JP6770837B2 - Method for Producing Radioactive Fluorine Labeled Organic Compounds - Google Patents
Method for Producing Radioactive Fluorine Labeled Organic Compounds Download PDFInfo
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- JP6770837B2 JP6770837B2 JP2016127173A JP2016127173A JP6770837B2 JP 6770837 B2 JP6770837 B2 JP 6770837B2 JP 2016127173 A JP2016127173 A JP 2016127173A JP 2016127173 A JP2016127173 A JP 2016127173A JP 6770837 B2 JP6770837 B2 JP 6770837B2
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- 230000002285 radioactive effect Effects 0.000 title claims description 94
- 150000002894 organic compounds Chemical class 0.000 title claims description 64
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims description 44
- 229910052731 fluorine Inorganic materials 0.000 title claims description 42
- 239000011737 fluorine Substances 0.000 title claims description 42
- 238000004519 manufacturing process Methods 0.000 title claims description 27
- -1 fluoride ions Chemical class 0.000 claims description 66
- 239000007864 aqueous solution Substances 0.000 claims description 62
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 44
- 239000004332 silver Substances 0.000 claims description 40
- 229910052709 silver Inorganic materials 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 22
- 239000003957 anion exchange resin Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 15
- 238000002600 positron emission tomography Methods 0.000 claims description 12
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000002504 physiological saline solution Substances 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000005341 cation exchange Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000003682 fluorination reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 150000002500 ions Chemical class 0.000 description 37
- 239000011775 sodium fluoride Substances 0.000 description 26
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Inorganic materials [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 20
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 description 4
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910021607 Silver chloride Inorganic materials 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 description 3
- 239000011698 potassium fluoride Substances 0.000 description 3
- 235000003270 potassium fluoride Nutrition 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
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- 238000003908 quality control method Methods 0.000 description 3
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- 229940121896 radiopharmaceutical Drugs 0.000 description 3
- 230000002799 radiopharmaceutical effect Effects 0.000 description 3
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 229940027541 fluciclovine f-18 Drugs 0.000 description 2
- VVECGOCJFKTUAX-HUYCHCPVSA-N flutemetamol ((18)F) Chemical compound C1=C([18F])C(NC)=CC=C1C1=NC2=CC=C(O)C=C2S1 VVECGOCJFKTUAX-HUYCHCPVSA-N 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- UVVFKNZCYIIHGM-UHFFFAOYSA-L tetrabutylazanium;carbonate Chemical compound [O-]C([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC UVVFKNZCYIIHGM-UHFFFAOYSA-L 0.000 description 2
- 229960004441 tyrosine Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- LSSQMISUDUUZCC-DWSYCVKZSA-N (2,5-dioxopyrrolidin-1-yl) 4-fluoranylbenzoate Chemical compound C1=CC([18F])=CC=C1C(=O)ON1C(=O)CCC1=O LSSQMISUDUUZCC-DWSYCVKZSA-N 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- SWDIHODJLJEUEJ-UPRLRBBYSA-N 5'-o-(4,4'-dimethoxytrityl)-2,3'-anhydrothymidine Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](OC=2N3C=C(C)C(=O)N=2)C[C@H]3O1 SWDIHODJLJEUEJ-UPRLRBBYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000015429 Mirabilis expansa Nutrition 0.000 description 1
- 244000294411 Mirabilis expansa Species 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-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
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 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
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- HXIXVACPUCDUBU-HSGWXFLFSA-N ethyl 3-fluoranyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclobutane-1-carboxylate Chemical compound CC(C)(C)OC(=O)NC1(C(=O)OCC)CC([18F])C1 HXIXVACPUCDUBU-HSGWXFLFSA-N 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000013536 miso Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 230000000717 retained effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940096017 silver fluoride Drugs 0.000 description 1
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、放射性フッ素標識有機化合物を製造する方法、並びに、放射性フッ素標識化合物を製造するためのキット、塩化物イオンを除去する方法、及び、カラムカートリッジに関する。 The present invention relates to a method for producing a radioactive fluorine-labeled organic compound, a kit for producing a radioactive fluorine-labeled compound, a method for removing chloride ions, and a column cartridge.
放射性フッ素標識有機化合物は、医療用画像診断法の一つであるポジトロン放出断層撮影（Positron Emission Tomography、ＰＥＴ）において利用される。主要な放射性フッ素標識有機化合物は、１８Ｏ濃縮水をターゲットとして、加速器により加速したプロトンを照射することにより放射性フッ化物イオンを生成し、放射性フッ化物イオン含有濃縮水の形で得た後、この放射性フッ化物イオン含有濃縮水から放射性フッ化物イオンを分離し、前駆体有機化合物と放射性フッ化物イオンとの有機化学反応により製造される（例えば、特許文献１、２）。 Radiofluorine-labeled organic compounds are used in positron emission tomography (PET), which is one of the medical diagnostic imaging methods. The major radioactive fluorine-labeled organic compounds generate radioactive fluoride ions by irradiating 18 O concentrated water with protons accelerated by an accelerator, and after obtaining this in the form of radioactive fluoride ion-containing concentrated water, this It is produced by separating radioactive fluoride ions from concentrated water containing radioactive fluoride ions and performing an organic chemical reaction between a precursor organic compound and radioactive fluoride ions (for example, Patent Documents 1 and 2).
放射性フッ素（１８Ｆ）は半減期が１１０分と非常に短いため、ＰＥＴへの利用にあたっては、医療機関でサイクロトロンを設置し、製剤化する方法が知られている。このため、医療機関で衛生的に放射性フッ素標識有機化合物を合成できるよう種々のカセット式の自動合成装置が開発されている（例えば、特許文献３）。 For radioactive fluorine (18 F) is very short and 110 minute half-life, when the use of the PET, established a cyclotron in medical institutions, there is known a method of formulating. For this reason, various cassette-type automatic synthesizers have been developed so that medical institutions can hygienically synthesize radioactive fluorine-labeled organic compounds (for example, Patent Document 3).
放射性フッ素標識有機化合物の中には、近年、デリバリー可能になったものもある（非特許文献１）。デリバリーにあたっては厳しい時間的制約の下に、安定かつ確実に供給するための取り組みが報告されている（例えば、特許文献４）。 In recent years, some radioactive fluorine-labeled organic compounds have become deliverable (Non-Patent Document 1). Efforts to ensure stable and reliable delivery under strict time constraints have been reported (for example, Patent Document 4).
ところで、放射性フッ化物イオンは、骨のイメージング剤としてＰＥＴに利用されることも知られている（例えば、非特許文献２）。 By the way, it is also known that radioactive fluoride ions are used in PET as a bone imaging agent (for example, Non-Patent Document 2).
非特許文献１にも記載されるように、加速器及び合成装置に関する初期投資・維持には、高額の資金が必要となり、それに見合う採算性が求められる。 As described in Non-Patent Document 1, a large amount of funds are required for initial investment and maintenance of accelerators and synthesizers, and profitability commensurate with them is required.
そこで、非特許文献２に記載されるような医療用の放射性フッ化物イオンを用いて放射性フッ素標識有機化合物が製造できれば、放射性フッ素の利用効率が高められることが期待される。しかしながら、医療用の放射性フッ化物イオンは、静脈投与のため体液と等張となるよう調製されることが一般的であり、そのままの状態で放射性フッ素標識有機化合物を合成するための有機化学反応に使用することは困難であった。 Therefore, if a radioactive fluorine-labeled organic compound can be produced using medical-grade radioactive fluoride ions as described in Non-Patent Document 2, it is expected that the utilization efficiency of radioactive fluorine will be improved. However, medical-grade radioactive fluoride ions are generally prepared to be isotonic with body fluids for intravenous administration, and are used as they are for organic chemical reactions for synthesizing radioactive fluorine-labeled organic compounds. It was difficult to use.
