WO2006054098A2 - Fluoridation process for the synthesis of 2- [18f] fluoro-2-deoxy-d-glucose - Google Patents
Fluoridation process for the synthesis of 2- [18f] fluoro-2-deoxy-d-glucose Download PDFInfo
- Publication number
- WO2006054098A2 WO2006054098A2 PCT/GB2005/004451 GB2005004451W WO2006054098A2 WO 2006054098 A2 WO2006054098 A2 WO 2006054098A2 GB 2005004451 W GB2005004451 W GB 2005004451W WO 2006054098 A2 WO2006054098 A2 WO 2006054098A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluoride
- fluoridated
- solvent
- water
- derivative
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 61
- 230000008569 process Effects 0.000 title claims abstract description 49
- 238000004334 fluoridation Methods 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title description 20
- 238000003786 synthesis reaction Methods 0.000 title description 17
- 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 title description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 92
- 235000000346 sugar Nutrition 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 98
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 32
- 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 claims description 14
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 229920002536 Scavenger resin Polymers 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 150000002772 monosaccharides Chemical class 0.000 claims description 4
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002303 glucose derivatives Chemical class 0.000 claims description 3
- 150000002703 mannose derivatives Chemical class 0.000 claims description 3
- WEDQSUHFUFBWEC-RKQHYHRCSA-N [(2r,3r,4s,5r,6s)-3,4,6-triacetyloxy-5-hydroxy-5-(trifluoromethylsulfonyl)oxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@](O)(S(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O WEDQSUHFUFBWEC-RKQHYHRCSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 238000002372 labelling Methods 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 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 6
- 239000008103 glucose Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- -1 fluoride ions Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000009919 sequestration Effects 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 238000000163 radioactive labelling Methods 0.000 description 4
- 239000000700 radioactive tracer Substances 0.000 description 4
- XLYOFNOQVPJJNP-NJFSPNSNSA-N ((18)O)water Chemical compound [18OH2] XLYOFNOQVPJJNP-NJFSPNSNSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- HXBYBCASAVUYKF-JBBNEOJLSA-N (4s,5s,6r,7r)-4,5,6,7,8-pentahydroxyoctane-2,3-dione Chemical compound CC(=O)C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO HXBYBCASAVUYKF-JBBNEOJLSA-N 0.000 description 1
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006227 byproduct 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
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910021397 glassy carbon Inorganic materials 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000003608 radiolysis 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
- 230000035484 reaction time Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000004007 reversed phase HPLC 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
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000005497 tetraalkylphosphonium group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- YOIAWAIKYVEKMF-UHFFFAOYSA-N trifluoromethanesulfonic acid Chemical group OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F YOIAWAIKYVEKMF-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/02—Monosaccharides
Definitions
- the present invention relates to a process for the fluoridation of sugar derivatives and in particular, the invention relates to the production of fluoridated glucose.
- the process is especially useful for the production of radiofluoridated sugar derivatives for use in procedures such as positron emission tomography (PET).
- PET positron emission tomography
- [ 18 F]-fluoride ion is typically obtained as an aqueous solution produced by the cyclotron irradiation of an [ 18 O]-water target. It has been widespread practice to carry out various steps in order to convert [ 18 F]-fluoride into a reactive nucleophilic reagent such that it is suitable for use in nucleophilic radiolabelling reactions. As with non-radioactive fluoridations, these steps include the elimination of water from the [ 18 F]-fluoride ion and the provision of a suitable counter-ion (Handbook of Radiopharmaceuticals 2003 Welch & Redvanly eds. ch. 6 pp 195-227).
- Nucleophilic radiofluoridation reactions are then carried out using anhydrous solvents (Aigbirhio et al, 1995 J. Fluor. Chem. 70 pp 279-87).
- the removal of water from the fluoride ion is referred to as making "naked" fluoride ion.
- the presence of significant quantities of water is believed to result in solvation of the fluoride ions, which shields the fluoride from nucleophilic attack on the protected sugar precursor.
