Publication

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. Sep-2017 In : ACS chemical neuroscience. 8, 9, p. 1925-1936 12 p.

Research output: Scientific - peer-reviewArticle

P-glycoprotein is an efflux transporter located in the blood brain barrier. (R)-[C-11]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[F-18]fluoroethylverapamil ([F-18]1) and (R)-O-[F-18]fluoroethylnorverapamil ([F-18]2) has been described. [F-18]1 was obtained in reaction of (R)-norverapamil with the volatile [F-18]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% +/- 1.2%. [F-18]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, [F-18]1 and [F-18]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [F-18] 1 and [F-18]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 [F-18]1 and [F-18]2, PET scans in Mdri1a/b((-1-)), Bcrpl((-1-)), and WT mice were acquired, in which [F-18]2 showed a more specific brain uptake in MdrIa/b((-1-)) mice and no increased signal in Bcrpl((-/-)) mice. [F-18]2 was selected as the best performing tracer and should be evaluated further in clinical studies.

Original languageEnglish
Pages (from-to)1925-1936
Number of pages12
JournalACS chemical neuroscience
Volume8
Issue number9
Early online date26-Jun-2017
StatePublished - Sep-2017

    Keywords

  • P-gp, BCRP, positron emission tomography, blood-brain barrier, verapamil, F-18, ABC transporters, POSITRON-EMISSION-TOMOGRAPHY, DRUG-DRUG INTERACTIONS, PERFORMANCE EVALUATION, PRECLINICAL EVALUATION, HIGH-RESOLUTION, PET, TRANSPORTERS, TRACERS, RADIOPHARMACEUTICALS, QUANTIFICATION

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