JP6018581B2 - 溶出溶液 - Google Patents
溶出溶液 Download PDFInfo
- Publication number
- JP6018581B2 JP6018581B2 JP2013546670A JP2013546670A JP6018581B2 JP 6018581 B2 JP6018581 B2 JP 6018581B2 JP 2013546670 A JP2013546670 A JP 2013546670A JP 2013546670 A JP2013546670 A JP 2013546670A JP 6018581 B2 JP6018581 B2 JP 6018581B2
- Authority
- JP
- Japan
- Prior art keywords
- radiofluorination
- eluate
- facbc
- reaction
- elution solution
- 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.)
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- 238000010828 elution Methods 0.000 title claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000002600 positron emission tomography Methods 0.000 claims description 20
- 239000002243 precursor Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000700 radioactive tracer Substances 0.000 claims description 13
- 125000002091 cationic group Chemical group 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000002739 cryptand Substances 0.000 claims description 9
- 238000005342 ion exchange Methods 0.000 claims description 8
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 claims description 6
- 238000005349 anion exchange Methods 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000003682 fluorination reaction Methods 0.000 claims description 5
- 230000002285 radioactive effect Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- -1 cryptand metal complex Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 claims description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical group [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical group OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 claims description 2
- 150000004696 coordination complex Chemical class 0.000 claims 2
- UXCAQJAQSWSNPQ-KXMUYVCJSA-N 1-[4-fluoranyl-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1OC(CO)C([18F])C1 UXCAQJAQSWSNPQ-KXMUYVCJSA-N 0.000 claims 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims 1
- SMYALUSCZJXWHG-VNRZBHCFSA-N 3-[2-[4-(4-fluoranylbenzoyl)piperidin-1-yl]ethyl]-2-sulfanylidene-1h-quinazolin-4-one Chemical compound C1=CC([18F])=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=S)=O)CC1 SMYALUSCZJXWHG-VNRZBHCFSA-N 0.000 claims 1
- WPKXGJXEAGYSBQ-RVRFMXCPSA-N 4-(2-aminoethyl)-5-fluoranylbenzene-1,2-diol Chemical compound NCCC1=CC(O)=C(O)C=C1[18F] WPKXGJXEAGYSBQ-RVRFMXCPSA-N 0.000 claims 1
- XIDVXDKBUJEBSC-NUTRPMROSA-N 5-(18F)fluoranyl-2-nitro-1H-imidazole Chemical compound [18F]C=1N=C(NC=1)[N+](=O)[O-] XIDVXDKBUJEBSC-NUTRPMROSA-N 0.000 claims 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims 1
- QHJLPOSPWKZACG-UHFFFAOYSA-N N-Methylspiperone Chemical compound C1CN(CCCC(=O)C=2C=CC(F)=CC=2)CCC21C(=O)N(C)CN2C1=CC=CC=C1 QHJLPOSPWKZACG-UHFFFAOYSA-N 0.000 claims 1
