F-18-labeled FECNT: A selective radioligand for PET imaging of brain dopamine transporters

Fluorine-18 labeled 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-(2-fluoro ethyl)nortropane (FECNT) was synthesized in the development of a dopamine t ransporter (DAT) imaging ligand for positron emission tomography (PET), The methods of radiolabeling and ligand synthesis of FECNT, and the results: o f the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [F-18]FECNT are described. Fluori ne-18 was introduced into 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-(2- fluoroethyl)nortropane (4) by preparation of 1-[F-18]fluoro-2-tosyloxyethan e (2) followed by alkylation of 2 beta-carbomethoxy-3 beta-(4-chlorophenyl) nortropane (3) in 21% radiochemical yield (decay corrected to end of bombar dment [EOB]), Competition binding in cells stably expressing the transfecte d human DAT serotonin transporter (SERT) and norepinephrine transporter (NE T) labeled by [H-3]WIN 35428, [H-3]citalopram, and [H-3]nisoxetine, respect ively, indicated the following order of DAT affinity: GBR 12909 > CIT >> 2 beta-carbomethoxy-3 beta-(4-chlorophenyl) -8-(3 -fluoropropyl) nortropane ( FPCT) > FECNT, The affinity of FECNT for SEPT and NET was 25- and 156-fold lower, respectively, than for DAT, Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brai n uptake of [F-18]FECNT was selective and specific for DAT-rich regions. PE T brain imaging studies in monkeys demonstrated high [F-18]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen- to-cerebellum ratios of 10.5 at 60 min. [F-18]FECNT uptake in the caudate/p utamen peaked in less than 75 min and exhibited higher caudate- and putamen -to-cerebellum ratios at transient equilibrium than reported for C-11-WIN 3 5,428, [C-11]CIT/RTI-55, or [F-18] beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined tha t there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [F-18]FECNT is a radioligand that is superior to C-11-WIN 35,428, [C-11]CIT/RTI-55, [F-18]b eta-CIT-FP, and [F-18]FPCT for mapping brain DAT in humans using PET. NUCL MED BIOL 27;1:1-12, 2000. (C) 2000 Elsevier Science Inc. All rights reserve d.