Evaluation of [¹⁸F]pitavastatin as a positron emission tomography tracer for in vivo organic transporter polypeptide function

Introduction: To understand the pathways involved in drug clearance from the body, quantitative evaluations of the hepatobiliary transport of drugs are important. The organic anion transporting polypeptide (OATP) family transporter, particularly OATP1B1 and 1B3, are considered to play an important role in hepatic uptake of organic anion compounds. Pitavastatin is a substrate of OATP, and it includes a fluorine group. Therefore, it represents an acceptable positron-emission tomography (PET) tracer using fluorine-18 to image in vivo hepatic transporter functions. Method: [¹⁸F]Pitavastatin was synthesized using the method we previously reported. To evaluate the potential of [¹⁸F]pitavastatin in PET imaging of in vivo OATP functions, we investigated the hepatic uptake with/without rifampicin as an OATP inhibitor after administration in normal SD rats. [¹⁸F]Pitavastatin metabolite was evaluated using reverse-phase thin-layer chromatography (TLC) autoradiography. We subsequently analyzed the PET image results and demonstrated that [¹⁸F]pitavastatin selectively accumulated in the liver post-administration. Result and discussion: In metabolite analysis using reverse-phase TLC, we found that the radioactivity detected in the plasma, liver (>90% intact), and bile mostly originated from the parent pitavastatin of the PET study (~40 min). [¹⁸F]pitavastatin's hepatic uptake decreased (approximately 76%) with rifampicin co-administration in PET analysis. Because [¹⁸F]pitavastatin has lower clearance in rats than other previously reported OATP1B PET s, it holds the potential of an imaging tracer that has a higher sensitivity in monitoring hepatic OATP1B function's changes. Conclusion: Compared with the previously reported OATP imaging tracers, [¹⁸F]pitavastatin is more suitable for the sensitive detection of functional changes in OATP transporters. We believe that [¹⁸F]pitavastatin enables quantitative analysis of the hepatobiliary transport system for organic anion compounds.