる。Agents known as "stabilizers" may also be included. These are Riga It maintains the radionuclide in a stable form until it reacts with the compound. These stabilizers are Particularly useful for stabilizing a metal in a reduced oxidation state until the gund captures it. "transfer ligands" which are used for may include drugs known as Examples of transfer ligands include glucose. salts of ptonic acid, tartaric acid and citric acid, or as explained in more detail below. Other suitable ligands are included.
上記したように標準的な金属放射性核種の放射性医薬製剤において、リガンドは 完全に予備合成してから、金属放射性核種と反応させる必要があり、それにより リガンドが水素イオンまたは保護基の除去を除けば本質的に錯体生成後に未変化 である錯体が得られる。これらの基の除去はリガンドの金属放射性核種への配位 を容易にする。As mentioned above, in standard metal radionuclide radiopharmaceutical formulations, the ligand is It must be fully presynthesized and then reacted with metal radionuclides, thereby Ligand remains essentially unchanged after complex formation except for removal of hydrogen ion or protecting group A complex is obtained. Removal of these groups results in coordination of the ligand to the metal radionuclide. Make it easier.
金属または金属錯体により促進されるリガンドの現場反応は従来技術において知 られている。数多くのこのタイプの例か無機化学分野の文献に開示されている。In situ reactions of ligands promoted by metals or metal complexes are known in the prior art. It is being Numerous examples of this type are disclosed in the inorganic chemistry literature.
良（知られている研究の幾つかは次の反応タイプを開示している。Good (some of the known studies disclose the following reaction types:
この研究においては、リガンド環化反応は、アクリル系リガンドの末端を所定の 位置に保持し、閉環によるリガンド生成物の良好な収率での生成を可能にするニ ッケルの存在により促進された。In this study, the ligand cyclization reaction terminates the terminus of the acrylic ligand in a given manner. position and enable formation of the ligand product by ring closure in good yields. Facilitated by the presence of Kkel.
金属は閉環反応のための「鋳型（ｔｅｍｐｌａｔｅ）」を与え、この効果により ｒ鋳型合成」なる用語はこの方法のために造り出された。このことはまた、多く の文献に記載されているような環状テトラペプチドを含む合成においても見い出 されている。これらの場合、リガンドは金属が最後に標準的な手段により除去さ れる目的生成物であった。The metal provides a "template" for the ring-closing reaction, and this effect The term "r-templated synthesis" was coined for this method. This also applies to many It has also been found in syntheses involving cyclic tetrapeptides, such as those described in the literature. has been done. In these cases, the ligand is the metal that is finally removed by standard means. This was the desired product.
幾つかの場合、究極のリガンド金属錯体が目的である。Ｓａｒｇｅｓｏｎらの研 究のような場合、鋳型反応は金属が所定の位置に固定され、容易にリガントから 除去されないため独自の物理化学的特性を有する金属錯体を生成する。このよう な反応の例は次式で示される。In some cases, the ultimate ligand metal complex is the goal. Sargeson et al. In some cases, the template reaction is such that the metal is fixed in place and easily separated from the ligand. Because they are not removed, they produce metal complexes with unique physicochemical properties. like this An example of such a reaction is shown by the following formula.
Ｗｈｅｒｅ Ｎ Ｎ ’ ＮＨｔＣＨｔＣＨｔＮＨ＋放射性医薬化学の分野にお いても、リガンドの金属錯体はリガンドおよび反応溶液中の成分と金属放射性核 種との反応によりその場で生成される例が存在する。この例において、溶液の成 分は最後には直接、金属放射性核種または放射性核種に結合しているリガンド原 子に結合されないことに注目すべきである・本発明の目的は、放射性核種および アクリル系リガンド錯体が錯体生成反応溶液の成分と反応して投与可能な放射性 医薬製剤を生成することを特徴とする放射性医薬製剤の現場での製造法を提供す ることである。Where N N’ NHtCHtCHtNH+ In the field of radiopharmaceutical chemistry Even if the metal complex of the ligand is Examples exist where they are produced in situ by reaction with a species. In this example, the formation of the solution Finally, the ligand source bound directly to the metal radionuclide or radionuclide It should be noted that radionuclides and The acrylic ligand complex reacts with the components of the complex-forming reaction solution to create a radioactive material that can be administered. Provides an in-situ manufacturing method for a radiopharmaceutical formulation, characterized in that it produces a pharmaceutical formulation. Is Rukoto.