- the removal of water is therefore regarded in the art as a step which is necessary to increase the reactivity of the fluoride as well as to avoid hydroxylated by-products arising from the presence of water (Moughamir et al, 1998 Tett. Letts. 39 pp 7305-6).
- the synthesis may require more drying cycles, whereas a more powerful heater may be required on the synthesiser to effect the synthesis.
- the present inventors have made the surprising discovery that it is not necessary to carry out the fluoridation of sugar derivatives under anhydrous conditions. 0 Indeed, if the amount of water in the reaction mixture is carefully controlled, the radiochemical purity (and thus the overall yield) of the process is actually improved. This is particularly surprising in view of the emphasis in the prior art on the necessity of conducting the reaction under anhydrous conditions.
- a process for the preparation of a fluoridated sugar derivative comprising reacting a non-fluoridated sugar derivative with a fluoride, characterised in that the reaction is conducted in a solvent containing water in an amount greater than 1000 ppm and less than 50,000 ppm.
- the method of the invention has considerable advantages over prior art methods. Firstly, it has been found that far from being decreased, the yield of the reaction is actually increased in the presence of these controlled amounts of water.
- reaction mixture contains water in an amount of greater than lOOOppm, it is much easier to ensure that a consistent amount of water is present in the reaction mixture (for instance by deliberately contaminating the labelling solvent with water) and this means that the reaction conditions are consistently reproducible.
- non fluoridated sugar derivative refers to a polysaccharide, oligosaccharide, disaccharide or monosaccharide sugar in which one of the OH groups is replaced by a leaving group and which is optionally bound to a solid support , for example as taught in WO-A-03/002157.
- the process of the invention is particularly suitable for fluoridating monosaccharides such as glucose, fructose, ribose, arabinose, mannose or galactose.
- a “protected non fluoridated sugar derivative” the other OH groups of the sugar are protected with a suitable protecting group.
- fluoridated sugar derivative refers to a polysaccharide, oligosaccharide, disaccharide or monosaccharide sugar such as glucose, fructose, ribose, arabinose, mannose or galactose in which one of the OH groups is replaced by a fluoro.
- Suitable protecting groups for the protected sugar derivatives used in the invention are well known in the art and are described, for example, in "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
- the particular protecting group chosen will depend upon the intended use of the fluoridated product but, for example, the hydroxy groups may be protected by conversion to alkyl or aromatic esters, for example by reaction with an alkanoyl chloride such as acetyl chloride.
- hydroxy groups may be converted to ethers, for example alkyl or benzyl ethers.
- both the starting material and the reaction product are protected sugar derivatives.
- Suitable leaving groups are also well known in the art and include toluene sulfonate and methane sulfonate. It is particularly preferred, however, that the leaving group is a trifluoromethane sulfonate (triflate) group.
- the fluoridation reaction will generally be a nucleophilic substitution reaction and replacement of the leaving group by fluoro may cause an inversion of the stereochemistry of the sugar via an SN2 mechanism.
- the starting non- fluoridated sugar derivative will often be a derivative of a different sugar from the product.
- a preferred product is a protected fluoridated glucose derivative, which can be prepared from the corresponding mannose derivative, for example a tetraacetyl mannose derivative.
- the reaction is especially suitable for the preparation of 2-fluoro-1 ,3,4,6-tetra-O- acetyl-D-glucose (tetraacetylfluoroglucose or pFDG) from 1 ,3,4,6-tetra-O-acetyl-2- trifluoromethanesulfonyl- ⁇ -D-mannopyranose (tetraacetyl mannose triflate).
- Suitable solvents include non protic organic solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxan, 1 ,2- dimethoxyethane, sulfolane or N-methylpyrrolidinone or a mixture of any thereof.
- acetonitrile has been found to be a particularly suitable solvent for the reaction.
- the improved reaction yield is obtained by including at least 1000 ppm but less than 50,000 ppm water in the solvent, even greater improvements have been achieved when the water content is from about 1000 to 15,000 ppm.
- the best results were obtained using a solvent with a water content of from about 2000 to 7000 ppm, suitably 2500 to 5000 ppm. In one embodiment, the preferred water content is from 3000ppm to 6000ppm.
