Identification of a major radiometabolite of [11C]PBB3.

Abstract Introduction [ 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. Conclusion 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.