- 229960005309 estradiol Drugs 0.000 claims 1
- 229930182833 estradiol Natural products 0.000 claims 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims 1
- 229960004884 fluconazole Drugs 0.000 claims 1
- 229960002748 norepinephrine Drugs 0.000 claims 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims 1
- 229960001180 norfloxacin Drugs 0.000 claims 1
- NTEDWGYJNHZKQW-DGMDOPGDSA-N fluciclovine ((18)F) Chemical compound OC(=O)[C@]1(N)C[C@H]([18F])C1 NTEDWGYJNHZKQW-DGMDOPGDSA-N 0.000 description 37
- 229940027541 fluciclovine f-18 Drugs 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000003860 storage Methods 0.000 description 18
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 238000002372 labelling Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000011194 good manufacturing practice Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- HIIJZYSUEJYLMX-UHFFFAOYSA-N 1-fluoro-3-(2-nitroimidazol-1-yl)propan-2-ol Chemical compound FCC(O)CN1C=CN=C1[N+]([O-])=O HIIJZYSUEJYLMX-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 238000012879 PET imaging Methods 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000008364 bulk solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- CKEOSLXCJBTWQG-AWDFDDCISA-N (1,4-dioxonaphthalen-2-yl)methyl 4-fluoranylbenzoate Chemical compound C1=CC([18F])=CC=C1C(=O)OCC1=CC(=O)C2=CC=CC=C2C1=O CKEOSLXCJBTWQG-AWDFDDCISA-N 0.000 description 1
- NTEDWGYJNHZKQW-KWCOIAHCSA-N 1-amino-3-fluoranylcyclobutane-1-carboxylic acid Chemical compound OC(=O)C1(N)CC([18F])C1 NTEDWGYJNHZKQW-KWCOIAHCSA-N 0.000 description 1
- HIIJZYSUEJYLMX-JZRMKITLSA-N 1-fluoranyl-3-(2-nitroimidazol-1-yl)propan-2-ol Chemical compound [18F]CC(O)CN1C=CN=C1[N+]([O-])=O HIIJZYSUEJYLMX-JZRMKITLSA-N 0.000 description 1
- AOYNUTHNTBLRMT-MXWOLSILSA-N 2-Deoxy-2(F-18)fluoro-2-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H]([18F])C=O AOYNUTHNTBLRMT-MXWOLSILSA-N 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 1
- 239000004713 Cyclic olefin copolymer Substances 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- OIBDVHSTOUGZTJ-PEBLQZBPSA-N [(2r,3r,4s,5s,6s)-3,4,6-triacetyloxy-5-(trifluoromethylsulfonyloxy)oxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O OIBDVHSTOUGZTJ-PEBLQZBPSA-N 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000005292 fiolax Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- PBVFROWIWWGIFK-KWCOIAHCSA-N fluoromethylcholine (18F) Chemical compound [18F]C[N+](C)(C)CCO PBVFROWIWWGIFK-KWCOIAHCSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000007141 radiochemical reaction Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