- ppm when describing water content of a given solvent, means ⁇ gram water/gram.
- the correct level of water in the solvent may either be achieved by drying a wet solvent until the desired water content is reached or by adding a suitable amount of water to a dry solvent.
- the fluoride may be produced in aqueous solution and, in this case, a fluoride solution having the desired water content may be obtained by repeated additions of the solvent followed by evaporation of the solvent/water mix, or by dilution of the aqueous fluoride with the desired organic solvent.
- Water content of the solvent may also be reduced by using a scavenger resin, such as a functionalised polystyrene resin, for example an epoxide, methylisocyanate, or acid anhydride functionalised resin to remove water from the fluoride solution.
- Suitable resins are available commercially, for example from Novabiochem. 5 Performance of the scavenger resin may be improved by using a suitable catalyst, for example 4-dimethylaminopyridine (4-DMAP).
- the drying step may be performed by mixing the scavenger resin with the fluoride solution in a container and then separating the scavenger o resin by filtration.
- the scavenger resin may be contained in a vessel through which the fluoride solution is passed.
- the fluoride solution may be passed through the scavenger resin as a continuous flow, for example at a flow rate of from 0.1ml/min to 100ml/min, or in batches, so as to 5 permit sufficient residence time on the scavenger resin for the drying to occur.
- scavenger resins are novel, therefore according to a further aspect of the invention, there is provided a method for reducing the water content of a solution of radiofluoride, particularly [ 18 F]fluoride, which comprises contacting o said solution with a scavenger resin.
- the solution comprises fluoride in a non protic organic solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxan, 1 ,2-dimethoxyethane, sulfolane and N- methylpyrrolidinone, more suitably the solvent is acetonitrile.
- reaction may be conducted in solution phase or alternatively, the non- fluoridated sugar derivative may be bound to a solid support to form a resin- linker-vector (RLV) of formula (I):
- the solid support is any suitable support; the protected non-fluoridated sugar derivative is as defined above; X is a group which promotes nucleophilic substitution at a specific site on the protected non-fluoridated sugar derivative, for example, -SO 2 O-; the linker is any suitable organic group which serves to space the reactive site sufficiently from the solid support structure so as to maximise reactivity; for example zero to four aryl groups (for example phenyl) and/or a CrC 6 alkyl or haloalkyl (especially fluoroalkyl) chain and optionally one to four additional functional groups such as amide or sulfonamide groups.
- aryl groups for example phenyl
- additional functional groups such as amide or sulfonamide groups.
- the RLV of formula (I) is contacted with a solution of the fluoride, resulting in the displacement of the sugar from the solid support to give a protected fluoridated sugar derivative.
- Suitable solid supports are also discussed in WO-A-03/002157 and include polymers such as polystyrene (which may be block grafted, for example with polyethylene glycol), polyacrylamide or polypropylene or glass or silicon coated with such a polymer. Alternatively a resin may be used for example as detailed in WO-A-03/002157.
- the solid support may be in the form of small discrete particles such as beads or pins or as a coating on the inner surface of a cartridge or on a microfabricated vessel. Carrying out the method of the invention on a solid support enables the product to be obtained in pure form without the need for any additional separation step. This is especially advantageous when the fluoridation is a radiofluoridation as any time saved in the process results in a higher non- corrected radiochemical yield.
- the reaction is usually carried out at a temperature of from 5 0 C to 18O 0 C, but particularly 75 0 C to 125 0 C.
- the process of the present invention may be carried out as part of an automated synthesis. This is the case whether the reaction takes place in solution or whether the non-fluoridated sugar is bound to a solid phase.
- the fluoride which is reacted with the non-fluoridated sugar derivative may be an ionic compound and may be provided with any suitable counter-ion. It is important, however, that the counter ion should be sufficiently soluble in the reaction solvent to maintain the solubility of the fluoride. Therefore, suitable counter ions include large but soft metal ions such as rubidium or cesium, or alternatively non-metallic ions such as tetraalkylammonium and tetraalkylphosphonium.