本発明の別の目的は、リガンド合成または錯体生成反応に伴なう問題のため従来 は達成できなかった放射性医薬製剤の製造法を提供することである。Another object of the present invention is to overcome the problems associated with ligand synthesis or complexation reactions by The purpose of this invention is to provide a method for producing radiopharmaceutical preparations that has not been achieved previously.
本発明は新規な、放射性医薬製剤の現場での製造法に関する。The present invention relates to a novel method for the in-situ production of radiopharmaceutical formulations.
特に、放射性医薬製剤は単純な化学変換により環状リガンドを生成することので きる非放射性アクリル系リガンドを放射性核種と反応させることにより現場で製 造することができる。アクリル系リガンドは最初に放射性核種と結合し、次いで それ自体との反応、反応溶液中の成分との反応、またはそれが放射性核種と結合 するような単純な転位反応による環状リガンドへの変換を行ない、最終の放射性 医薬製剤を生成する。In particular, since radiopharmaceutical preparations generate cyclic ligands through simple chemical transformations, produced on-site by reacting a non-radioactive acrylic ligand with a radionuclide. can be built. The acrylic ligand first binds to the radionuclide and then reaction with itself, with components in the reaction solution, or when it combines with a radionuclide The final radioactive Produce pharmaceutical formulations.
Ｔｃ、Ｒｅ、Ｃｏ、Ｃｕ、Ｎｉ、Ｒｕ、Ｃｒ、Ｗ、Ｒｈ、Ｚｎ、Ｉｎ、Ｇａ、Ｍ ｏ、Ｍｎ、Ｐｔ、Ｐｄ、Ｏｓ、Ｉ ｒおよびＳｍからなる群より選択される金属 放射性核種を含む、適当な放射性核種を使用することができる。好ましくは、放 射性核種はＴｃ−９９ｍ、Ｒｅ−１８６またはＲｅ−１１１１８である。Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, M metal selected from the group consisting of o, Mn, Pt, Pd, Os, Ir and Sm Any suitable radionuclide can be used, including radionuclides. Preferably, The radionuclide is Tc-99m, Re-186 or Re-11118.
本発明の方法に使用することのできる非環状リガンドには放射性核種錯体の生成 に適した公知のリガンドが含まれる。例えば、閉環反応を行なうことができるよ うに補助基が結合された非環状のジー、トリーペプチド、さらにテトラ−、ペン タ−ペプチドのようなリガンドを使用してもよい。特に、非環状リガンドは一般 式 〔式中、ｗ、ｘ、ｙおよびＺは同一または異なってＳ、Ｏ，ＰＲｌＮＲまたはＡ ｓＲであり； Ｒは水素または１２個までの炭素原子、好ましくは１〜８個の炭素原子の直鎖も しくは分枝鎖基（ここで１個または２個の炭素原子は０で置換されていてもよく 、そして炭素基は水素、または場合によっては＝Ｏ，Ｆ、ＣＩ、Ｂｒ、■、ＯＲ ’ 、ＣＯ，Ｒ’ 、ＳＯ，Ｒ’ のような置換基を含有する）であり：Ｒ′は 水素、またはそのうち１個の炭素原子が０またはＳで置換されていてもよい１〜 ４個の炭素原子の直鎖もしくは分枝鎖基であり。Acyclic ligands that can be used in the method of the invention include the formation of radionuclide complexes; Included are known ligands suitable for. For example, ring-closing reactions can be performed. Acyclic di- and tri-peptides with auxiliary groups attached, as well as tetra- and pen Ligands such as tar-peptides may also be used. In particular, acyclic ligands are commonly formula [In the formula, w, x, y and Z are the same or different and are S, O, PRlNR or A sR; R can also be hydrogen or a straight chain of up to 12 carbon atoms, preferably 1 to 8 carbon atoms. or a branched chain group (where one or two carbon atoms may be substituted with 0) , and the carbon group is hydrogen, or in some cases =O, F, CI, Br, ■, OR ’, CO, R’, SO, R’): R’ is Hydrogen, or 1 to 1 in which one carbon atom may be substituted with 0 or S It is a straight chain or branched chain group of 4 carbon atoms.
