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 [ 18 F] 1 and [ 18 F] 2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [ 18 F] 1- d 4 , [ 18 F] 2- d 4 , [ 18 F] 3- d 3 and [ 18 F] 3- d 7 . Methods The following deuterium containing tracers were synthesized and evaluated in mice and rats: [ 18 F] 1- d 4 , [ 18 F] 2- d 4 , [ 18 F] 3- d 3 and [ 18 F] 3- d 7 . Results The deuterated analogs [ 18 F] 2- d 4 , [ 18 F] 3- d 3 and [ 18 F] 3- d 7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [ 18 F] 3- d 3 and [ 18 F] 3- d 7 might be caused by steric hindrance for enzymes. Conclusion The striking similar in vivo behavior of [ 18 F] 3- d 7 to that of ( R )-[ 11 C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [ 18 F] 3- d 7 as a PET radiopharmaceutical for P-gp evaluation.