Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1′-fluoro-2-propoxy-3β-(4-chlorophenyl) tropanes.: Ligands for the imaging of dopamine transporters by positron emission tomography

2 beta-(R)-Carbo-1-fluoro-2-propoxy-3 beta-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2 beta-(S)-carbo-1-fluoro-2-propoxy-3 beta-(4-chlorophenyl)tropane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [F-18](R)-FIPCT and [F-18](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2 beta-carbo-R-1-mesyloxy-2-propoxy-3 beta-(4-chlorophenyl)tr (R-12) and 2 beta-carbo-S-1-mesyloxy-2-propoxy-3 beta-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[F-18]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [H-3]WIN 35428 and [H-3]-citalopram, respectively, demonstrated the following order of DAT affinity (K-i in nM): GBR 12909 (0.36) > CIT(0.48) > (S)-FIPCT(0.67) much greater than (R)-FIPCT (3.2). The affinity of(S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [F-18](R)-FIPCT and [F-18](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [F-18](R)-FIPCT and [F-18](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [F-18](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [F-18](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [F-18](R)-FIPCT and [F-18](S)-FIPCT for DAT indicate [F-18](R)-FIPCT and [F-18](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.