Ｗ、Ｘ、ＹまたはＺがＮＲの場合、ＲはＮＲまたはＯＲであってよく； Ａ、ＢおよびＣは同一または異なって、そのうち１〜４個の炭素原子が幾つかま たは全ての位置でＲまたは＝０、Ｆ、ＣＬ Ｂｒ、１、ＯＲ’ 、Ｃ０ｔＲ’ 、５ＯｘＲ’ ０）ようなｆｌ換基ト置換サすタ２〜５個の炭素原子の直鎖状炭 素基（ここでＲ゛は水素またはそのうち１個の炭素原子がＯまたはＳで置換され ていてもよい１〜４個の炭素原子の直鎖もしくは分枝鎖基である）であり：そし てＤは放射性核種との反応によりＷとの結合を生成することのできる基を末端と する２〜６個の炭素原子の鎖を含む１〜８個の炭素原子を含有し、さらに場合に よっては、Ｏ，Ｆ、Ｃ１，Ｂｒ、Ｉ、ＯＲ’ 、Ｃｏ□Ｒ’ 、ＳＯ，Ｒ’ の ような置換基（ここでＲ。When W, X, Y or Z is NR, R may be NR or OR; A, B and C are the same or different, and some of them have 1 to 4 carbon atoms. or R or = 0, F, CL Br, 1, OR', C0tR' at all positions , 5OxR'0) An elementary group (where R゛ is hydrogen or one carbon atom is substituted with O or S) is a straight or branched chain group of 1 to 4 carbon atoms which may be In this case, D has a terminal group that can form a bond with W by reaction with a radionuclide. containing 1 to 8 carbon atoms, including chains of 2 to 6 carbon atoms, and optionally Therefore, O, F, C1, Br, I, OR', Co□R', SO, R' A substituent such as (where R.
は水素、またはそのうち１個の炭素原子が０またはＳで置換されていてもよい１ 〜４個の炭素原子の直鎖もしくは分枝鎖基である）を含有する〕を有するリガン ドの何れであってもよい。is hydrogen, or 1 in which one carbon atom may be substituted with 0 or S a straight or branched chain group of ~4 carbon atoms] It may be any of the following.
本発明の好ましい悪様において、非環状リガンドは少なくとも３個、多くて５個 のアミノ酸基を含有し、式〔式中、ＲＩ−Ｒｓは同一または異なって水素、また は天然もしくは合成アミノ酸置換基からなる群より選択され、ＸはＯＨまたはＮ ＨＣ（Ｒｅ ）（Ｒ＋。）Ｃｏ、Ｈ（ここでＲ９およびＲ９゜は」二重Ｒ０〜Ｒ ，と同じ意味を有する）である〕を有する。In a preferred embodiment of the invention, there are at least 3 and at most 5 acyclic ligands. containing an amino acid group of the formula [wherein RI-Rs are the same or different and hydrogen or is selected from the group consisting of natural or synthetic amino acid substituents, and X is OH or N HC(Re )(R+.)Co,H(Here, R9 and R9゜ are double R0~R , which has the same meaning as ).
放射性医薬製剤を生成する反応は放射性核種およびリガンド錯体と錯体生成から すでに存在する成分との反応により所定の期間現場で行なわれる。特に、水、Ｈ ” 、ＯＨ−、塩化物またはエタノールのような成分を使用して最終投与形態の 放射性医薬製剤を生成することができる。さらに、錯体は単にそれ自体と反応し て放射性医薬製剤を生成することができる。The reactions that produce radiopharmaceutical preparations involve the formation of complexes with radionuclides and ligands. It is carried out in situ for a defined period of time by reaction with components already present. In particular, water, H ”, OH-, chloride or ethanol in the final dosage form. Radiopharmaceutical formulations can be produced. Furthermore, the complex simply reacts with itself. can be used to produce radiopharmaceutical formulations.
特に、本発明の反応は一般反応 〔式中、Ｍは場合によっては１種以上の追加のリガンドが金属に結合された金属 放射性核種を示し、そしてＡ、 Ｂ、 Ｃ，Ｄ、 Ｗ。In particular, the reaction of the present invention is a general reaction [wherein M is a metal optionally bound to one or more additional ligands Radionuclides are shown, and A, B, C, D, W.
Ｘ、ＹおよびＺは上記の式（Ｉ）と同じ定義を有する〕に従うことができる。X, Y and Z have the same definitions as in formula (I) above.
