Improving metabolic stability of fluorine-18 labeled verapamil analogs

Abstract

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 [¹⁸F]1 and [¹⁸F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [¹⁸F]1-d₄, [¹⁸F]2-d₄, [¹⁸F]3-d₃ and [¹⁸F]3-d₇.

Methods: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [¹⁸F]1-d₄, [¹⁸F]2-d₄, [¹⁸F]3-d₃ and [¹⁸F]3-d₇.

Results: The deuterated analogs [¹⁸F]2-d₄, [¹⁸F]3-d₃ and [¹⁸F]3-d₇ showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [¹⁸F]3-d₃ and [¹⁸F]3-d₇ might be caused by steric hindrance for enzymes.

Conclusion: The striking similar in vivo behavior of [¹⁸F]3-d₇ to that of (R)-[¹¹C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [¹⁸F]3-d₇ as a PET radiopharmaceutical for P-gp evaluation.

Keywords: Deuterium isotope effect; Deuterium substitution; Metabolism; P-glycoprotein; Positron emission tomography; Radiopharmaceuticals.