JP5870031B2 - 自動化放射合成 - Google Patents
自動化放射合成 Download PDFInfo
- Publication number
- JP5870031B2 JP5870031B2 JP2012532611A JP2012532611A JP5870031B2 JP 5870031 B2 JP5870031 B2 JP 5870031B2 JP 2012532611 A JP2012532611 A JP 2012532611A JP 2012532611 A JP2012532611 A JP 2012532611A JP 5870031 B2 JP5870031 B2 JP 5870031B2
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- Japan
- Prior art keywords
- fluoride
- nitro
- minutes
- hydrogen
- mmol
- 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.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 38
- -1 activated fluoride ions Chemical class 0.000 claims description 36
- 239000002243 precursor Substances 0.000 claims description 36
- 230000015572 biosynthetic process Effects 0.000 claims description 27
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
- 235000003270 potassium fluoride Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
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- 229940121896 radiopharmaceutical Drugs 0.000 claims description 4
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000006654 (C3-C12) heteroaryl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
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- 238000006243 chemical reaction Methods 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
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- IHISDHNVVJHQPP-UHFFFAOYSA-N ethyl 5-methyl-8-nitro-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N(C)C(=O)C2=CC([N+]([O-])=O)=CC=C2N2C=NC(C(=O)OCC)=C21 IHISDHNVVJHQPP-UHFFFAOYSA-N 0.000 description 15
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- YOQLMKCPYDESNW-UHFFFAOYSA-N 7-(dimethylamino)-4-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound N1C(=O)CN(C)C(=O)C2=CC(N(C)C)=CC=C21 YOQLMKCPYDESNW-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- OFBIFZUFASYYRE-GKTGUEEDSA-N ethyl 8-fluoranyl-5-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N(C)C(=O)C2=CC([18F])=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-GKTGUEEDSA-N 0.000 description 10
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 10
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- SNRRKCPVXFFFKC-UHFFFAOYSA-N 4-methyl-7-nitro-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound O=C1N(C)CC(=O)NC2=CC=C([N+]([O-])=O)C=C21 SNRRKCPVXFFFKC-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZOECHMQVKQIVPX-UHFFFAOYSA-O trimethyl-(4-methyl-2,5-dioxo-1,3-dihydro-1,4-benzodiazepin-7-yl)azanium Chemical compound O=C1N(C)CC(=O)NC2=CC=C([N+](C)(C)C)C=C21 ZOECHMQVKQIVPX-UHFFFAOYSA-O 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 229940049706 benzodiazepine Drugs 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 4