この一般反応によれば、リガンドを放射性核種と反応させて放射性核種錯体を生 成することができ、次いでそれはリガンドが放射性核種と反応する時に存在する 成分とさらに反応することにより、所定の時間で所望の生物分布特性を有する放 射性医薬製剤に変化する。したがって、従来技術で必要な個々の反応のすべてを 行なう必要がなくなる。むしろ、放射性医薬製剤を生成する全工程はこのような 生成に必要な成分を用意することにより１回の反応段階で行なうことができる。According to this general reaction, a ligand is reacted with a radionuclide to form a radionuclide complex. can be formed and then it is present when the ligand reacts with the radionuclide. Further reaction with the components produces a release with the desired biodistribution characteristics at a given time. It is transformed into a radioactive pharmaceutical preparation. Therefore, all of the individual reactions required in the prior art are There's no need to do it. Rather, the entire process of producing a radiopharmaceutical preparation is The production can be carried out in one reaction step by preparing the necessary components.
本発明の方法はさらに、リガンドの合成または放射性核種錯体の生成に伴なう問 題のため従来は得られなかった放射性医薬製剤を生成するための手段を提供する 。特に、このような従来は得られなかった放射性医薬製剤は、リガンドを予備合 成する必要がなく、または金属を最終形態のリガンドと錯化させる必要がないた め（これらは共に化学的、かつ放射性医薬的に好ましくない工程でありうる）、 今般生成することができる。The methods of the invention further address the problems associated with the synthesis of ligands or the production of radionuclide complexes. Provides a means for producing radiopharmaceutical preparations hitherto unavailable due to . In particular, such previously unavailable radiopharmaceutical formulations require pre-prepared ligands. or complex the metal with the final form of the ligand. (both of which can be chemically and radiopharmaceutically unfavorable steps), It can now be generated.
本発明の放射性医薬製剤は一般に診断または治療に適した組成物の形態で使用さ れる。このような放射性医薬組成物は放射性薬剤の他に、通常、液状の薬学的に 許容しうる担体物質、好ましくは生理的食塩水を含有する。放射線診断検査はこ のような組成物を患者に投与し、次いで例えばγ−カメラを用いて患者から放出 される放射線を記録することにより行なうことができる。The radiopharmaceutical formulation of the present invention is generally used in the form of a composition suitable for diagnosis or therapy. It will be done. In addition to radiopharmaceuticals, such radiopharmaceutical compositions typically include liquid pharmaceutical compositions. Contains an acceptable carrier material, preferably physiological saline. This is the radiological diagnostic test. to a patient and then released from the patient using, for example, a γ-camera. This can be done by recording the radiation emitted.
本発明はさらに、放射性核種溶液の形態の放射性核種を還元剤および場合によっ ては適当なキレート化剤の存在下で適当な化合物と反応させることにより本発明 の放射性医薬製剤を製造する方法に関する。還元剤は発生器から得られる。また は製造業者から供給される溶液中の金属放射性核種を還元する働きをする。適当 な還元剤は例えば次亜硫酸塩、ホルムアミジンスルフィン酸、ジアミノメタンジ スルフィン酸塩、あるいは適当な金属還元剤例えばスズ金属のような還元金属、 またはＳｕ （ＩＩ） 、 Ｆｅ （ＩＩ）、Ｃｕ （Ｉ） 、Ｔｉ （ＩＩ） もしくは５ｂ（Ｉ［［）のような還元イオンであり、Ｓｕ （ＩＩ）が特に適し ていることがわかった。The invention further provides that the radionuclide in the form of a radionuclide solution is combined with a reducing agent and optionally The present invention can be obtained by reacting with a suitable compound in the presence of a suitable chelating agent. The present invention relates to a method for producing a radiopharmaceutical formulation. The reducing agent is obtained from the generator. Also serves to reduce the metal radionuclides in the solution supplied by the manufacturer. suitable Reducing agents include, for example, hyposulfites, formamidine sulfinic acid, diaminomethane di sulfinate or a suitable metal reducing agent such as a reducing metal such as tin metal, Or Su (II), Fe (II), Cu (I), Ti (II) or a reduced ion such as 5b(I[[), with Su(II) being particularly suitable. I found out that
