量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果（学会誌発表論文、学会発表、研究開発報告書、特許等）を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum Science and Technology.
Thank you very much for using our website. On the 11th of March 2019, this site was moved from our own network server to the JAIRO Cloud network server. If you previously bookmarked this site, that bookmark will no longer work. We would be grateful if you could bookmark the website again. Thank you very much for your understanding and cooperation.
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.
会議概要（会議名, 開催地, 会期, 主催者等）
Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry
IN VIVO, IN VITRO, AND IN SILICO EVALUATION OF RADIOMETABOLITE OF [11C]PBB3 AS A CLINICALLY USEFUL PET PROBE FOR IMAGING OF TAU PATHOLOGY.