- 230000000717 retained effect Effects 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- JGFYQVQAXANWJU-UHFFFAOYSA-M sodium fluoroacetate Chemical compound [Na+].[O-]C(=O)CF JGFYQVQAXANWJU-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 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
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical compound NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B9/00—General methods of preparing halides
- C01B9/08—Fluorides
-
- 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
-
- 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
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
(i)18F-水溶液をイオン交換カラムに捕捉するステップと、
(ii)18F-が表面に吸着されたイオン交換カラムに溶出溶液を流して18F-溶出液を得るステップであって、溶出溶液がアセトニトリルを含んでいないことを条件として、溶出溶液が適当な溶媒中にカチオン性対イオンを含んでいる、ステップと
を含む方法を提供する。
(iii)ステップ(ii)でカラムから溶出された18F-を乾燥する追加のステップ
を含んでいてもよい。
(i)18F-水溶液の捕捉に適した、本明細書で定義されるアニオン交換カラム、
(ii)本明細書で定義される溶出溶液を収容した第1の容器、
(iii)本明細書で定義される方法によって得られた18F-と反応することにより本明細書で定義される18F−標識PETトレーサーを生じる前駆体化合物が入っている第2の容器
を含む。
実施例1は、保存された従来技術の溶出溶液の分析について記載する。
ATR 減衰した全反射率
DTGS 重水素を含むトリグリシンスルフェート
[18F]FACBC
1−アミノ−3−[18F]フルオエオシクロブタン−1−カルボン酸
[18F]FDG 2−デオキシ−2−[18F]フルオロ−D−グルコース
FT−IR フーリエ変換赤外線
K222 Kryptofix 222
MeCN アセトニトリル
MeOH メタノール
QMA 第4級メチルアンモニウム
RCY 放射化学的収率
SPE 固相抽出
TLC 薄層クロマトグラフィー
UV 紫外線
Fluorotec(登録商標)(West)でコーティングされたクロロブチルストッパでキャップされ、溶出溶液を充填した後にアルミニウムキャップで密封される、タイプ−1のホウケイ酸ガラス(FIOLAX(MGlas社製(ドイツ、ミュンナーシュタット)))からなる3.0mlのFASTlab溶出液溶出溶液バイアルを、[18F]FACBC合成又は[18F]FDG合成のどちらかに合わせて最適化した2種の溶出溶液の保存に使用した。
[18F]FACBC及び[18F]FDGの合成を、新たに調製された溶出液及び保存された溶出液の両方を用いて試験をして、アセトアミド及び酢酸アンモニウムの発生レベルがRCYに及ぼす影響を調査した。
バイアルAは、79.5%(v/v)MeCN水溶液(825μl)中のK222(43.7mg、117μmol)、K2CO3(7.8mg、56.7μmol)を含んでいた。バイアルBは、1700ppmの水を含むMeCN 2.0ml中に前駆体(39mg、81.2μmol)を含んでいた。バイアルCは、MeCN(4.1ml)を含んでいた。バイアルDは、2M NaOH(4.1ml)を含んでいた。バイアルEは、2.3Mリン酸(4.1ml)を含んでいた。水性[18F]フッ化物(1ml、100〜200Mbq)を、QMA内に通して18O−H2O回収バイアル内へと移動させた。捕捉[18F]フッ化物を、バイアルA(450μl)から溶出液を使用して反応器内に溶出し、次いでアセトニトリル(80μl、バイアルC)を用いた共沸蒸留によって濃縮乾固した。バイアルBからの前駆体溶液約1.6ml(31.2mg;65μmol前駆体に相当)を反応器に添加し、125℃で2分間加熱した。反応混合物を水で希釈し、tC18カートリッジを通した。反応器を水で洗浄し、tC18カートリッジを通した。tC18カートリッジに固定された、標識された中間体を、最初に水で洗浄し、次いで2M NaOH(2.0ml)と共に2分間インキュベートした。粗製混合物を水(1.5ml)及び2.3Mリン酸(1.5ml)と混合し、HLB及びアルミナカートリッジ内に通してガラスで作製された生成物バイアル(30ml)内へと移動させた。次いで水(9ml)を、HLB及びアルミナカートリッジ内に送り出し、生成物バイアルへと移動させた。精製された[18F]FDGの配合物は、最終体積15mlを含んでいた。放射化学純度を、移動相としてMeCN:H2O(95:5)の混合物を使用する放射−TLCにより試験した。放射化学的収率(RCY)は、[18F]FDG中の放射能の値を、使用された全[18F18F]フッ化物活性(減衰補正)で除した値として表した。全合成時間が22分であった。
バイアルAは、79.5%(v/v)MeCN水溶液(1105μl)中のK222(58.8mg、156μmol)、K2CO3(8.4mg、60.8μmol)を含んでいた。バイアルBは、4M HCl(2.0ml)を含んでいた。バイアルCは、MeCN(4.1ml)を含んでいた。バイアルDは、前駆体(48.4mg、123.5μmol)の乾燥形態を含んでいた(カセットの組立てまで−20℃で保存)。バイアルEは、2M NaOH(4.1ml)を含んでいた。30mlの生成物収集ガラスバイアルに、200mMクエン酸緩衝液(10ml)を充填した。水性[18F]フッ化物(1〜1.5ml、100〜200Mbq)をQMA内に通して、18O−H2O回収バイアルへと移動させた。次いでQMAをMeCNでフラッシュし、廃棄物に送り出した。捕捉された[18F]フッ化物を、バイアルA(730μl)からの溶出液を使用して反応器内に溶出し、次いでアセトニトリル(80μl、バイアルC)を用いた共沸蒸留によって濃縮乾固した。