上記の錯体生成反応において、放射性核種溶液は上記の一般式（Ｉ）を有するリ ガンドと直接、または最初に金属がトランスファリガンドに結合し、次いで選択 リガンドで置換される２段階反応で反応する。放射性核種に適したトランスファ ーリガンドの例はジカルボン酸、ポリカルボン酸またはヒドロキシカルボン酸例 えばシュウ酸、マロン酸、コハク酸、マレイン酸、オルトフタル酸、リンゴ酸、 乳酸、酒石酸、クエン酸、アスコルビン酸、サリチル酸またはこれらの酸の誘導 体、リン化合物例えばピロリン酸塩：またはエノラートである。放射性核種がテ クネチウム−９９ｍである場合、クエン酸、酒石酸、アスコルビン酸、グルコヘ プトン酸またはこれらの誘導体は特に適したトランスファーリガンドである。In the above complex formation reaction, the radionuclide solution is a phosphor having the above general formula (I). directly with the ligand or the metal first binds to the transfer ligand and then selects Reacts in a two-step reaction in which the ligand is substituted. Transfer suitable for radionuclides - Examples of ligands are dicarboxylic acids, polycarboxylic acids, or hydroxycarboxylic acids. For example, oxalic acid, malonic acid, succinic acid, maleic 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. radionuclide In the case of Cunetium-99m, citric acid, tartaric acid, ascorbic acid, glucose Ptonic acids or derivatives thereof are particularly suitable transfer ligands.
本発明はまた、（１）一般式（Ｉ）を有するリガンドであって、好ましくは乾燥 状態であり、また好ましくは不活性の、薬学的に許容しうる担体および／または それに加えられた補助物質を有するリガンド；並びに（２）還元剤および場合に よってはキレート化剤を含有し、成分（１）および（２）は場合によっては混合 されていてもよく、そしてさらに、成分（１）および（２）を放射性核種溶液と 反応させることによる上記の方法を行なうための手順を記載した使用説明書を場 合によっては含むことのできるキットに関する。The present invention also provides (1) a ligand having general formula (I), preferably dried a pharmaceutically acceptable carrier and/or a ligand with auxiliary substances added thereto; and (2) a reducing agent and optionally Therefore, it may contain a chelating agent, and components (1) and (2) may be mixed in some cases. and further, components (1) and (2) may be combined with a radionuclide solution. A manual containing instructions for carrying out the above method by reacting is available locally. kits that may optionally be included.
上記のキットに適した還元剤およびキレート化剤の例は上記に列挙しである。放 射性核種溶液は使用者により入手しつる発生器から簡単に得ることができ、また は溶液として製造業者から供給される。上記したように、成分（１１および（２ ）は相溶しつる場合に混合することができる。好ましくは混合された成分は凍結 乾燥されている。このような単一成分のキットは使用者が簡単な方法で放射性核 種溶液と反応させるのに適している。Examples of reducing agents and chelating agents suitable for the above kits are listed above. release Radionuclide solutions can be easily obtained from user-supplied generators and is supplied by the manufacturer as a solution. As mentioned above, components (11 and (2) ) can be mixed if they are compatible. Preferably the mixed ingredients are frozen It has been dried. These single-component kits allow users to easily prepare radionuclides. Suitable for reacting with seed solutions.
上記キットの成分（１）は例えば生理的食塩水またはある種の緩衝溶液の形態で 、溶液として提供することができるが、好ましくは乾燥状態、例えば凍結乾燥状 態で存在する。注射液用成分とじて使用される場合、それは滅菌する必要があり 、また成分（１）が乾燥状態で存在する場合、使用者は溶媒として滅菌生理的食 塩水を使用すべきである。所望ならば、成分（１）はアスコルビン酸、ゲンチシ ン酸またはこれらの酸の塩のような適当な安定剤を用いて常法により安定化する ことができ、または充填剤、例えばグルコース、ラクトース、マンニトール、イ ノシトールなどのような他の補助剤を添加することができる。Component (1) of the above kit is, for example, in the form of physiological saline or some kind of buffer solution. , can be provided as a solution, but preferably in dry form, e.g. in lyophilized form. It exists in a state. When used as an injectable component, it must be sterilized. , and if component (1) is present in dry form, the user may use sterile physiological saline as a solvent. Salt water should be used. If desired, component (1) can include ascorbic acid, gentis stabilized by conventional methods using suitable stabilizers such as acid or salts of these acids. or fillers such as glucose, lactose, mannitol, etc. Other adjuvants such as nositol etc. can be added.