本発明は上記事情に鑑みてなされたものであり、医療用の放射性フッ化物イオンを用いて放射性フッ素標識有機化合物の製造を可能にするための技術を提供することにある。 The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a technique for enabling the production of a radioactive fluorine-labeled organic compound using medical-grade radioactive fluoride ions.
本発明者らは、フッ化銀以外のハロゲン化銀が共沈することに着目し、鋭意工夫を重ねた結果、塩化ナトリウムが混在した放射性フッ化物イオンであっても、水溶液の状態で銀イオンを担持する担体に接触させた後、放射性フッ化物イオンを含む水溶液を担体から分離することで、既存の放射性フッ素標識有機化合物の製造に利用できることを見出し、本発明を完成させた。 The present inventors have focused on the co-precipitation of silver halides other than silver fluoride, and as a result of repeated diligent efforts, even radioactive fluoride ions mixed with sodium chloride are silver ions in the state of an aqueous solution. The present invention was completed by finding that it can be used for the production of an existing radioactive fluorine-labeled organic compound by separating an aqueous solution containing radioactive fluoride ions from the carrier after contacting the carrier carrying the above.
本発明の一態様によれば、放射性フッ化物イオンと塩化ナトリウムとを含む第１の水溶液を、銀イオンを担持する担体に接触させた後、前記担体から分離された、放射性フッ化物イオンを含む第２の水溶液を得る工程と、前記第２の水溶液に含まれる放射性フッ化物イオンを用いて放射性フッ素標識有機化合物を合成する工程と、を含む、放射性フッ素標識有機化合物の製造方法が提供される。 According to one aspect of the present invention, a first aqueous solution containing radioactive fluoride ions and sodium chloride is brought into contact with a carrier carrying silver ions, and then separated from the carrier, containing radioactive fluoride ions. Provided is a method for producing a radioactive fluorine-labeled organic compound, which comprises a step of obtaining a second aqueous solution and a step of synthesizing a radioactive fluorine-labeled organic compound using the radioactive fluoride ions contained in the second aqueous solution. ..
また、本発明の他の態様によれば、放射性フッ化物イオンと塩化ナトリウムとを含む水溶液と、銀イオンが担持された担体とを備える、放射性フッ素標識有機化合物を製造するためのキットが提供される。 Further, according to another aspect of the present invention, there is provided a kit for producing a radioactive fluorine-labeled organic compound, which comprises an aqueous solution containing radioactive fluoride ions and sodium chloride and a carrier on which silver ions are supported. Fluoride.
また、本発明の他の態様によれば、銀イオンが担時された担体と、放射性フッ化物イオンと置換されるための脱離基を有する非放射性有機化合物と、を備える、放射性フッ素標識有機化合物を製造するためのキットが提供される。 Further, according to another aspect of the present invention, a radioactive fluorine-labeled organic compound comprising a carrier carrying silver ions and a non-radioactive organic compound having a leaving group for replacement with radioactive fluoride ions. Kits for making compounds are provided.
また、本発明の他の態様によれば、放射性フッ化物イオンと塩化ナトリウムとを含む水溶液を、銀イオンを担持する担体が充填されたカラムカートリッジに通液させることで塩化物イオンを除去する方法が提供される。 Further, according to another aspect of the present invention, a method for removing chloride ions by passing an aqueous solution containing radioactive fluoride ions and sodium chloride through a column cartridge packed with a carrier carrying silver ions. Is provided.
また、本発明の他の態様によれば、銀イオンを担持する担体が充填されたカラムカートリッジであって、放射性フッ化物イオンと塩化ナトリウムとを含む水溶液から塩化物イオンを除去するために用いられるカラムカートリッジが提供される。 Further, according to another aspect of the present invention, it is a column cartridge filled with a carrier carrying silver ions, and is used for removing chloride ions from an aqueous solution containing radioactive fluoride ions and sodium chloride. A column cartridge is provided.
本発明によれば、医療用の放射性フッ化物イオンから放射性フッ素標識有機化合物を製造することができるため、放射性フッ素の利用効率を高めることが可能になる。 According to the present invention, since a radioactive fluorine-labeled organic compound can be produced from radioactive fluoride ions for medical use, it is possible to improve the utilization efficiency of radioactive fluorine.
本発明の放射性フッ素標識有機化合物の製造方法は、放射性フッ化物イオン（１８Ｆイオン）と塩化ナトリウムとを含む第１の水溶液を、銀イオンを担持する担体に接触させた後、前記担体から分離された、１８Ｆイオンを含む第２の水溶液を得る工程（塩除去工程）と、第２の水溶液に含まれる１８Ｆイオンを用いて放射性フッ素標識有機化合物（１８Ｆ標識有機化合物）を合成する工程（合成工程）と、を含む。 Method for producing a radioactive fluorine-labeled organic compound of the present invention, after the first aqueous solution comprising a radioactive fluoride ions (18 F ions) and sodium chloride was brought into contact with a carrier carrying a silver ion, separated from the carrier A step of obtaining a second aqueous solution containing 18 F ions (salt removal step) and a step of synthesizing a radioactive fluorine-labeled organic compound ( 18 F labeled organic compound) using the 18 F ions contained in the second aqueous solution. Includes a step (synthesis step).
［塩除去工程］
塩除去工程では、１８Ｆイオンと塩化ナトリウムとを含む第１の水溶液を、銀イオンを担持する担体に接触させる。次いで、第１の水溶液から塩化物イオンが除去されたものを前記担体と分離し、放射性フッ化物イオンを含む第２の水溶液を得る。
[Salt removal process]
The salt removal step 18 a first aqueous solution containing F ions and sodium chloride, is contacted with a carrier carrying a silver ion. Next, the one from which chloride ions have been removed from the first aqueous solution is separated from the carrier to obtain a second aqueous solution containing radioactive fluoride ions.
第１の水溶液は、１８Ｆイオンの塩化ナトリウム水溶液であれば制限されない。この１８Ｆイオンの塩化ナトリウム水溶液は、１８Ｏ濃縮水をターゲットとして、加速器により加速したプロトンを照射することにより１８Ｆイオンを生成し、１８Ｆイオン含有１８Ｏ濃縮水の形で得た後、この１８Ｆイオン含有１８Ｏ濃縮水を陰イオン交換樹脂に吸着捕集させ、所望の濃度の塩化ナトリウム水溶液で溶出させることで得ることができる。 The first aqueous solution is not limited as long as it is an aqueous sodium chloride solution of 18 F ions. Aqueous sodium chloride solution in this 18 F ions, the 18 O enriched water is used as a target, after generating the 18 F ions by irradiating protons accelerated by the accelerator is obtained in the form of a 18 F ion containing 18 O enriched water, It can be obtained by adsorbing and collecting this 18 F ion-containing 18 O concentrated water on an anion exchange resin and eluting it with an aqueous solution of sodium chloride having a desired concentration.
第１の水溶液は、１８Ｆイオンの生理食塩水溶液であることが好ましい。言い換えると、第１の水溶液は、塩化ナトリウムを０．９重量／体積％含有する塩化ナトリウム水溶液に１８Ｆイオンが溶解したものであることが好ましい。こうした１８Ｆイオンの生理食塩水溶液は、例えば、「ＰＥＴ用放射性薬剤の製造および品質管理−合成と臨床使用へのてびき−第４版」p.211-212や特開２０１５−１４３２１２号公報記載の方法に従い調製することができる。 The first aqueous solution is preferably a physiological saline solution of 18 F ions. In other words, the first aqueous solution is preferably one in which 18 F ions are dissolved in a sodium chloride aqueous solution containing 0.9% by volume / volume of sodium chloride. Such 18- F ion physiological saline aqueous solutions are described in, for example, "Manufacturing and Quality Control of Radiopharmaceuticals for PET-Tobiki for Synthesis and Clinical Use-Fourth Edition" p.211-212 and JP-A-2015-143212. It can be prepared according to the method of.