- CZGRTVPQCGVQBA-UHFFFAOYSA-N 7-amino-4-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound O=C1N(C)CC(=O)NC2=CC=C(N)C=C21 CZGRTVPQCGVQBA-UHFFFAOYSA-N 0.000 description 4
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
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- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 229940098788 GABA receptor antagonist Drugs 0.000 description 1
- 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 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical group [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004848 alkoxyethyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000005011 alkyl ether group Chemical group 0.000 description 1
- 229940125516 allosteric modulator Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- VLDUBDZWWNLZCU-UHFFFAOYSA-N ethyl 5-methyl-1h-imidazole-4-carboxylate Chemical compound CCOC(=O)C=1NC=NC=1C VLDUBDZWWNLZCU-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- UXKUODQYLDZXDL-UHFFFAOYSA-N fulminic acid Chemical compound [O-][N+]#C UXKUODQYLDZXDL-UHFFFAOYSA-N 0.000 description 1
- 230000007849 functional defect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical compound C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000005258 radioactive decay Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- IQSYKHVFMYGJER-UHFFFAOYSA-N tert-butyl 2-isocyanoacetate Chemical compound CC(C)(C)OC(=O)C[N+]#[C-] IQSYKHVFMYGJER-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
R1及びR2の一方は18Fであって、他方は水素であり、
R3はC3-5複素環であるか、或いはR3はC(=O)−O−R4(式中、R4は水素又は直鎖若しくは枝分れC1-4アルキルである。)である。)
(i)次の式Iaの前駆体化合物を用意する段階、及び
R11及びR12の一方は脱離基であって、他方は水素であり、
R11が前記脱離基である場合、それはトリ−C1-3アルキルアンモニウム及び−I+−Ar(式中、Arは1以上のR*基で置換されたフェニルであり、R*は水素、ニトロ、シアノ、ハロゲン、C1-10ヒドロキシアルキル、C2-10カルボキシアルキル、C1-10アルキル、C2-10アルコキシアルキル、C1-10ヒドロキシアルキル、C1-10アミノアルキル、C1-10ハロアルキル、C6-14アリール、C3-12ヘテロアリール、C3-20アルキルアリール、C2-10アルケニル及びC2-10アルキニルから選択される。)から選択され、
R12が前記脱離基である場合、それはニトロ、トリ−C1-3アルキルアンモニウム及び−I+−Ar(式中、ArはR11に関して上記に定義した通りである。)から選択され、
R13は式IのR3に関して定義した通りである。)
(ii)前記前駆体化合物を適当な[18F]フッ化物イオン源と反応させる段階
を含んでなる方法を提供する。
(iii)過剰の[18F]フッ化物イオンを除去する段階、及び/又は
(iv)存在する場合には保護基を除去する段階、及び/又は
(v)有機溶媒を除去する段階、及び/又は
(vi)得られた化合物を生体適合性キャリヤーと共に製剤化して、哺乳動物への投与に適した放射性医薬組成物を得る段階
を含み得る。
(i)上記に好適なもの及び好ましいものとして定義した前駆体化合物を含む容器、及び
(ii)上記に好適なもの及び好ましいものとして定義した適当な[18F]フッ化物イオン源を用いて容器を溶出するための手段
を含んでなるカセットが提供される。
比較例1は、ニトロ前駆体化合物からの[18F]フルマゼニルの製法を記載している。