次の実施例は本発明の１態様を記載する。The following example describes one embodiment of the invention.
〔実施例１〕直接の標識付けによる放射性医薬製剤の合成反応容器中に１■のテ トラ−し−アラニン、０．２−のリン酸塩緩衝剤（０，５Ｍ、ｐＨ１２） 、２ ５−の０．０５ＮＨＣ１中に溶解された１００μｍのＳｎＣ１，・Ｈ，Ｏｌおよ びペルテクネテートとしての３７０ＭＢＱの９９ｍＴｃを含有する２−の発生器 溶離液を加えた。室温で１０分間放置した後、反応混合物をエタノールおよび０ ．０２５Ｍリン酸塩緩衝剤（ｐＨ５，８５）の混合物（３０・７０）を用いて常 法により１ｍ／／分の速度で溶離する２５０ｍｍＸ４．６ｍｍ（内径）のＨｙｐ ｅｒｓ ｉ ｌ０ＤＳカラム上におけるＲＰ−ＨＰＬＣにより分析した。流出液 中の放射能を単チヤンネル分析器および積分器と連結された２インチのＮａ１（ ｔｉりシンチレーション検出器を用いて監視した。 [Example 1] Synthesis of radiopharmaceutical preparation by direct labeling. tri-alanine, 0.2-phosphate buffer (0.5M, pH 12), 2 5-100 μm of SnC1,·H,Ol and dissolved in 0.05N HCl 2- generator containing 370 MBQ of 99mTc as pertechnetate and pertechnetate. Eluent was added. After standing for 10 minutes at room temperature, the reaction mixture was diluted with ethanol and 0 ．． using a mixture (30.70) of 0.25M phosphate buffer (pH 5.85). Hyp of 250 mm x 4.6 mm (inner diameter) eluting at a speed of 1 m//min by method. Analyzed by RP-HPLC on an ers i 10DS column. Effluent The radioactivity in the 2-inch Na1 ( Monitoring was performed using a scintillation detector.
ＨＰＬＣ−クロマトグラムは主として１種の放射性物質（ピークＡ）と少量の別 の化合物（ピークＢ）の存在を示した。単離したピークＡおよびピークＢについ ての電気泳動実験は、ピークＡは遊離のカルボキシル基を有する（移行距離がよ り高いｐＨにおいてより大きい）が、一方、ピークＢの移行距離はｐＨの増加に 伴なって増加せず、したがって遊離カルボキシル基は存在しないことを示した。The HPLC chromatogram mainly shows one type of radioactive substance (peak A) and a small amount of other substances. showed the presence of a compound (peak B). Regarding isolated peak A and peak B In all electrophoresis experiments, peak A has a free carboxyl group (the migration distance is large). (larger at higher pH), whereas the migration distance of peak B increases with increasing pH. There was no concomitant increase, thus indicating that there were no free carboxyl groups.
ピークＢを９９Ｔｃ−シクロテトラ−し−アラニン（構造はＦＡＢ−質量分析お よび単結晶Ｘ線分析により確認された）と−緒に注入すると、ピークＢはスキー ムＩに示されるような９９ｍＴｃ−シクロテトラ−アラニンであることがわかっ た。ピークＡはスキームＩに示されるような非環状の９９ｍＴｃ−テトラ−し− アラニンであると考えられる。Peak B is 99Tc-cyclotetra-alanine (structure is FAB-mass spectrometry peak B was confirmed by single-crystal X-ray analysis). It was found to be 99mTc-cyclotetra-alanine as shown in Figure I. Ta. Peak A is a non-cyclic 99mTc-tetra- as shown in Scheme I. It is thought to be alanine.
単離したピークＡをｐＨ５，８５（リン酸塩緩衝剤）で定温放置すると徐々にピ ークＢに変換し、一方、ピークＢは同じ条件下で安定したままであった。When the isolated peak A is incubated at pH 5.85 (phosphate buffer), the peak gradually increases. peak B, while peak B remained stable under the same conditions.
