Improving metabolic stability of fluorine-18 labeled verapamil analogs

Introduction: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [F-18]1 and [F-18]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [F-18]1-d(4), [F-18]2-d(4), [F-18]3-d(3) and[F-18]3-d(7). Methods: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [F-18]1-d(4), [F-18]2-d(4), [F-18]3-d(3) and [F-18]3-d(7). Results: The deuterated analogs [F-18]2-d(4), [F-18]3-d(3), and[F-18]3-d(7). showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [F-18]3-d(3) and[F-18]3-d(7). might be caused by steric hindrance for enzymes. Conclusion: The striking similar in vivo behavior of [F-18]3-d(7) to that of (R)-[C-11]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [F-18]3-d(7) as a PET radiopharmaceutical for P-gp evaluation. (C) 2018 The Authors. Published by Elsevier Inc.