また、塩除去工程で用いられる１８Ｆイオンの生理食塩水溶液は、陽電子放射断層撮像（Positron Emission Tomography, ＰＥＴ）用検査薬であってもよい。このＰＥＴ用検査薬は、有効成分を１８Ｆ−フッ化ナトリウムとしたものであってもよい。これを投与し、ＰＥＴ検査を行うことで、骨をイメージングすることができ骨疾患の診断が可能になる。こうしたＰＥＴ用検査薬は、１８Ｆイオンの生理食塩水溶液を滅菌フィルターで通液するなどの無菌化処理することで、製造することができる。 Further, the 18- F ion physiological saline solution used in the salt removal step may be a test agent for positron emission tomography (PET). This PET test agent may have an active ingredient of 18 F-sodium fluoride. By administering this and performing a PET examination, bone can be imaged and bone disease can be diagnosed. Such a PET test agent can be produced by sterilization treatment such as passing an aqueous solution of 18- F ion physiological saline through a sterilization filter.
塩除去工程で用いられる銀イオンを担持する担体は、１８Ｆイオンと塩化ナトリウムとを含む第１の水溶液と接触させることで、水に溶解しにくい塩化銀を形成させることにより、第１の水溶液から塩化物イオンを除去できるものであれば特に制限はないが、陽イオン交換性を有する担体であることが好ましい。陽イオン交換性を有する担体として、例えば、スルホン酸基が固定化された担体が挙げられる。また、担体の基材としては、シリカ、又は、ジビニルベンゼン、スチレン−ジビニルベンゼン共重合体などの樹脂製のものが挙げられる。基材として樹脂製のものを使用する場合、担体は、水素イオンを担持する樹脂層と銀イオンを担持する樹脂層との複層構造であってもよいし、銀イオンを担持する樹脂層からなる単層構造であってもよいが、銀イオンを担持する樹脂層からなる単層構造は、第２の水溶液のｐＨの低下を抑制し、１８Ｆ標識有機化合物の合成収率を向上させるという観点から好ましい。 Carrier carrying a silver ion used in the salt removal step 18 is contacted with the first aqueous solution containing F ions and sodium chloride, by forming a hardly soluble silver chloride in water, the first aqueous solution The carrier is not particularly limited as long as it can remove chloride ions from the aqueous solution, but a carrier having cation exchange property is preferable. Examples of the carrier having cation exchange property include a carrier on which a sulfonic acid group is immobilized. Further, examples of the base material of the carrier include those made of silica or a resin such as divinylbenzene or a styrene-divinylbenzene copolymer. When a resin-made base material is used, the carrier may have a multi-layer structure of a resin layer carrying hydrogen ions and a resin layer supporting silver ions, or from a resin layer supporting silver ions. of becoming may have a single layer structure, a single-layer structure made of a resin layer carrying the silver ions, a reduction in the pH of the second aqueous solution is suppressed, improving the synthesis yield of 18 F-labeled organic compound Preferred from the point of view.
また、塩除去工程で用いられる銀イオンを担持する担体は、カラムカートリッジに充填されたものを用いてもよい。銀イオンを担持する担体が充填されたカラムカートリッジに、１８Ｆイオンと塩化ナトリウムとを含む第１の水溶液を通液することで、簡便に塩化物イオンの除去を行い、第２の水溶液を得ることができる。 Further, as the carrier supporting silver ions used in the salt removal step, one packed in a column cartridge may be used. A column cartridge carrier filled carrying a silver ion, 18 by first aqueous liquid passage including the F ions and sodium chloride, subjected to simple removal of chloride ions to obtain a second aqueous solution be able to.
銀イオンを担持する陽イオン交換樹脂が充填されたカラムカートリッジとしては、使い捨てのものが種々市販されており、例えば、MetaSEP（登録商標）IC-Ag（ジーエルサイエンス社製）、AllTech（登録商標）Maxi-CleanTM IC-Ag（グレース社製）、Dionex OnGuard II Ag, Dionex OnGuard II Ag/H（サーモサイエンティフィック社製）を使用することができる。こうしたカラムカートリッジは、使用前に水でプレコンディショニングされることが好ましい。担体が充填されたカラムカートリッジに、１８Ｆイオンと塩化ナトリウムとを含む第１の水溶液を通液することで、塩化物イオンが除去された第２の水溶液を得ることができる。 Various disposable column cartridges filled with a cation exchange resin carrying silver ions are commercially available. For example, MetaSEP (registered trademark) IC-Ag (manufactured by GL Sciences) and AllTech (registered trademark). Maxi-Clean TM IC-Ag (manufactured by Grace), Dionex OnGuard II Ag, Dionex OnGuard II Ag / H (manufactured by Thermo Scientific) can be used. Such column cartridges are preferably preconditioned with water before use. A column cartridge carrier is filled, the first aqueous solution containing 18 F ions and sodium chloride by liquid passage, it is possible to obtain a second aqueous solution which chloride ions are removed.
［合成工程］
塩除去工程で得られた第２の水溶液は、１８Ｆ標識有機化合物の合成反応において１８Ｆイオンと競合する塩化物イオンが除去されているため、濃縮することにより通常の１８Ｆ標識有機化合物の合成反応に用いることができる。
[Synthesis process]
Second aqueous solution obtained in the salt removal step, 18 F for chloride ions to compete in the synthesis reaction with 18 F ions of the labeled organic compound is removed, the normal 18 F-labeled organic compound by concentrating It can be used for synthetic reactions.
第２の水溶液の濃縮の方法は制限されないが、例えば、第２の水溶液を陰イオン交換樹脂に通液して、陰イオン交換樹脂に１８Ｆイオンを吸着させる工程（吸着工程）と、陰イオン交換樹脂から１８Ｆイオンを溶出させて、１８Ｆイオンを含む溶出液を得る工程（溶出工程）が挙げられる。 The method for concentrating the second aqueous solution is not limited. For example, a step of passing the second aqueous solution through an anion exchange resin to adsorb 18 F ions on the anion exchange resin (adsorption step) and an anion. Examples thereof include a step (eluting step) of eluting 18 F ions from the exchange resin to obtain an eluate containing 18 F ions.
吸着工程で使用される陰イオン交換樹脂は、１８Ｆイオンを吸着でき、かつ、溶出工程で１８Ｆイオンを溶離できるもので制限はされないが、カートリッジ型のものが使い捨てできる観点から好ましい。このような陰イオン交換樹脂として、例えば、Sep-Pak（登録商標）QMA (Waters社製)を使用することができる。陰イオン交換樹脂は、炭酸カリウムなどを用いて対イオンを炭酸型に調整しておくことが好ましい。 The anion exchange resin used in the adsorption step is not limited as it can adsorb 18 F ions and can elute 18 F ions in the elution step, but it is preferable from the viewpoint that the cartridge type is disposable. As such an anion exchange resin, for example, Sep-Pak (registered trademark) QMA (manufactured by Waters) can be used. The anion exchange resin preferably uses potassium carbonate or the like to adjust the counterion to a carbonic acid type.
溶出工程では、陰イオン交換樹脂から１８Ｆイオンを溶出させる。この際、使用する溶離液は、１８Ｆイオンを溶離できるものであれば制限されないが、塩基が溶解した水溶液が好ましく、例えば、炭酸カリウムやテトラブチルアンモニウム炭酸塩の水溶液を使用することができる。 In the elution step, 18 F ions are eluted from the anion exchange resin. At this time, the eluent used is 18 although F ions are not limited as long as it can elute an aqueous solution base was dissolved are preferred, for example, may be used an aqueous solution of potassium carbonate and tetrabutylammonium carbonate.