〔スキームＩ）ＴｃＯＡａおよびＴｃ０−シクロ−Ａ４ （Ａ４＝テトラ−アラ ニン）の製造 Ｌ −４ｅｔｒａ−ａｌａｎｉｎｅ ＋ Ｓｎ”＋ Ｔｃ０ａ−〔実施例２〕交 換標識付けによる放射性医薬製剤の合成反応容器中に１■のテトラ−し−アラニ ン、０．３４の水中に溶解された４、５■の酒石酸ナトリウム、０．２４のリン 酸塩緩衝剤（０，５Ｍ、 ｐＨ４） 、２５ ｕｌ！の０．０５ＮＨＣ１中に溶 解された１００．ｃｚｍの５ｎＣ１，・Ｈ，Ｏおよびペルテクネテートとしての ３７０ＭＢｑの９９ｍＴｃを含有する２ｒｎｌの発生器溶離液を加えた。溶液を 沸騰水浴で１０分間加熱した。冷却した反応混合物のＨＰＬＣ分析は実施例１の ピークＢに相当する物質（環状９９ｍＴｃ−Ａ４ ） 、実施例１のピークＡに 相当する少量の物質および少量の９９ｍＴｃ−酒石酸塩の存在を示した。標識付 けがより高いｐＨ値で行なわれる場合、ピークＢの相対量は減少する。[Scheme I) TcOAa and Tc0-cyclo-A4 (A4=tetra-ara production of nin) L-4etra-alanine + Sn"+ Tc0a- [Example 2] Cross Synthesis of radiopharmaceutical preparations by labeling 1 μg of tetra-silane in a reaction vessel 4.5 parts sodium tartrate, 0.24 parts phosphorous dissolved in 0.34 parts water. Acid buffer (0.5M, pH 4), 25 ul! Dissolved in 0.05N HCl 100. czm as 5nC1,·H,O and pertechnetate 2rnl of generator eluate containing 370MBq of 99mTc was added. solution Heat in a boiling water bath for 10 minutes. HPLC analysis of the cooled reaction mixture was as in Example 1. Substance corresponding to peak B (cyclic 99mTc-A4), corresponding to peak A of Example 1 It showed the presence of a corresponding small amount of material and a small amount of 99mTc-tartrate. with sign If injury is performed at a higher pH value, the relative amount of peak B decreases.
Ａａ ＋ Ｓｎ”＋ ｔａｒｔｒａｔｅ ＋Ｔｃ０ａ−して本発明を限定するも のではな０゜むしろ、詳細畳こわたっての多くの変更、変形および変化は本発明 の範囲内である。Although the present invention is limited by Aa + Sn” + tartrate + Tc0a- On the contrary, many modifications, variations and changes in detail are contemplated by the present invention. is within the range of
国際調査報告 国際調査報告 ＵＳ ９２００６３０ Ｓ＾５ン７６９international search report international search report US9200630 S^5n769
Claims (23)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US656,346 | 1984-10-01 | ||
| US65634691A | 1991-02-14 | 1991-02-14 | |
| PCT/US1992/000630 WO1992014492A1 (en) | 1991-02-14 | 1992-01-27 | In situ synthesis of radiopharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06505268A true JPH06505268A (en) | 1994-06-16 |
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|---|---|---|---|
| JP4506601A Pending JPH06505268A (en) | 1991-02-14 | 1992-01-27 | In situ synthesis of radiopharmaceutical formulations |
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|---|---|
| EP (1) | EP0571545A1 (en) |
| JP (1) | JPH06505268A (en) |
| AU (1) | AU1429392A (en) |
| CA (1) | CA2101642A1 (en) |
| WO (1) | WO1992014492A1 (en) |
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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 |
| ATE52516T1 (en) * | 1986-05-28 | 1990-05-15 | Mallinckrodt Inc | TECHNETIUM CHELATE FOR DETERMINING KIDNEY FUNCTION. |
-
1992
- 1992-01-27 WO PCT/US1992/000630 patent/WO1992014492A1/en not_active Ceased
- 1992-01-27 EP EP19920907162 patent/EP0571545A1/en not_active Withdrawn
- 1992-01-27 CA CA002101642A patent/CA2101642A1/en not_active Abandoned
- 1992-01-27 JP JP4506601A patent/JPH06505268A/en active Pending
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| CA2101642A1 (en) | 1992-08-15 |
| AU1429392A (en) | 1992-09-15 |
| EP0571545A1 (en) | 1993-12-01 |
| WO1992014492A1 (en) | 1992-09-03 |
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