- Potassium ions may also be used as counter ions, in which case, in order to increase the reactivity of the fluoride, a phase transfer catalyst such as 4,7,13,16,21 ,24-hexaoxa-1 ,10-diazabicyclo-[8,8,8]-hexacosane (sold under the trade mark KryptofixTM 2.2.2) may be added to solubilise the potassium salt in organic solvents.
- a phase transfer catalyst such as 4,7,13,16,21 ,24-hexaoxa-1 ,10-diazabicyclo-[8,8,8]-hexacosane (sold under the trade mark KryptofixTM 2.2.2) may be added to solubilise the potassium salt in organic solvents.
- the process of the present invention is well suited to the production of radiofluoridated derivatives, particularly [ 18 F]-labelled derivatives and therefore, the fluoride may comprise an [ 18 F]-fluoride ion.
- the [ 18 F]-fluoride ion may be prepared by the irradiation of an [ 18 O]-water target and this may be an initial step in the process of the invention.
- the process of the present invention is particularly useful for producing radiofluoridated sugar derivatives such as [ 18 F]-pFDG, which can then be deprotected to give compounds such as [ 18 F]-FDG, a well-known PET tracer.
- the deprotection may be an additional step in the process.
- the protecting group in the product fluoridated sugar is an ester, for example an acetyl derivative
- deprotection may be achieved by acid or base hydrolysis.
- Additional steps include removal of excess [ 18 F]-fluoride from the solution and removal of the organic solvent.
- the excess [ 18 F]-fluoride may be removed by any standard method, for example by ion-exchange chromatography or solid- phase absorbents.
- Suitable ion exchange resins include BIO-RADAG 1-X8TM and Waters QMATM and suitable solid-phase absorbents include alumina.
- the organic solvent may be removed by evaporation at elevated temperature in vacuo or by passing a stream of inert gas such as nitrogen or argon over the solution.
- the [ 18 F]-tracer compound which is the final product of these steps may be formulated for administration to a patient, for example as an aqueous solution which may be prepared by dissolving the [ 18 F]-labelled tracer in sterile isotonic saline which may contain up to 10% of a suitable organic solvent such as ethanol, or alternatively in a suitable buffered solution such as phosphate buffer.
- a suitable organic solvent such as ethanol
- a suitable buffered solution such as phosphate buffer.
- Other additives may be used, for example ascorbic acid, which reduces radiolysis.
- a particularly preferred compound which can be prepared by the process of the invention is [ 18 F]-pFDG and therefore, in a second aspect of the invention there is provided a process for the preparation of [ 18 F]-pFDG, the process comprising reacting tetraacetyl mannose triflate with [ 18 F]-fluoride, characterised in that the fluoride is dissolved in a solvent containing water in an amount greater than 1000 ppm and less than 50,000 ppm.
- tetraacetyl mannose triflate (1 equivalent) is reacted with [ 18 F]-fluoride in the presence of KryptofixTM 2.2.2 ( 0.9 to 1.1 molar equivalent, suitably 0.98 to 0.99 molar equivalent), potassium carbonate ( 0.4 to 0.6 molar equivalent, suitably 0.50 to 0.60 molar equivalent) in acetonitrile containing water in an amount greater than 1000 ppm and less than 50,000 ppm.
- the process may comprise the initial step of producing the [ 18 F]-fluoride by irradiating an [ 18 O]-water target and a further step of converting the [ 18 F]-pFDG to [ 18 F]-FDG by acid or alkaline hydrolysis.
- FIGURE 1 is a plot which shows the correlation of radiochemical purity of a [ 18 F]- pFDG product with the water content of the solvent.
- FIGURE 2 is a graph showing the correlation between the formation of [ 18 F]-pFDG and pGlucose during the labelling process with resin-linker-vector.
- FIGURE 3 is a plot which shows the correlation of radiochemical purity of a [ 18 F]- pFDG product in an automated synthesis with the water content of the solvent.
- the 18 F " was introduced to the Tracerlab MXTM and dried using the standard drying process used in the production of 2-[18F]fluoro-2-deoxyglucose.
