Abstract
IntroductionFluorine-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. MethodsThe 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. ResultsThe 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. ConclusionThe 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.
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