溶出工程で得られた溶出液中の１８Ｆイオンを用いることで、１８Ｆ標識有機化合物の合成反応を行うことができる。溶出工程において、溶離液として炭酸カリウムの水溶液を使用した場合は、クリプタンドやクラウンエーテルなどの相関移動触媒を溶出液に加えてもよい。また、溶出工程において、炭酸カリウムとともに相関移動触媒を溶解させた水溶液を溶離液として用いてもよい。なお、溶離液としてテトラブチルアンモニウム炭酸塩の水溶液を用いた場合は、テトラブチルアンモニウムの炭酸塩が相関移動触媒の役割も果たす。こうした相関移動触媒を使用することで、１８Ｆ標識有機化合物の合成反応を促進させることが可能になる。 By using the 18 F ions in the eluate obtained in the elution step, the synthesis reaction of the 18 F labeled organic compound can be carried out. When an aqueous solution of potassium carbonate is used as the eluent in the elution step, a phase transfer catalyst such as cryptondand or crown ether may be added to the eluate. Further, in the elution step, an aqueous solution in which the phase transfer catalyst is dissolved together with potassium carbonate may be used as the eluent. When an aqueous solution of tetrabutylammonium carbonate is used as the eluent, the carbonate of tetrabutylammonium also serves as a phase transfer catalyst. The use of such phase transfer catalyst, it is possible to accelerate the synthesis reaction of 18 F-labeled organic compound.
溶出液は、そのまま合成工程に用いてもよいが、溶出工程の後、更に蒸発乾固させてもよい。蒸発乾固させる場合、アセトニトリルなど水と共沸する有機溶剤を使用することで、短時間で蒸発乾固させることができる。こうすることで、１８Ｆイオンが活性化されるとともに脱水されることにより、１８Ｆ標識有機化合物の合成反応を収率よく実行させることが可能になる。 The eluate may be used as it is in the synthesis step, or may be further evaporated to dryness after the elution step. When evaporating to dryness, it can be evaporated to dryness in a short time by using an organic solvent such as acetonitrile that azeotropes with water. By doing so, by 18 F ions is dehydrated with activated, becomes a synthesis reaction of 18 F-labeled organic compound can be performed in good yield.
このようにして濃縮された１８Ｆイオンに、標識前駆体として、脱離基を有する非放射性有機化合物を加えて、脱離基と１８Ｆイオンとの置換による放射性フッ素化反応（１８Ｆ化反応）を実行する。脱離基としては、トリフルオロメタンスルホン酸エステル、ｐ−トルエンスルホン酸エステル、メチルスルホン酸エステルなどのスルホン酸エステル基が例示される。 A non-radioactive organic compound having a leaving group is added as a labeling precursor to the 18 F ions concentrated in this manner, and a radioactive fluorination reaction ( 18 F conversion reaction) by substitution of the leaving group with the 18 F ions. ) Is executed. Examples of the leaving group include sulfonic acid ester groups such as trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester, and methylsulfonic acid ester.
標識前駆体である非放射性有機化合物は、脱離基に加えて保護基を更に有していてもよい。保護基としては、目的とする１８Ｆ標識有機化合物がヒドロキシ基を有する場合は、ヒドロキシ基の保護基、アミノ基を有する場合は、アミノ基の保護基、カルボキシル基を有する場合は、カルボキシル基の保護基が挙げられる。こうした保護基としては、Greene's Protective Groups in Organic Synthesis（John Wiley & Sons Inc; 5th Revised版）記載のものを用いることができる。そして、１８Ｆ化反応を実行した後、保護基を除去することで、１８Ｆ標識有機化合物を合成することができる。 The non-radioactive organic compound that is the labeling precursor may have an additional protecting group in addition to the leaving group. As the protecting group, if 18 F-labeled organic compound of interest is a hydroxy group, the hydroxy-protecting group, if having an amino group, an amino-protecting group, if having a carboxyl group, the carboxyl group Protecting groups can be mentioned. As such protecting groups, those described in Greene's Protective Groups in Organic Synthesis (John Wiley & Sons Inc; 5th Revised Edition) can be used. Then, 18 after executing the F reaction, removing the protecting group, can be synthesized 18 F-labeled organic compound.
なお、１８Ｆ標識有機化合物として１８Ｆ標識ペプチド、１８Ｆ標識抗体、あるいは、１８Ｆ標識タンパク質を合成してもよい。この場合、塩除去工程を経て得られた１８Ｆイオンを用いた１８Ｆ化反応により、ＦＭＴ（フルオロメチル−Ｌ−チロシン）やＦＥＴ（フルオロエチル−Ｌ−チロシン）など１８Ｆフッ素含有アミノ酸や、１８Ｆ−ＳＦＢ（Ｎ−スクシンイミジル−４−［１８Ｆ］フルオロベンゾエート）等の１８Ｆ標識中間体化合物を合成する。そして、これをペプチドに作用することで１８Ｆ標識ペプチド、抗体に作用させることで１８Ｆ標識抗体、タンパク質に作用させることで１８Ｆ標識タンパク質をそれぞれ合成することができる。 Incidentally, 18 F-labeled peptides as 18 F-labeled organic compound, 18 F-labeled antibody or may be synthesized 18 F-labeled protein. In this case, 18- F fluorine-containing amino acids such as FMT (fluoromethyl-L-tyrosine) and FET (fluoroethyl-L-tyrosine) and 18- F fluorine-containing amino acids by the 18- F conversion reaction using 18- F ions obtained through the salt removal step the 18 F-SFB (N- succinimidyl -4- [18 F] fluorobenzoate) 18 F-labeled intermediate compounds such as synthesized. Then, this 18 F-labeled peptide by acting on peptides, can be 18 F-labeled antibody is allowed to act on the antibody, by the action on the protein 18 F-labeled protein synthesized, respectively.
合成した１８Ｆ標識有機化合物を用いて、これを有効成分とするＰＥＴ用検査薬を調製することもできる。このＰＥＴ用検査薬は、合成した１８Ｆ標識有機化合物を生体内への投与に適した形態で含むように調製されればよいが、適宜、ｐＨ調節剤、製薬学的に許容される可溶化剤、安定剤又は酸化防止剤などの追加成分を添加してもよい。 Synthesized 18 using F-labeled organic compound, which can also be prepared for PET test agent as an active ingredient. The PET inspection agents, the synthesized 18 F-labeled organic compound may be employed to prepared to include in a form suitable for administration to the living organism, solubilization appropriate, pH regulators agent, it is pharmaceutically acceptable Additional ingredients such as agents, stabilizers or antioxidants may be added.
ＰＥＴ用検査薬として用いられる１８Ｆ標識有機化合物としては、例えば、１８Ｆ−ＦＤＧ（１８Ｆ−フルオロデオキシグルコース）、１８Ｆ−ＦＬＴ（18F-フルオロチミジン）, １８Ｆ−ＦＭＩＳＯ（１８Ｆ−フルオロミソニタゾール）、18F-fluciclovine（１８Ｆ−ＦＡＣＢＣ）, 18F-flutemetamol（１８Ｆ−フルテメタモル）、18F-Flobetapir、その他「ＰＥＴ用放射性薬剤の製造および品質管理−合成と臨床使用へのてびき−第４版」に記載された種々の１８Ｆ標識有機化合物が挙げられる。 The 18 F-labeled organic compound used as PET for test agents, for example, 18 F-FDG (18 F- fluorodeoxyglucose), 18 F-FLT (18 F- fluoro thymidine), 18 F-FMISO (18 F- Fluoromisonitazole), 18 F-fluciclovine ( 18 F-FACBC), 18 F-flutemetamol ( 18 F-flutemetamol), 18 F-Flobetapir, and others "Manufacturing and quality control of radiopharmaceuticals for PET-synthesis and clinical use" guidance to - various 18 F-labeled organic compounds described in the fourth edition "and the like.