- KryptofixTM 2.2.2/ potassium carbonate were used to solubilise the fluoride in acetonitrile.
- a sample of the dried 18 F " in acetonitrile was taken for water content analysis and measured on a Karl Fisher titration meter. Where necessary, extra additions of water were introduced to bring the water content above that normally obtained by the drying process.
- a 1 ml Hi Trap ® cartridge was packed with around 370 mg of a solid-phase bound protected mannose precursor at a substitution of 0.003 mmol/g.
- One end of the cartridge was connected via a loop to a syringe driver.
- the other end of the cartridge was then connected to a N 2 filled vial fitted with a molecular sieve vent.
- a hot air gun was then used to heat the cartridge at an external cartridge temperature of 8O 0 C. 6x0.5ml of dry acetonitrile was then injected through the system to wash out any impurities and water (naturally present on the resin due for instance from incomplete drying) and the acetonitrile was then discarded.
- the auto sampler vial containing the dried 18 F " solution (450 ⁇ l) was fitted to the apparatus in its place.
- the syringe driver then moved the dried fluoride backwards and forwards at a flow rate of 180 ⁇ l/min through 5 cycles.
- the dried fluoride reacted with the solid-phase mannose precursor to liberate a protected [ 18 F]-2-deoxy glucose derivative (which post deprotection gives 2-[ 18 F]-2-deoxyglucose).
- a 5 ⁇ l sample was then taken from the auto sampler vial for thin-layer chromatography (TLC) analysis and spotted onto a silica gel 60 F254 plate and then run in an acetonitrile/water solvent made up to a ratio of 90/10.
- TLC thin-layer chromatography
- the sample for TLC analysis was spotted onto a silica gel strip and then run in an acetonitrile/water solvent made up to a ratio of 95/5.
- the radiochemical purity was established on a Perkin Elmer Instant Imager.
- the top of the reaction vessel was then removed and a 50 ⁇ l sample taken for water content analysis on a Karl Fisher Titration meter.
- the labelling was performed on a prototype automated synthesis platform comprising 25 three way valves with an onboard heated reactor vessel and a disposable polypropylene cassette.
- the cassette fluid pathway also allows for SPE purification of intermediates or the final product.
- Fluoride was initially trapped on a QMA cartridge and eluted with a solution of 20mg KryptofixTM 2.2.2, 4.1 mg K 2 CO 3 , 320 ⁇ L CH 3 CN, 80 ⁇ L H 2 O. This was then dried at 105 0 C/ 12O 0 C for around 6 minutes in a stream of nitrogen and redissolved in 1.5 ml of around 20 mg/ml tetraacetyl mannose triflate in acetonitrile.
- the labelling reaction was performed at a labelling temperature of either 105 or 125 0 C with reaction times at either 90 or 270 seconds. After labelling the 2[ 18 F]- 2-deoxyglucose was analysed by TLC.
- the TLC plate was a silica gel 60 F254 employing 95% acetonitrile, 5% water as the developing solvent. The radiochemical purity was established on a Perkin Elmer Instant Imager.
- This cassette comprises a 25 valve disposable cassette comprising various reagent-containing vials together with syringes and space for solid-phase extraction cartridges.
- a synthesis sequence was executed which trapped around 50 MBq of 18-fluoride in 2 ml water on to a Waters Access PlusQMA cartridge (as its carbonate form) and then eluted the cartridge with a solution of kryptofix and carbonate in acetonitrile/ water ( kryptofix 222 - 20.3 mg, potassium carbonate - 4.3 mg, acetonitrile - 320 ⁇ l, water - 80 ⁇ l) into a heated reactor. This was dried by heating in a stream of dry nitrogen and then a mannose triflate solution in acetonitrile at defined water contents was added to the reactor.
- the reaction was allowed to proceed for a further 80 seconds with an external heater temperature of 125 ° C, then 0.6 ml withdrawn and discarded to waste (to remove any residual water from the lines) and the remainder was transferred to the product vial.