MeCN約1.7mlをバイアルDの前駆体と混合し、そこから、溶解した前駆体1.0ml(28.5mg、72.7mmol前駆体に相当)を反応器に添加し、85℃で3分間加熱した。反応混合物を水で希釈し、tC18カートリッジ内に送り出した。反応器を水で洗浄し、tC18カートリッジ内に送り出した。tC18カートリッジに固定された、標識された中間体を、水で洗浄し、次いで2M NaOH(2.0ml)と共に5分間インキュベートした。標識された中間体(エステル基なし)を、水を使用してtC18カートリッジから反応器内へと溶出させた。BOC基を、4M HCl(1.4ml)を添加し、反応器を60℃で5分間加熱することによって、加水分解した。粗製[18F]FACBCを含む反応器内容物を、HLB及びアルミナカートリッジを通して、30mlの生成物バイアル内へと移動させた。HLB及びアルミナカートリッジを水(合計0.9ml)で洗浄し、生成物バイアルに収集した。最後に、2M NaOH(0.9ml)及び水(2.1ml)を生成物バイアルに添加することにより、全体積が26mlの、[18F]FACBCの精製された配合物が得られた。放射化学純度を、移動相としてMeCN:MeOH:H2O:CH3COOH(20:5:5:1)の混合物を使用する放射−TLCにより測定した。放射化学的収率(RCY)は、[18F]FACBC中の放射能の値を、使用された全[18F]フッ化物活性(減衰補正した)で除した値として表した。全合成時間は43分であった。
アセトニトリルの代わりにメタノールを用いるFACBC溶出液バイアルを、所定時間にわたり保存し、[18F]FACBCの合成で試験をした。図4は、30℃(▲)、50℃(●)でMeOHと共に溶出液を保存した後の[18F]FACBCのRCYと、30℃(◆)、40℃(■)でMeCNと共に溶出液を保存した後の[18F]FDGのRCYとを示す。アセトニトリル系溶出液は、保存時間が長くなるにつれてRCYが徐々に低下したが、メタノール系溶出液は、50℃で6カ月間保存した場合であってもRCYは変化しないままであった。
Claims (15)
- 放射性フッ素化反応で使用される18F-の調製方法であって、
(i)18F-水溶液をアニオン交換カラムに捕捉するステップと、
(ii)18F-が表面に吸着されたイオン交換カラムに溶出溶液を流して18F-溶出液を得るステップであって、溶出溶液がカチオン性対イオンを適当な溶媒中に含んでおり、溶出溶液がアセトニトリルを含んでいないことを条件として、適当な溶媒がエタノール及びメタノールから選択されるアルカノールを含んでいる、ステップと
を含む方法。 - アニオン交換カラムが第4級メチルアンモニウム(QMA)カラムである、請求項1記載の方法。
- カチオン性対イオンが、クリプタンドの金属錯体である、請求項1又は請求項2記載の方法。
- クリプタンドの金属錯体の金属がカリウムである、請求項3記載の方法。
- クリプタンドの金属錯体のクリプタンドがKryptofix 222(K222)である、請求項3又は請求項4記載の方法。
- 適当な溶媒が、アルカノールの水溶液である、請求項1乃至請求項5のいずれか1項記載の方法。
- アルカノールがメタノールである、請求項6記載の方法。
- (iii)ステップ(ii)でカラムから溶出された18F-を乾燥するステップ
をさらに含む、請求項1乃至請求項7のいずれか1項記載の方法。 - 自動化された、請求項1乃至請求項8のいずれか1項記載の方法。
- 自動化放射合成装置での使用に適したカセットで実施される、請求項9記載の方法。
- 18F−標識陽電子放射断層撮影(PET)トレーサーを得るための放射性フッ素化方法であって、放射性フッ素化方法が、前駆体化合物と18F-との反応を含み、前駆体化合物が、1つ以上の保護基を含んでいてもよく、18F-が、請求項1乃至請求項9のいずれか1項記載の方法によって得られる、放射性フッ素化方法。
- 18F−標識PETトレーサーが、2−デオキシ−2−[18F]フルオロ−D−グルコース、[18F]フルオロチミジン、[18F]フルオロニトロイミダゾール、6−[18F]フルオロDOPA、[18F]セトペロン、[18F]アルタンセリン、[18F]N−メチルスピペロン、6−[18F]フルオロドーパミン、(−)6−[18F]フルオロ−ノルエピネフリン、16α−[18F]フルオロエストラジオール、[18F]フレロキサシン、又は[18F]フルコナゾールである、請求項11記載の放射性フッ素化方法。
- 自動化された、請求項11又は請求項12記載の放射性フッ素化方法。
- 自動化放射合成装置での使用に適したカセットで実施される、請求項13記載の放射性フッ素化方法。
- (i)18F-水溶液の捕捉に適した請求項1又は請求項2記載のアニオン交換カラムと、
(ii)請求項1又は請求項3乃至請求項7のいずれか1項記載の溶出溶液を収容した第1の容器と、
(iii) 18 F -との反応によって請求項11又は請求項12記載の18F−標識PETトレーサーを生じる前駆体化合物を収容した第2の容器と
を含む、請求項14記載の放射性フッ素化方法を実施するためのカセット。
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- 2012-12-21 PT PT128065000T patent/PT2793954T/pt unknown
- 2012-12-21 KR KR1020197030135A patent/KR102137348B1/ko active IP Right Grant
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2019
- 2019-02-28 US US16/288,650 patent/US20190192660A1/en not_active Abandoned
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10023525B2 (en) | 2012-08-09 | 2018-07-17 | Ge Healthcare Limited | Preparation of 18F-fluciclovine |
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