［キット］
本発明の他の態様として、前述した１８Ｆ標識有機化合物を製造する方法を実行するためのキットがある。このキットの一態様として、１８Ｆイオンと塩化ナトリウムとを含む水溶液と、銀イオンが担持された担体とを備えるもの（キットＡ）が挙げられる。キットＡは、１８Ｆイオンと置換されるための脱離基を備えた非放射性有機化合物を更に備えていてもよい。また、銀イオンが担持された担体と、放射性フッ化物イオンと置換されるための脱離基を有する非放射性有機化合物とを備える態様が挙げられる（キットＢ）。
[kit]
Another aspect of the present invention, there is a kit for performing a method of manufacturing the 18 F-labeled organic compound as described above. One aspect of the kit, 18 and aqueous solution containing F ions and sodium chloride, silver ions can be cited and a carrier supported (kit A) is. Kit A is a leaving group to be replaced with 18 F ions nonradioactive organic compound may further include having. Another embodiment includes a carrier on which silver ions are supported and a non-radioactive organic compound having a leaving group for replacement with radioactive fluoride ions (Kit B).
キットＡ、Ｂが共通して備える銀イオンが担持された担体としては、前述の塩除去工程で用いられるものと同様のものを使用することができる。 As the carrier on which the silver ions commonly provided in the kits A and B are supported, the same carriers as those used in the above-mentioned salt removal step can be used.
また、キットＡが備える１８Ｆイオンと塩化ナトリウムとを含む水溶液としては、前述の塩除去工程で用いられる第１の水溶液と同様のものを使用することができる。 As the aqueous solution containing 18 F ions and sodium chloride kit A is provided, it is possible to use the same as the first aqueous solution used in the above-mentioned salts removing step.
また、キットＡ，Ｂに備えられる非放射性有機化合物は、前述の合成工程で用いられるものと同様のものを使用することができるが、マンノーストリフレート（１，３，４，６−テトラ−Ｏ−アセチル−２−Ｏ−トリフルオロメタンスルホニル−Ｄ−マンノピラノース）を備えることで１８Ｆ−ＦＤＧを製造するためのキットとなり、ｓｙｎ−１−（Ｎ−（ｔ−ブトキシカルボニル）アミノ）−３−［（（トリフルオロメチル）スルホニル）オキシ］−シクロブタン−１−カルボン酸エチルエステルを備えることで１８Ｆ−ＦＡＣＢＣを製造するためのキットとなり、５’−Ｏ−（４，４’−ジメトキシトリチル）−２，３’−無水チミジン、３−Ｎ−Ｂｏｃ−５’−Ｏ−ジメトキシトリチル−３’−Ｏ−ノシルチミジン又は５’−Ｏ−（ベンゾイル）−２，３’−無水チミジンを備えることで１８Ｆ−ＦＬＴを製造するためのキットとなり、１−（２’−ニトロ−１’−イミダゾリル）−２−Ｏ−テトラヒドロキシピラニル−３−Ｏ−オシル−プロパンジオールを備えることで１８Ｆ−ＦＭＩＳＯを製造するためのキットとなり、（Ｅ−２−（２−（２−（５−（４−（ｔｅｒｔ−ブトキシカルボニル（メチル）アミノ）スチリル）ピリジン−２−イルオキシ）エトキシ）−エトキシ）エチル ４−メチルベンゼンスルホネートを備えることで18F-Flobetapirを製造するためのキットとなり、６−エトキシメトキシ−２−（４’−（Ｎ−ホルミル−Ｎ−メチル）アミノ−３’−ニトロ）フェニルベンゾチアゾールを備えることで１８Ｆ−フルテメタモルを製造するためのキットとなる。 Further, as the non-radioactive organic compounds provided in the kits A and B, the same non-radioactive organic compounds as those used in the above-mentioned synthesis step can be used, but mannose triflate (1,3,4,6-tetra-O) can be used. -Acetyl-2-O-trifluoromethanesulfonyl-D-mannopyranose) provides a kit for producing 18 F-FDG, and syn-1- (N- (t-butoxycarbonyl) amino) -3. -[((Trifluoromethyl) sulfonyl) oxy] -cyclobutane-1-carboxylic acid ethyl ester provides a kit for producing 18 F-FACBC, and 5'-O- (4,4'-dimethoxytrityl). ) -2,3'-Anhydrous thymidin, 3-N-Boc-5'-O-dimethoxytrityl-3'-O-nosyltimidine or 5'-O- (benzoyl) -2,3'-anhydrous timidine It becomes a kit for producing 18 F-FLT in, and is provided with 1- (2'-nitro-1'-imidazolyl) -2-O-tetrahydroxypyranyl-3-O-osyl-propanediol to produce 18 F. It became a kit for producing -FMISO, and became (E-2- (2-(2-(5-(5- (4- (tert-butoxycarbonyl (methyl) amino) styryl) pyridin-2-yloxy) ethoxy) -ethoxy). The inclusion of ethyl 4-methylbenzene sulfonate provides a kit for the production of 18 F-Flobetapir, 6-ethoxymethoxy-2- (4'-(N-formyl-N-methyl) amino-3'-nitro) phenyl. The inclusion of benzothiazole provides a kit for producing 18 F-flutemethamol.
本発明の方法、キット及びカラムカートリッジによれば、塩化ナトリウムが混在した医療用の放射性フッ化物イオンであっても、水溶液の状態で銀イオンを担持する担体に接触させることで、水に難溶の塩化銀を形成させ、塩化物イオンを放射性フッ化物イオン含有水溶液（第１の水溶液）から除去することができる。このため、従来、１８Ｏ濃縮水を出発物質として使用して実行していた放射性フッ素標識有機化合物の合成法のうち、出発物質である放射性フッ化物イオン含有１８Ｏ濃縮水を、塩化物イオンが除去された放射性フッ化物イオン含有水溶液（第２の水溶液）に置き換える以外は、従来と同様な方法で放射性フッ素標識有機化合物を得ることができる。したがって、簡便に放射性フッ素の利用効率を高めることが可能になる。 According to the method, kit and column cartridge of the present invention, even medical radioactive fluoride ions mixed with sodium chloride are hardly soluble in water by being brought into contact with a carrier carrying silver ions in an aqueous solution state. The silver chloride of silver chloride can be formed, and chloride ions can be removed from the radioactive fluoride ion-containing aqueous solution (first aqueous solution). For this reason, among the methods for synthesizing radioactive fluorine-labeled organic compounds, which have been conventionally carried out using 18 O concentrated water as a starting material, chloride ions use 18 O concentrated water containing radioactive fluoride ion as a starting material. A radioactive fluorine-labeled organic compound can be obtained in the same manner as before, except that it is replaced with the removed radioactive fluoride ion-containing aqueous solution (second aqueous solution). Therefore, it is possible to easily increase the utilization efficiency of radioactive fluorine.
以下、実施例を記載して本発明をさらに詳しく説明するが、本発明はこれらの内容に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these contents.
（製造例１）18F-NaF溶液（第１の水溶液）の調製
必要放射能量の１８Ｆイオン含有１８Ｏ濃縮水を陰イオン交換樹脂（Sep-Pak（登録商標）AccellTM Plus QMA Plus Lightカートリッジ（充填量１３０ｍｇ） (Waters社製)）に捕集し、注射用水３ｍＬで洗浄後、生理食塩液２ｍＬで18F-NaF溶液を抽出した。なお、以下各実施例及び比較例に示す放射能量は、18F-NaF溶液の調製開始時（製造例１の開始時）を基準として、減衰補正計算を行ったものを示した。また、放射化学的収率は、減衰補正計算を行った後の放射能量を用いて算出した。
(Production Example 1) Preparation of 18 F-NaF solution (first aqueous solution) Anion exchange resin (Sep-Pak® Accel TM Plus QMA Plus Light cartridge) with 18 F ion-containing 18 O concentrated water with the required radioactivity (Filling amount: 130 mg) (manufactured by Waters)), and after washing with 3 mL of water for injection, an 18 F-NaF solution was extracted with 2 mL of physiological saline. The amount of radioactivity shown in each of the Examples and Comparative Examples below is obtained by performing attenuation correction calculation based on the start of preparation of the 18 F-NaF solution (at the start of Production Example 1). The radiochemical yield was calculated using the amount of radioactivity after the attenuation correction calculation.