- the water content of the product vial was determined by Karl Fisher titration using 50 ⁇ l of solution and the RCP measured by instant thin-layer chromatography (ITLC).
- ITLC instant thin-layer chromatography
- a synthesis sequence analogous to the radiolabelling experiment was executed where 2 ml water was passed through a Waters Access PlusQMA cartridge (as its carbonate form) and then the cartridge was eluted with a solution of kryptofix and carbonate in acetonitrile/ water (kryptofix 222 - 20.3 mg, potassium carbonate - 4.3 mg, acetonitrile - 320 ⁇ l, water - 80 ⁇ l) into a heated reactor. This was dried by heating in a stream of dry nitrogen and then a mannose triflate solution in acetonitrile at defined water contents was added to the reactor.
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Abstract
Description
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Priority Applications (15)
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BRPI0518316-2A BRPI0518316A2 (en) | 2004-11-19 | 2005-11-18 | A process for preparing a fluorinated sugar derivative and a method for reducing the water content of a radiofluoride solution |
EP05813632A EP1817320B1 (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2-[18f] fluoro-2-deoxy-d-glucose |
MX2007006052A MX2007006052A (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2- [18f] fluoro-2-deoxy-d-glucose. |
AU2005305624A AU2005305624B2 (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2- [18F] fluoro-2-deoxy-D-glucose |
CN2005800394892A CN101061130B (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2-[18f]fluoro-2-deoxy-d-glucose |
NZ554613A NZ554613A (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2-[18F] fluoro-2-deoxy-D-Glucose |
AT05813632T ATE472552T1 (en) | 2004-11-19 | 2005-11-18 | FLUORIZATION PROCESS FOR THE SYNTHESIS OF 2-Ä18FÜ FLUORO-2-DEOXY-D-GLUCOSE |
JP2007542100A JP5318416B2 (en) | 2004-11-19 | 2005-11-18 | Fluorination method |
CA2584649A CA2584649C (en) | 2004-11-19 | 2005-11-18 | Fluoridation process of saccharides |
US11/719,601 US20090076259A1 (en) | 2004-11-19 | 2005-11-18 | Fluoridation Process |
DE602005022099T DE602005022099D1 (en) | 2004-11-19 | 2005-11-18 | FLUORIZATION PROCEDURE FOR SYNTHESIS OF 2-E18FU FLUORO-2-DEOXY-D-GLUCOSE |
PL05813632T PL1817320T3 (en) | 2004-11-19 | 2005-11-18 | Fluoridation process for the synthesis of 2-[18f] fluoro-2-deoxy-d-glucose |
IL182740A IL182740A0 (en) | 2004-11-19 | 2007-04-23 | Fluoridation process |
NO20073037A NO20073037L (en) | 2004-11-19 | 2007-06-14 | Fluoridation Process |
HK08101069.6A HK1107353A1 (en) | 2004-11-19 | 2008-01-28 | Fluoridation process for the synthesis of 2-[18f] fluoro-2-deoxy-d-glucose |
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GBGB0425501.4A GB0425501D0 (en) | 2004-11-19 | 2004-11-19 | Fluoridation process |
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EP (1) | EP1817320B1 (en) |
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CN (1) | CN101061130B (en) |
AT (1) | ATE472552T1 (en) |
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NO (1) | NO20073037L (en) |
NZ (1) | NZ554613A (en) |
PL (1) | PL1817320T3 (en) |
PT (1) | PT1817320E (en) |
RU (1) | RU2394040C2 (en) |
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EP1958954A1 (en) * | 2005-12-06 | 2008-08-20 | Nihon Medi-Physics Co., Ltd. | Process for production of compound labeled with radioactive fluorine |
WO2008140616A2 (en) * | 2006-12-21 | 2008-11-20 | Hammersmith Imanet Limited | Nucleophilic radiofluorination using microfabricated devices |
