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Development of Scandium-catalyzed [18F]fluoroalkylation of aniline analogs with [18F]epifluorohydrin under a mild condition
https://repo.qst.go.jp/records/73013
https://repo.qst.go.jp/records/7301331969024-2a30-40bb-b09f-f3a51fbeba76
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-02-21 | |||||
| タイトル | ||||||
| タイトル | Development of Scandium-catalyzed [18F]fluoroalkylation of aniline analogs with [18F]epifluorohydrin under a mild condition | |||||
| 言語 | ||||||
| 言語 | jpn | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
藤永, 雅之
× 藤永, 雅之× 藤永 雅之 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: [18F]Fluoroalkylation is a useful method for introduction of fluorine-18 into molecules containing NH, OH, and SH-groups, analogously to the 11C-methylation with [11C]CH3I. Moreover, introduction of [18F]fluoroalkyl group could often lead to significant improvement of in vitro properties and in vivo behaviors over the corresponding 11C-methylated tracer. We have developed a 18F-fluoroalkylation methodology with [18F]FMeOTf, [18F]FEtBr or [18F]FPrBr etc. These radiolabeled agents were synthesized by [18F]fluorination and purified by simple distillation under an automated synthesis system developed in house [1]. Using these reagents, we are routinely producing clinically-useful 18F-radiotracers, such as [18F]FMeNER-d2, [18F]FEDAA1106, [18F]FEDAC, [18F]FE-SPARQ and [18F]FEtPE2I. Recently, we have determined a convenient [18F]fluoroalkylation route to introduce 3-[18F]fluoro-2-hydroxypropyl ([18F]FHP) group into a target molecule via ring-opening reaction of [18F]epifluorohydrin ([18F]2) with phenol analogs by using an automated synthesis system [2]. However, despite the usefulness of epifluorohydrin in organic chemistry, the reaction of [18F]2 with nucleophilic reagents containing amino group has rarely been reported. To extend application of our technique with [18F]2, in this study, we developed a simple method for introducing [18F]FHP group into aniline analogs in the presence of Sc(OTf)3. Methods: [18F]Epifluorohydrin 2 was synthesized by the reaction of glycidyl tosylate 1 (10 mg) and [18F]KF/K2.2.2 in 1,2-dichlorobenzene at 130 oC for 2 min. Unlabeled 3a-l were prepared by reaction of aniline analogs and epifluorohydrin in the presence of Sc(OTf)3 at moderate yields (40-84%). The reaction conditions for the [18F]fluoroalkylation of p-anisidine as a model compound with [18F]2 were optimized with regard to solvents, temperatures and times. Under optimized condition, [18F]3a-l were synthesized by the reaction of various aniline analogs and [18F]2. Radiochemical conversions (RCCs) were determined by radio-HPLC for these reaction mixtures. Results: Firstly, a suitable solvent for [18F]fluoroalkylation of p-anisidine with [18F]2 in the presence of Sc(OTf)3 (10 mol%) was examined. In coordinating solvent such as THF and DMF, the reaction did not effectively proceed. On the other hand, the reaction efficiency was significantly increased by the use of nonpolar solvent such as CCl4. Under several temperatures and times investigated, the reaction performed in CCl4 was found to give the best [18F]fluoroalkylating results at 50 oC for 20 min. Under optimized condition, [18F]3a was synthesized by reaction of p-anisidine (3 mg) and [18F]2 using an automated synthesis system. By purification for the reaction mixture with semi-preparative HPLC, [18F]3a was obtained with a synthesis time of 85 ± 3 min and 27% radiochemical yield (isolated-yield based on the cyclotron-produced [18F]F-). In order to demonstrate suitability of this method, [18F]3b-l were synthesized by using various aniline analogs containing halogen, alkyl, acetyl, hydroxyl group. Radio-HPLC analyses for the reaction mixtures indicated that [18F]3b-l were obtained in 25–69% RCCs. Conclusion: Scandium-catalyzed [18F]fluoroalkylation allow facile introduction of [18F]FHP group into aniline analogs under a mild condition using a home-made automated synthesis system. Next, we will focus on [18F]fluoroalkylation of heteoaryl amine and synthesize optically-selective [18F]3a containing (R)- or (S)-[18F]FHP group. Acknowledgements: We are grateful to the staff of the National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology for their help with the radioisotope production and autoradiosynthesis. References: [1] Zhang MR, et al (2007) Curr Top Med Chem, 7(18), 1817-1828. [2] Fujinaga M, et al (2018) ChemMedChem, 13(16), 1723-1731. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | The 10th China-Japan-Korea Symposium on Radiopharmaceutical Sciences (CJKSRS 2018)でのポスター発表 | |||||
| 発表年月日 | ||||||
| 日付 | 2018-11-03 | |||||
| 日付タイプ | Issued | |||||