（実施例１）銀処理18F-NaF溶液（第２の水溶液）の調製
銀カートリッジ（OnGuard II Ag/H固相抽出カートリッジ（充填量２．５ｃｃ）、サーモサイエンティフィック社製）を注射用水１５ｍＬで前処理し、製造例１に示す方法に従って得た18F-NaF溶液２ｍＬを通液した後、さらに注射用水２ｍＬを銀カートリッジに通液し、銀処理18F-NaF溶液４ｍＬを得た。
(Example 1) Preparation of silver-treated 18 F-NaF solution (second aqueous solution) Silver cartridge (OnGuard II Ag / H solid-phase extraction cartridge (filling amount 2.5 cc), manufactured by Thermo Scientific) is injected with water for injection. After pretreatment with 15 mL and passing 2 mL of the 18 F-NaF solution obtained according to the method shown in Production Example 1, 2 mL of water for injection was further passed through a silver cartridge to obtain 4 mL of the silver-treated 18 F-NaF solution. ..
実施例１で得られた銀処理18F-NaF溶液中の塩化物イオンの濃度を以下の条件で定量したところ、０．６８３ｐｐｍであった。また、ｐＨメータ（ＨＭ−３０Ｒ）で測定したｐＨは３．５８であった。なお、同じ分析条件で、定量した製造例１の18F-NaF溶液中の塩化物イオンの濃度は、２７７９ｐｐｍであり、ｐＨは８．１４であった。
＜塩化物イオンの定量方法＞
機器： 高速液体クロマトグラフシステムＩＣＳ―３０００
検出器： 電気伝導度検出器、サプレッサー使用
注入量： ２５μＬ
カラム： Ion Pac AS12A（内径４ｍｍ、長さ２０ｃｍ）
ガードカラム：Ion Pac AG12A（内径４ｍｍ、長さ５ｃｍ）
カラム温度： ３０℃
移動相： ４ｍｍｏｌ／Ｌ炭酸水素ナトリウム水溶液
流量： 毎分１．２ｍＬ
分析時間： ２０分
The concentration of chloride ions in the silver-treated 18 F-NaF solution obtained in Example 1 was quantified under the following conditions and found to be 0.683 ppm. The pH measured with a pH meter (HM-30R) was 3.58. Under the same analytical conditions, the concentration of chloride ions in the quantified 18 F-NaF solution of Production Example 1 was 2779 ppm, and the pH was 8.14.
<Method for quantifying chloride ions>
Equipment: High Performance Liquid Chromatograph System ICS-3000
Detector: Electrical conductivity detector, suppressor used Injection volume: 25 μL
Column: Ion Pac AS12A (inner diameter 4 mm, length 20 cm)
Guard column: Ion Pac AG12A (inner diameter 4 mm, length 5 cm)
Column temperature: 30 ° C
Mobile phase: 4 mmol / L sodium bicarbonate aqueous solution Flow rate: 1.2 mL / min
Analysis time: 20 minutes
（実施例２）１−（Ｎ−（ｔ−ブトキシカルボニル）アミノ）−３−［１８Ｆ］フルオロシクロブタン−１−カルボン酸エチルエステル（18F-FBE）の合成
実施例１に示す方法に従って得られた銀処理18F-NaF溶液（１１２９．７２ＭＢｑ）を、陰イオン交換樹脂に通液し、［１８Ｆ］フッ化物イオンを、吸着捕集した。次いで、該カラムに炭酸カリウム（５．５ｍｇ）の水溶液（０．６ｍＬ）及びクリプトフィックス２２２（商品名）（４０ｍｇ）のアセトニトリル溶液（１．６ｍＬ）の混液を通液して［１８Ｆ］フッ化物イオンを溶出し、１１０℃に加熱して水及びアセトニトリルを蒸散させた後、アセトニトリル（０．５ｍＬ×２回）を加えて共沸し、乾固させた。ここに、ＷＯ２００９／０７８３９６記載の方法に従って合成したｓｙｎ−１−（Ｎ−（ｔ−ブトキシカルボニル）アミノ）−３−［（（トリフルオロメチル）スルホニル）オキシ］−シクロブタン−１−カルボン酸エチルエステル３１．７ｍｇをアセトニトリル１ｍＬに溶解させた液を加え、８５℃で３分間加熱した。反応液中の18F-FBEの放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、ジエチルエーテル／ヘキサン＝１／１）から６７．５９％であり、得られた放射能量が１０６１．４０ＭＢｑであることから、18F-FBEの放射化学的収率（使用した18F-NaF溶液の放射能量比）は、６３．５％であることが見積もられた。
(Example 2) Synthesis of 1- (N- (t-butoxycarbonyl) amino) -3- [ 18 F] fluorocyclobutane-1-carboxylic acid ethyl ester ( 18 F-FBE) Obtained according to the method shown in Example 1. The silver-treated 18 F-NaF solution (1129.72 MBq) was passed through an anion exchange resin, and [ 18 F] fluoride ions were adsorbed and collected. Next, a mixed solution of an aqueous solution (0.6 mL) of potassium carbonate (5.5 mg) and an acetonitrile solution (1.6 mL) of Cryptofix 222 (trade name) (40 mg) was passed through the column to pass [ 18 F] fluoride. The fluoride ion was eluted, heated to 110 ° C. to evaporate water and acetonitrile, and then acetonitrile (0.5 mL × 2 times) was added to azeotrope and dry. Here, syn-1-(N- (t-butoxycarbonyl) amino) -3-[((trifluoromethyl) sulfonyl) oxy] -cyclobutane-1-carboxylic acid ethyl ester synthesized according to the method described in WO2009 / 078396. A solution prepared by dissolving 31.7 mg in 1 mL of acetonitrile was added, and the mixture was heated at 85 ° C. for 3 minutes. The radiochemical purity of 18 F-FBE in the reaction solution was 67.59% from radio TLC (plate: silica gel, diethyl ether / hexane = 1/1), and the obtained radioactivity amount was 1061.40 MBq. From this, it was estimated that the radiochemical yield of 18 F-FBE (ratio of radioactivity of the 18 F-NaF solution used) was 63.5%.
（比較例１）18F-FBEの合成
銀処理18F-NaF溶液に変えて、製造例１に示す方法に従って得られた18F-NaF溶液（１０９４．２６ＭＢｑ）を用いた以外は実施例２と同じ方法に従って、18F-FBEを合成した。反応液中の18F-FBEの放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、ジエチルエーテル／ヘキサン＝１／１）から７７．７４％であり、得られた放射能量が１６．８５ＭＢｑであることから、18F-FBEの放射化学的収率（使用した18F-NaF溶液の放射能量比）は、１．２％であることが見積もられた。
(Comparative Example 1) Synthesis of 18 F-FBE Example 2 except that the 18 F-NaF solution (1094.26MBq) obtained according to the method shown in Production Example 1 was used instead of the silver-treated 18 F-NaF solution. 18 F-FBE was synthesized according to the same method as above. The radiochemical purity of 18 F-FBE in the reaction solution was 77.74% from radio TLC (plate: silica gel, diethyl ether / hexane = 1/1), and the amount of radioactivity obtained was 16.85 MBq. From this, it was estimated that the radiochemical yield of 18 F-FBE (ratio of radioactivity of the 18 F-NaF solution used) was 1.2%.
