Synthesis and evaluation of new fluorine-18 labeled verapamil analogs to investigate the function of P-glycoprotein in the blood-brain barrier

Raaphorst, R. M., Luurtsema, G., Schuit, R. C., Kooijman, E. J. M., Elsinga, P. H., Lammertsma, A. A. & Windhorst, A. D. 26-Jun-2017 In : ACS chemical neuroscience.

Research output: Scientific - peer-reviewArticle

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 silvertrilate 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 117.2 ± 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 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.

Original languageEnglish
JournalACS chemical neuroscience
StateE-pub ahead of print - 26-Jun-2017


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