Journal Article Identification of a major radiometabolite of [11C]PBB3

Hashimoto, Hiroki  ,  Kawamura, Kazunori  ,  Takei, Makoto  ,  Igarashi, Nobuyuki  ,  Fujishiro, Tomoya  ,  Shiomi, Satoshi  ,  Ryuji, Watanabe  ,  Muto, Masatoshi  ,  Furutsuka, Kenji  ,  Ito, Takehito  ,  Yamasaki, Tomoteru  ,  Yui, Joji  ,  Nemoto, Kazuyoshi  ,  Kimura, Yasuyuki  ,  Higuchi, Makoto  ,  Ming-Rong, Zhang

42 ( 12 )  , pp.905 - 910 , 2015-11 , Elsevier
Introduction: [11C]PBB3 is a clinically used positron emission tomography(PET) probe for in vivo imaging of tau pathology in the brain. Our previousstudy showed that [11C]PBB3 was rapidly decomposed to a polarradiometabolite in the plasma of mice. For the pharmacokinetic evaluationof [11C]PBB3 it is important to elucidate the characteristics ofradiometabolites. In this study, we identified the chemical structure of amajor radiometabolite of [11C]PBB3 and proposed the metabolic pathway of[11C]PBB3.Methods: Carrier-added [11C]PBB3 was injected into a mouse for in vivometabolite analysis. The chemical structure of a major radiometabolite wasidentified using LC–MS. Mouse and human liver microsomes and liver S9samples were incubated with [11C]PBB3 in vitro. In silico predictionsoftware was used to assist in the determination of the metabolite andmetabolic pathway of [11C]PBB3.Results: In vivo analysis showed that the molecular weight of a majorradiometabolite of [11C]PBB3, which was called as [11C]M2, was m/z 390[M+H+]. In vitro analysis 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.Conclusion: The major radiometabolite, [11C]M2, was identified as asulfated conjugate of [11C]PBB3. [11C]PBB3 was metabolized mainly by a sulfotransferase and subsidiarily by CYPs.

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