aq 水性
CIP 2−クロロ−2,3−ジメチルイミダゾリジウムヘキサフルオロホスフェ ート
DCM ジクロロメタン
DIPEA N,N−ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EOS 合成終了時
Et エチル
g グラム
h 時間
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー質量分析法
MeCN アセトニトリル
min 分
mL ミリリットル
mM ミリモル濃度
mmol ミリモル
mol モル
QMA 第四級メチルアンモニウム
Rf 保持因子
rt 室温
SPE 固相抽出
TBA テトラブチルアンモニウム
TEA トリエチルアミン
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
UV 紫外
比較例1:ニトロマゼニルからの[ 18 F]フルマゼニル([ 18 F]FMZ)の製法
比較例1(i):4−メチル−7−ニトロ−3,4−ジヒドロ−1H−ベンゾ[e][1,4]ジアゼピン−2,5−ジオン(1)の合成
1)DCM/酢酸エチルを用いたCompanion(2回)
2)ベトロール/酢酸エチルを用いたCompanion(2回)
50mgの純物質2を無色の固体(収率4%)として得た。
実施例2(i):4−メチル−7−アミノ−3,4−ジヒドロ−1H−ベンゾ[e][1,4]ジアゼピン−2,5−ジオン(3)の合成
窒素流下0℃で2−フルオロ−6−ニトロ安息香酸(1.5g、8mmol)をDCM(30mL)中に懸濁した。塩化オキサリル(1.5g、1.06mL、12mmol)をゆっくりと添加し、反応物を一晩撹拌し続けた。塩化アシルの生成はTLC(酢酸エチル)によって追跡できた。溶媒を真空中で除去し、残留物をDCM(20mL)に再溶解した。エタノール(0.4g、0.5mL、8mmol)をTEA(0.8g、1.1mL、8mmol)と共に0℃で添加し、反応物を室温で3時間撹拌し続けた。この時間後、少量の混合物を1H及び19F NMRによって分析することで、12の定量的生成が示された。
12(3g、0.014mol)及びエチル4−メチル−5−イミダゾールカルボキシレート(1.96g、0.013mol)を30mLのDMSOに溶解した。炭酸セシウム(4.8g、0.014mol)を添加し、混合物を室温で3日間撹拌した。
臭化物(4.25g、0.010mol)を50mLのメタノールに溶解した撹拌溶液に、DIPEA(2.84g、3.8mL、0.022mol)及びメチルアミン(2Mメタノール溶液6.5mL、0.013mol)をメタノール(50mL)に溶解した溶液をゆっくりと添加した。反応物を一晩還流した。酢酸エチルを用いたTLC分析は、出発原料13から2つの主要新スポット(rf 0.5及び0.3)への定量的転化を示した。3分間にわたる5〜95%アセトニトリル/水勾配を用いたLCMSによって粗生成物を分析した。これは、正イオンとして331.03の質量を有する新しい化学種及び2つの他の主ピークを示した。溶媒を除去乾固し、粗生成物をDCM/酢酸エチル/1%メタノールを用いるフラッシュクロマトグラフィー用のカラム上に液体装填した。2つの主画分を合わせてLCMSに付したところ、2種の他の生成物との混合物中に所望の物質が示された。
FASTlab自動化合成モジュール(GE Healthcare社)上で放射性フッ素化を行った。
エタノール(5mL)中の2,6−ジニトロ安息香酸(0.5g、2.36mmol)を80℃に加熱した。次いで、硫化アンモニウム(水中40〜48%)(0.36mL、2.36mmol)を添加し(黄色の溶液が鮮橙色の懸濁液になった)、混合物を0.5時間加熱還流した。TLC(DMF 80%、MeOH 20%)は、出発原料の下方にかすかなスポットを示した。硫化アンモニウム(3.6mL、20.4mmol)を添加したところ、混合物は一層濃い橙色になった。次いで、この混合物を1時間加熱還流した後、TLCは反応が完了したことを示した。溶媒を減圧下で除去し、次いで残留物をメタノールで洗浄した。メタノール溶液をデカントして分離し、蒸発乾固することで、2−ニトロ−6−アミノ安息香酸を橙色の固体として得た。次いでこれを、フラッシュクロマトグラフィー(60CVにわたりDMF 90%/MeOH 10%→20%MeOH)を用いて精製することで、所望の物質(0.2g、46%)を得た。
ニトロイサト酸無水物(15)(3.5g、16.8mmol)及びサルコシン(1.50g、16.8mmol)をDMSO(8mL)に溶解した。次いで、混合物を150℃に予熱された加熱マントル内に配置した。次いで、混合物をこの温度で約30分間加熱した後、反応混合物を水(50mL)中に注ぎ込んだ。得られた褐色の沈殿を濾過によって集め、酢酸エチルでトリチュレートすることで、淡褐色の粉末(0.9g、11%)を得た。
THF(56mL)中の中間体16(0.7g、2.98mmol)に、0℃でカリウムtert−ブトキシド(0.37g、3.27mmol)を添加した。次に、混合物を0℃で20分間撹拌し(その間に鮮黄色の沈殿が認められた)、次いで−35℃に冷却した。ジエチルクロロホスフェート(0.67g、3.88mmol、0.56mL)をゆっくりと添加した。反応物を0℃で30分間撹拌し、その間に混合物はわずかに黄色味を増した。反応フラスコを−35℃に冷却し、tert−ブチルイソシアノアセテートの溶液(0.46g、3.26mmol、0.48mL)を添加し、次いでカリウムtert−ブトキシド(0.37g、3.27mmol)を添加した。次いで、懸濁液を室温で一晩撹拌し続けた。反応物をNaHCO3水溶液(50mL)で奪活し、EtOAc(3×50mL)で抽出した。有機層を合わせ、MgSO4上で乾燥し、濃縮して褐色の油状物を得た。粗物質を、酢酸エチル(A):メタノール(B)(0〜1%B、100g、40mL/分)で溶出するシリカゲルクロマトグラフィーによって精製した。17を淡黄色の固体(9mg、1%)として得た。
