Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood–Brain Barrier

[Image: see text] P-glycoprotein is an efflux transporter located in the blood–brain barrier. (R)-[(11)C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer’s disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[(18)F]fluoroethylverapamil ([(18)F]1) and (R)-O-[(18)F]fluoroethylnorverapamil ([(18)F]2) has been described. [(18)F]1 was obtained in reaction of (R)-norverapamil with the volatile [(18)F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% ± 1.2%. [(18)F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% ± 9.9%. Both tracers, [(18)F]1 and [(18)F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [(18)F]1 and [(18)F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [(18)F]1 and [(18)F]2, PET scans in Mdr1a/b((−/−)), Bcrp1((−/−)), and WT mice were acquired, in which [(18)F]2 showed a more specific brain uptake in Mdr1a/b((−/−)) mice and no increased signal in Bcrp1((−/−)) mice. [(18)F]2 was selected as the best performing tracer and should be evaluated further in clinical studies.