title: Identification of a major radiometabolite of [11C]PBB3.
abstract: BACKGROUND
  [(11)C]PBB3 is a clinically used positron emission tomography (PET) probe for in vivo imaging of tau pathology in the brain. Our previous study showed that [(11)C]PBB3 was rapidly decomposed to a polar radiometabolite in the plasma of mice. For the pharmacokinetic evaluation of [(11)C]PBB3 it is important to elucidate the characteristics of radiometabolites. In this study, we identified the chemical structure of a major radiometabolite of [(11)C]PBB3 and proposed the metabolic pathway of [(11)C]PBB3.
  
  
  METHODS
  Carrier-added [(11)C]PBB3 was injected into a mouse for in vivo metabolite analysis. The chemical structure of a major radiometabolite was identified using LC-MS. Mouse and human liver microsomes and liver S9 samples were incubated with [(11)C]PBB3 in vitro. In silico prediction software was used to assist in the determination of the metabolite and metabolic pathway of [(11)C]PBB3.
  
  
  RESULTS
  In vivo analysis showed that the molecular weight of a major radiometabolite of [(11)C]PBB3, which was called as [(11)C]M2, was m/z 390 [M+H(+)]. In vitro analysis assisted by in silico prediction showed that [(11)C]M2, which was not generated by cytochrome P450 enzymes (CYPs), was generated by sulfated conjugation mediated by a sulfotransferase.
  
  
  CONCLUSIONS
  The major radiometabolite, [(11)C]M2, was identified as a sulfated conjugate of [(11)C]PBB3. [(11)C]PBB3 was metabolized mainly by a sulfotransferase and subsidiarily by CYPs.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. Electronic address: kawamur@nirs.go.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Tokyo Nuclear Services Co., Ltd., Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Igarashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Tokyo Nuclear Services Co., Ltd., Tokyo, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fujishiro
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Tokyo Nuclear Services Co., Ltd., Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shiomi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Tokyo Nuclear Services Co., Ltd., Tokyo, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Tokyo Nuclear Services Co., Ltd., Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Muto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; SHI Accelerator Service Ltd., Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; SHI Accelerator Service Ltd., Tokyo, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods*; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D055432:Metabolomics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000378:metabolism*
chemical_list: C000592806:2-(4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo(d)thiazol-6-ol; D000631:Aminopyridines; D052160:Benzothiazoles; D019275:Radiopharmaceuticals; D003577:Cytochrome P-450 Enzyme System
keywords: PET; [(11)C]PBB3; cytochrome P450; radiometabolite; sulfotransferase; tau probe