（実施例３）銀処理18F-NaF溶液の調製
銀カートリッジ（OnGuard II Ag固相抽出カートリッジ（充填量１〜２．５ｃｃ）、サーモサイエンティフィック社製）を注射用水１０〜１５ｍＬで前処理し、製造例１に示す方法に従って得た18F-NaF溶液２ｍＬを通液した後、さらに注射用水２ｍＬを銀カートリッジに通液し、銀処理18F-NaF溶液４ｍＬを得た。
(Example 3) Preparation of silver-treated 18 F-NaF solution Pre-treat a silver cartridge (OnGuard II Ag solid-phase extraction cartridge (filling amount 1 to 2.5 cc), manufactured by Thermo Scientific) with 10 to 15 mL of water for injection. Then, 2 mL of the 18 F-NaF solution obtained according to the method shown in Production Example 1 was passed through the silver cartridge, and then 2 mL of water for injection was passed through the silver cartridge to obtain 4 mL of the silver-treated 18 F-NaF solution.
（実施例４）18F-fluciclovineの合成
ＷＯ２００７／１３２６８９の実施例２に記載の方法において、［１８Ｆ］フッ化物イオン含有Ｈ２ １８Ｏ（７〜３６ＧＢｑ）に変えて、実施例３に示す方法に従って得られた銀処理18F-NaF溶液（６５５．００ＭＢｑ）を用いた以外は同じ方法に従って、18F-fluciclovine（２４７．５７ＭＢｑ）を合成した。放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、展開溶媒：アセトニトリル／水／酢酸＝４／１／１）にて調べた。
In the method described in Example 2 (Example 4) 18 F-fluciclovine synthesis of WO2007 / 132689, instead of [18 F] fluoride ion-containing H 2 18 O (7~36GBq), shown in Example 3 18 F-fluciclovine (247.57 MBq) was synthesized according to the same method except that the silver-treated 18 F-NaF solution (655.00 MBq) obtained according to the method was used. The radiochemical purity was examined by radio TLC (plate: silica gel, developing solvent: acetonitrile / water / acetic acid = 4/1/1).
（比較例２）18F-fluciclovineの合成
ＷＯ２００７／１３２６８９の実施例２に記載の方法において、［１８Ｆ］フッ化物イオン含有Ｈ２ １８Ｏ（７〜３６ＧＢｑ）に変えて、製造例１に示す方法に従って得られた18F-NaF溶液（６０．７０ＭＢｑ）を用いた以外は同じ方法に従って、18F-fluciclovine（１５．２７ＭＢｑ）を合成した。放射化学的純度は、実施例４と同じ条件で調べた。
In the method described in Example 2 (Comparative Example 2) 18 F-fluciclovine synthesis of WO2007 / 132,689, instead of [18 F] fluoride ion-containing H 2 18 O (7~36GBq), shown in Production Example 1 18 F-fluciclovine (15.27 MBq) was synthesized according to the same method except that the 18 F-NaF solution (60.70 MBq) obtained according to the method was used. The radiochemical purity was examined under the same conditions as in Example 4.
（実施例５）18F-FDG（１８Ｆ−フルオロデオキシグルコース）の合成
実施例３に示す方法に従って得られた銀処理18F-NaF溶液（７１９．００ＭＢｑ）を陰イオン交換樹脂に吸着捕集させることにより保持させた。炭酸カリウム（２．７５ｍｇ）の水溶液（０．３ｍＬ）及びクリプトフィックス２２２（商品名）（２０ｍｇ）のアセトニトリル溶液（０．８ｍＬ）の混液を前記陰イオン交換樹脂に通液し、[１８Ｆ]フッ化カリウム溶出液を得た後、加熱により濃縮乾固した。残渣に、１，３，４，６−テトラ−Ｏ−アセチル−２−Ｏ−トリフルオロメタンスルホニル−β−Ｄ−マンノピラノース（２０ｍｇ）をアセトニトリルで溶解した溶液（１ｍＬ）を加えて、８５℃で５分間加熱して反応させた後、加熱により濃縮乾固した。残渣に１ｍｏｌ／Ｌ塩酸溶液（２．０ｍＬ）を加えて、１３０℃で１５分間攪拌させた後、一連の精製カラム（陽イオン交換樹脂，イオン遅滞樹脂，オクタデシルシリル化シリカゲル及びアルミナ）に通液し、更に、反応容器を水（１０ｍＬ）により洗浄し、同様に一連の精製カラムに通液して、18F-FDG（２６３．７２ＭＢｑ）を得た。放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、展開溶媒：アセトニトリル／水＝１９：１）にて調べた。
(Example 5) Synthesis of 18 F-FDG ( 18 F-fluorodeoxyglucose) A silver-treated 18 F-NaF solution (719.00 MBq) obtained according to the method shown in Example 3 is adsorbed and collected on an anion exchange resin. It was held by letting it hold. A mixed solution of an aqueous solution (0.3 mL) of potassium carbonate (2.75 mg) and an acetonitrile solution (0.8 mL) of Cryptofix 222 (trade name) (20 mg) was passed through the anion exchange resin, and [ 18 F] After obtaining a potassium fluoride eluate, it was concentrated to dryness by heating. A solution (1 mL) of 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose (20 mg) dissolved in acetonitrile was added to the residue at 85 ° C. After heating for 5 minutes to react, the mixture was concentrated to dryness by heating. A 1 mol / L hydrochloric acid solution (2.0 mL) was added to the residue, and the mixture was stirred at 130 ° C. for 15 minutes, and then passed through a series of purification columns (cation exchange resin, ion retardation resin, octadecylsilylated silica gel and alumina). Further, the reaction vessel was washed with water (10 mL) and passed through a series of purification columns in the same manner to obtain 18 F-FDG (263.72 MBq). The radiochemical purity was examined by radio TLC (plate: silica gel, developing solvent: acetonitrile / water = 19: 1).
（実施例６）18F-FLT（１８Ｆ−3'-デオキシ-3'-フルオロチミジン）の合成
実施例３に示す方法に従って得られた銀処理18F-NaF溶液（６０１．００ＭＢｑ）を陰イオン交換樹脂に吸着捕集させることにより保持させた。炭酸カリウム（２．２９ｍｇ）の水溶液（０．２５ｍＬ）及びクリプトフィックス２２２（商品名）（７．５ｍｇ）のアセトニトリル溶液（０．３ｍＬ）の混液を前記陰イオン交換樹脂に通液し、[１８Ｆ]フッ化カリウム溶出液を得た後、加熱により濃縮乾固した。残渣に、5’-O-(4,4’-Dimethoxytrityl)-2,3’-anhydrothymidine（１５ｍｇ）をアセトニトリルで溶解した溶液（０．７５ｍＬ）を加えて、１３０℃で１０分間加熱して反応させた後、加熱により濃縮乾固した。残渣に１ｍｏｌ／Ｌ塩酸溶液（０．５ｍＬ）を加えて、１２０℃で５分間加熱して、18F-FLT（４９６．７２ＭＢｑ）を得た。放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、展開溶媒：メタノール／アンモニア水＝９：１）にて調べた。
(Example 6) Synthesis of 18 F-FLT ( 18 F-3'-deoxy-3'-fluorothymidine) The silver-treated 18 F-NaF solution (601.00 MBq) obtained according to the method shown in Example 3 was shaded. It was retained by adsorbing and collecting it on an ion exchange resin. A mixed solution of an aqueous solution (0.25 mL) of potassium carbonate (2.29 mg) and an acetonitrile solution (0.3 mL) of Cryptofix 222 (trade name) (7.5 mg) was passed through the anion exchange resin, and [ 18] F] After obtaining a potassium fluoride eluate, it was concentrated to dryness by heating. To the residue, add a solution (0.75 mL) of 5'-O- (4,4'-Dimethoxytrityl) -2,3'-anhydrothymidine (15 mg) dissolved in acetonitrile, and heat at 130 ° C. for 10 minutes to react. After that, it was concentrated to dryness by heating. A 1 mol / L hydrochloric acid solution (0.5 mL) was added to the residue, and the mixture was heated at 120 ° C. for 5 minutes to obtain 18 F-FLT (496.72 MBq). The radiochemical purity was examined by radio TLC (plate: silica gel, developing solvent: methanol / aqueous ammonia = 9: 1).