TRACERlab自動化合成モジュール(GE Healthcare社)上で放射性フッ素化を行った。プレコンディショニング済みのQMAカートリッジ上に[18F]フッ化物イオンを捕捉し、次いでKryptofix 2.2.2(11mg)をMeCN(2000μL)及びK2CO3(80μLの水中、1.7mg)に溶解した溶液を用いてバイアル1から反応器に移した。窒素+真空フローを使用しながら、溶液を100℃で10分間、次いで120℃で20分間乾燥し、次いで50℃に冷却した。
マイクロ波容器内において、14(製法は実施例4(iii)に記載、20mg、0.06mmol)を2mLのイソプロパノールに溶解し、50μlのチタン(IV)イソプロポキシドを添加した。マイクロ波条件は、温度:85℃、時間:60分であった。LCMSにより、出発原料から所望生成物への定量的転化が確認された。これはまた、酢酸エチルを用いるTLCによっても確認された。過剰のイソプロパノールを除去乾固し、粗混合物を溶離剤としてペトロール及び酢酸エチルを用いるフラッシュクロマトグラフィー用のカラム上に液体装填した。DCM/メタノールを用いて該物質を再び精製した。18(15mg)が純粋に得られた(73%)。
TRACERlab自動化合成モジュール(GE Healthcare社)上で放射性フッ素化を行った。プレコンディショニング済みのQMAカートリッジ上に[18F]フッ化物イオンを捕捉し、次いでKryptofix 2.2.2(11mg)をMeCN(2000μL)及びK2CO3(80μLの水中、1.7mg)に溶解した溶液を用いてバイアル1から反応器に移した。窒素+真空フローを使用しながら、溶液を100℃で10分間、次いで120℃で20分間乾燥し、次いで50℃に冷却した。
成体雄Sprague−Dawleyラット(体重202±37g、平均±SD)に、側尾静脈を通して1〜5MBqのo−[18F]フルマゼニルを注射した。いずれの動物も意識があったが、注射中は軽く拘束し、次いで短期代謝ケージ内に収容した。特定の時点、即ち注射後(pi)30秒、2分、10分、30分及び60分(各時点についてn=3)に、動物を頸部脱臼によって屠殺した。剖検後、脳及び末梢の組織又は体液を試料採取した。Wallacガンマカウンターを用いて脳試料中の放射能を測定した。アッセイ後、放射性崩壊に関する自動補正を含む双晶ガンマカウンターシステム(BASIL社)を用いて脳組織を残りの器官又は組織試料と共にアッセイした。下記表は、脳領域において得られたデータを示している。データは平均(±SD)として表され、すべてがn=3である。アステリスク(*)で示されたデータは%id/gである。
Claims (11)
- 次の式Iの化合物を得るための方法であって、
R1は水素であって、R2は18Fであり、
R3はC3-5複素環であるか、或いはR3はC(=O)−O−R4(式中、R4は水素又は直鎖若しくは枝分れC1-4アルキルである。)である。)
(i)次の式Iaの前駆体化合物を用意する段階、及び
R11は水素であって、R12は、ニトロ、トリ−C1-3アルキルアンモニウム及び−I+−Ar(式中、Arは1以上のR*基で置換されたフェニルであり、R*は水素、ニトロ、シアノ、ハロゲン、C1-10ヒドロキシアルキル、C2-10カルボキシアルキル、C1-10アルキル、C2-10アルコキシアルキル、C1-10アミノアルキル、C1-10ハロアルキル、C6-14アリール、C3-12ヘテロアリール、C3-20アルキルアリール、C2-10アルケニル及びC2-10アルキニルから選択される。)から選択される脱離基であり、
R13は式IのR3に関して定義した通りである。)
(ii)前記前駆体化合物を適当な[18F]フッ化物イオン源と反応させる段階
を含んでなり、当該方法が自動化されていて自動化合成装置上で実施される、方法。 - R12がトリメチルアンモニウムである、請求項1記載の方法。
- R12が−I+−Arである、請求項1記載の方法。
- R12がニトロである、請求項1記載の方法。
- R3及びR13が独立にC(=O)−O−R4(式中、R4は直鎖又は枝分れC1-4アルキルである。)である、請求項1乃至請求項4のいずれか1項記載の方法。
- R4がエチル、イソプロピル又はtert−ブチルである、請求項5記載の方法。
- 前記適当な[18F]フッ化物イオン源が[18F]フッ化カリウム及び[18F]フッ化セシウムから選択される、請求項1乃至請求項6のいずれか1項記載の方法。
- 前記適当な[18F]フッ化物イオン源が[18F]フッ化カリウムであり、Kryptofix(商標)を用いてフッ化物イオンが活性化される、請求項7記載の方法。
- さらに、
(iii)過剰の[18F]フッ化物イオンを除去する段階、及び/又は
(iv)存在する場合には保護基を除去する段階、及び/又は
(v)有機溶媒を除去する段階
を含む、請求項1乃至請求項8のいずれか1項記載の方法。 - 哺乳動物への投与に適した放射性医薬組成物を得るための方法であって、当該方法が、請求項1乃至請求項9のいずれか1項の方法と、それに続いて、得られた化合物を生体適合性キャリヤーと共に製剤化する段階とを含んでいる、方法。
- 請求項1乃至請求項9のいずれか1項記載の方法を実施するためのカセットであって、
(i)請求項1乃至請求項6のいずれか1項記載の方法で定義された前駆体化合物を含む容器、並びに
(ii)請求項1、請求項7又は請求項8で定義された適当な[18F]フッ化物イオン源を用いて容器を溶出するための手段
を含んでなるカセット。
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