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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.