（実施例７）18F-FMISO（１８Ｆ−フルオロミソニダゾール）の合成
実施例３に示す方法に従って得られた銀処理18F-NaF溶液（９１６．００ＭＢｑ）を陰イオン交換樹脂に吸着捕集させることにより保持させた。炭酸カリウム（２．２９ｍｇ）の水溶液（０．２５ｍＬ）及びクリプトフィックス２２２（商品名）（７．５ｍｇ）のアセトニトリル溶液（０．３ｍＬ）の混液を前記陰イオン交換樹脂に通液し、[１８Ｆ]フッ化カリウム溶出液を得た後、加熱により濃縮乾固した。残渣に、1-(2’-Nitro-1’-imidazolyl)-2-O-tetrahydropyranyl-3-O-osyl-propanediol（５ｍｇ）をアセトニトリルで溶解した溶液（１ｍＬ）を加えて、１１０℃で１０分間加熱して反応させた後、加熱により濃縮乾固した。残渣に１ｍｏｌ／Ｌ塩酸溶液（０．３ｍＬ）を加えて、８０℃で１分間加熱して、18F-FMISO（８０５．０４ＭＢｑ）を得た。放射化学的純度は、ラジオＴＬＣ（プレート：シリカゲル、展開溶媒：酢酸エチル）にて調べた。
(Example 7) 18 F-FMISO (18 F- fluoro miso NIDA tetrazole) silver treatment 18 F-NaF solution obtained according to the method shown in Synthesis Example 3 (916.00MBq) capturing adsorbed on the anion exchange resin It was held by collecting it. A mixed solution of an aqueous solution (0.25 mL) of potassium carbonate (2.29 mg) and an acetonitrile solution (0.3 mL) of Cryptofix 222 (trade name) (7.5 mg) was passed through the anion exchange resin, and [ 18] F] After obtaining a potassium fluoride eluate, it was concentrated to dryness by heating. To the residue, add a solution (1 mL) of 1- (2'-Nitro-1'-imidazolyl) -2-O-tetrahydropyranyl-3-O-osyl-propanediol (5 mg) dissolved in acetonitrile, and add 10 at 110 ° C. After heating for 1 minute to react, the mixture was concentrated to dryness by heating. A 1 mol / L hydrochloric acid solution (0.3 mL) was added to the residue, and the mixture was heated at 80 ° C. for 1 minute to obtain 18 F-FMISO (805.04 MBq). The radiochemical purity was examined by radio TLC (plate: silica gel, developing solvent: ethyl acetate).
実施例４〜７及び比較例２の結果を表１に示す。各実施例の放射化学的収率は、使用した銀処理18F-NaF溶液の放射能量に対する目的物の放射能量の割合（％）である。また、比較例の放射化学的収率は、使用した18F-NaF溶液の放射能量に対する目的物の放射能量の割合（％）である。 The results of Examples 4 to 7 and Comparative Example 2 are shown in Table 1. The radiochemical yield of each example is the ratio (%) of the radioactivity of the target product to the radioactivity of the silver-treated 18 F-NaF solution used. The radiochemical yield of the comparative example is the ratio (%) of the radioactivity of the target product to the radioactivity of the 18 F-NaF solution used.
実施例２と比較例１との比較、及び、実施例４と比較例２の比較で示されるとおり、18F-NaF溶液を銀カートリッジ処理することで１８Ｆ標識有機化合物の放射化学的収率が向上した。また、銀カートリッジ処理した18F-NaF溶液により種々の 1８ Ｆ標識有機化合物が合成できることも示された。なお、実施例６，７では、精製を行っていないため、放射化学的純度が低くなっているが、「ＰＥＴ用放射性薬剤の製造および品質管理−合成と臨床使用へのてびき−第４版」で示されるようなＨＰＬＣ精製を行うことで、従来どおりの放射化学的純度が得られる。 As shown in the comparison between Example 2 and Comparative Example 1 and the comparison between Example 4 and Comparative Example 2, the radiochemical yield of the 18 F-labeled organic compound was obtained by treating the 18 F-NaF solution with a silver cartridge. Has improved. It was also shown that various 18 F- labeled organic compounds can be synthesized by the 18 F-NaF solution treated with a silver cartridge. In Examples 6 and 7, the radiochemical purity was low because no purification was performed. However, "Production and quality control of radiopharmaceuticals for PET-Tobiki for synthesis and clinical use-Fourth edition" By performing HPLC purification as shown in ", the conventional radiochemical purity can be obtained.
Claims (14)
前記第２の水溶液に含まれる放射性フッ化物イオンを用いて放射性フッ素標識有機化合物を合成する工程と、
を含む、放射性フッ素標識有機化合物の製造方法。 A step of contacting a first aqueous solution containing radioactive fluoride ions and sodium chloride with a carrier carrying silver ions, and then obtaining a second aqueous solution containing radioactive fluoride ions separated from the carrier.
A step of synthesizing a radioactive fluorine-labeled organic compound using the radioactive fluoride ion contained in the second aqueous solution, and
A method for producing a radioactive fluorine-labeled organic compound, which comprises.
前記陰イオン交換樹脂から放射性フッ化物イオンを溶出させて、放射性フッ化物イオンを含む溶出液を得る工程と、
を更に含み、
前記放射性フッ素標識有機化合物を合成する前記工程において、
前記溶出液に含まれる放射性フッ化物イオンを用いて前記放射性フッ素標識有機化合物を合成する、請求項１乃至５いずれか一項に記載の放射性フッ素標識有機化合物の製造方法。 A step of passing the second aqueous solution through an anion exchange resin to adsorb radioactive fluoride ions on the anion exchange resin.
A step of eluting radioactive fluoride ions from the anion exchange resin to obtain an eluate containing radioactive fluoride ions, and
Including
In the step of synthesizing the radioactive fluorine-labeled organic compound,
The method for producing a radioactive fluorine-labeled organic compound according to any one of claims 1 to 5, wherein the radioactive fluorine-labeled organic compound is synthesized using the radioactive fluoride ions contained in the eluent.
前記放射性フッ素化標識化合物を合成する前記工程において、
蒸発乾固させる前記工程により得られた放射性フッ化物イオンを含む残渣に、脱離基を有する非放射性有機化合物を加えて、前記脱離基と放射性フッ化物イオンとの置換による放射性フッ素化反応を実行する、請求項６に記載の放射性フッ素標識有機化合物の製造方法。 The step of evaporating and drying the eluate in the presence of a phase transfer catalyst is further included.
In the step of synthesizing the radiofluorinated labeled compound,
A non-radioactive organic compound having a leaving group is added to the residue containing the radioactive fluoride ion obtained by the step of evaporating to dryness, and a radioactive fluorination reaction is carried out by substituting the leaving group with the radioactive fluoride ion. The method for producing a radioactive fluorine-labeled organic compound according to claim 6, which is carried out.
銀イオンが担持された担体と
を備える、放射性フッ素標識有機化合物を製造するためのキット。 An aqueous solution containing radioactive fluoride ions and sodium chloride,
A kit for producing a radioactive fluorine-labeled organic compound, which comprises a carrier on which silver ions are supported.
放射性フッ化物イオンと置換されるための脱離基を有する非放射性有機化合物と、
を備える、放射性フッ素標識有機化合物を製造するためのキット。 A carrier carrying silver ions and
Non-radioactive organic compounds with leaving groups to replace radioactive fluoride ions,
A kit for producing radioactive fluorine-labeled organic compounds.
放射性フッ化物イオンと塩化ナトリウムとを含む水溶液から塩化物イオンを除去するために用いられるカラムカートリッジ。 A column cartridge packed with a carrier that supports silver ions.
A column cartridge used to remove chloride ions from an aqueous solution containing radioactive fluoride ions and sodium chloride.
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