@misc{oai:repo.qst.go.jp:00071873,
 author = {Hashimoto, Hiroki and Kawamura, Kazunori and Takei, Makoto and Igarashi, Nobuyuki and Fujishiro, Tomoya and Shiomi, Satoshi and Ryuji, Watanabe and Muto, Masatoshi and Furutsuka, Kenji and Ito, Takehito and Yamasaki, Tomoteru and Yui, Joji and Nemoto, Kazuyoshi and Kimura, Yasuyuki and Higuchi, Makoto and Zhang, Ming-Rong and 橋本 裕輝 and 河村 和紀 and 武井 誠 and 五十嵐 延行 and 藤代 智也 and 潮見 聡 and 渡辺 竜二 and 武藤 正敏 and 古塚 賢士 and 伊藤 岳人 and 山崎 友照 and 由井 譲二 and 根本 和義 and 木村 泰之 and 樋口 真人 and 張 明栄},
 month = {Nov},
 note = {Objectives: 2-((1E,3E)-4-(6-(11C-methylamino)pyridin-3-yl)buta-1,3-dienyl)
benzo[d]thiazol-6-ol ([11C]PBB3, Fig. 1) is a clinically useful PET probe for in vivo imaging of tau pathology in the brain. For the pharmacokinetic evaluation of [11C]PBB3, it is important to elucidate the characteristics of radiometabolites. In this study, we evaluated radiometabolite after injection of [11C]PBB3 in mice brain and plasma, identified the chemical structure of a major radiometabolite of [11C]PBB3, and proposed the metabolic pathway of [11C]PBB3. 
Methods: [11C]PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor with [11C]methyl iodide using potassium hydroxide as a base, followed by deprotection. [11C]PBB3 or carrier-added [11C]PBB3 was injected into a mouse for in vivo metabolite analysis. The chemical structure of a major radiometabolite was identified using radio-HPLC and LC–MS. Mouse and human liver microsomes and liver S9 samples were incubated with [11C]PBB3 in vitro, and its radiometabolite was analyzed using radio-HPLC. In silico prediction software was used to assist in the determination of the metabolite and metabolic pathway of [11C]PBB3. 
Results and discussion: In in vivo metabolite study, more than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the parent [11C]PBB3, despite its rapid metabolism in the plasma. Also, in vivo metabolite study using carrier-added [11C]PBB3 showed that the molecular weight of a major radiometabolite of [11C]PBB3, which was called as [11C]M2 (Fig. 1), was m/z 390 [M+H+]. In vitro metabolite study assisted by in silico prediction showed that [11C]M2, which was not generated by cytochrome P450 enzymes (CYPs), was generated by sulfated conjugation mediated by a sulfotransferase. Our data demonstrated that [11C]PBB3 was mainly metabolized to [11C]M2 by sulfate conjugation mediated by sulfotransferases, and a minor radiometabolite, [11C]M1 (Fig. 1), was yielded through oxidation mediated by CYPs. These results suggest that [11C]M2 may be retained in the plasma, recirculated throughout the whole body, and may gradually enter the brain notwithstanding its relatively high polarity.
Conclusion: [11C]PBB3 was rapidly decomposed to a polar radiolabeled metabolite in the plasma. The major radiometabolite, [11C]M2, was identified as a sulfated conjugate of [11C]PBB3. [11C]PBB3 was metabolized mainly by a sulfotransferase and subsidiary by CYPs., Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry},
 title = {IN VIVO, IN VITRO, AND IN SILICO EVALUATION OF RADIOMETABOLITE OF [11C]PBB3 AS A CLINICALLY USEFUL PET PROBE FOR IMAGING OF TAU PATHOLOGY.},
 year = {2015}
}