EP2070937A1 (en) * | 2006-09-06 | 2009-06-17 | Nihon Medi-Physics Co., Ltd. | Process for producing radioactive fluorine labeled organic compound, and relevant synthetic apparatus and program |
WO2013049431A3 (en) * | 2011-09-30 | 2013-06-27 | Ge Healthcare Limited | Reactor for multi-step radiochemistry |
US9073802B2 (en) | 2010-02-12 | 2015-07-07 | Tokyo Institute Of Technology | Method for producing 18F-labeled compound and high molecular compound to be used in the method |
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JP2007031647A (en) * | 2005-07-29 | 2007-02-08 | Japan Health Science Foundation | Method for producing compound containing nuclide with ultrashort half-life by utilizing solid-phase synthesis, and compound usable therefor |
WO2011127345A1 (en) * | 2010-04-08 | 2011-10-13 | Siemens Medical Solutions Usa, Inc. | Synthesis of 18f-labeled tracers in hydrous organic solvents |
ES2621950T3 (en) | 2010-12-29 | 2017-07-05 | Ge Healthcare Limited | Eluent solution |
US9101895B2 (en) | 2011-04-15 | 2015-08-11 | General Electric Company | System for mixing and dispersing microbubble pharmaceuticals |
JP6758065B2 (en) * | 2016-03-30 | 2020-09-23 | 日本メジフィジックス株式会社 | Equipment and method for producing radioactively labeled compounds |
CN113801173B (en) * | 2021-09-24 | 2024-03-12 | 上海安迪科正电子技术有限公司 | Preparation method and application of fluorine-18 marked deoxyglucose injection |
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- 2005-11-18 PT PT05813632T patent/PT1817320E/en unknown
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- 2005-11-18 CN CN2005800394892A patent/CN101061130B/en not_active Expired - Fee Related
- 2005-11-18 CA CA2584649A patent/CA2584649C/en not_active Expired - Fee Related
- 2005-11-18 WO PCT/GB2005/004451 patent/WO2006054098A2/en active Application Filing
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- 2007-06-14 NO NO20073037A patent/NO20073037L/en not_active Application Discontinuation
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EP1958954A1 (en) * | 2005-12-06 | 2008-08-20 | Nihon Medi-Physics Co., Ltd. | Process for production of compound labeled with radioactive fluorine |
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AU2007292578B2 (en) * | 2006-09-06 | 2012-11-29 | Nihon Medi-Physics Co., Ltd. | Process for producing radioactive fluorine labeled organic compound, and relevant synthetic apparatus and program |
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US20140256970A1 (en) * | 2011-09-30 | 2014-09-11 | Ge Healthcare Limited | Reactor for multi-step radiochemistry |
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KR101267122B1 (en) | 2013-05-24 |
CN101061130B (en) | 2012-08-15 |
CA2584649A1 (en) | 2006-05-26 |
KR20070084361A (en) | 2007-08-24 |
CA2584649C (en) | 2013-09-24 |
WO2006054098A3 (en) | 2006-08-03 |
DE602005022099D1 (en) | 2010-08-12 |
EP1817320A2 (en) | 2007-08-15 |
ES2347165T3 (en) | 2010-10-26 |
NZ554613A (en) | 2011-01-28 |
AU2005305624B2 (en) | 2012-05-10 |
GB0425501D0 (en) | 2004-12-22 |
PT1817320E (en) | 2010-09-13 |
PL1817320T3 (en) | 2010-11-30 |
JP5318416B2 (en) | 2013-10-16 |
US20090076259A1 (en) | 2009-03-19 |
ZA200705015B (en) | 2008-09-25 |
HK1107353A1 (en) | 2008-04-03 |
MX2007006052A (en) | 2007-07-10 |
EP1817320B1 (en) | 2010-06-30 |
RU2007115903A (en) | 2008-12-27 |
CN101061130A (en) | 2007-10-24 |
BRPI0518316A2 (en) | 2008-11-11 |
ATE472552T1 (en) | 2010-07-15 |
IL182740A0 (en) | 2007-07-24 |
NO20073037L (en) | 2007-08-16 |
JP2008520636A (en) | 2008-06-19 |
RU2394040C2 (en) | 2010-07-10 |
AU2005305624A1 (en) | 2006-05-26 |
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