Synthesis, radiosynthesis, and biological evaluation of carbon-11 and iodine-123 labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes: candidate radioligands for in vivo imaging of the serotonin transporter

2beta-Carbomethoxy-3beta-4'-((Z)-2-iodoethenyl)phenyl]tropane (ZIET) and 2beta-carbomethoxy-3beta-4'-((Z)-2-bromoethenyl)phenyl]tropane (ZBrET) were synthesized as well as their nortropane congeners ZIENT and ZBrENT. Binding affinities of these compounds were determined in cells transfected to express human SERT, DAT, and NET using 3H]citalopram, 125I]RTI-55, and 3H]nisoxetine, respectively. Both ZIET and ZBrET displayed high affinity for the SERT (Ki = 0.11 and 0.08 nM, respectively).The affinities of ZIET and ZBrET for the DAT were 200 and 38-fold lower, respectively, than for the SERT. 11C]ZIET and 11C]ZBrET were prepared by alkylation of their corresponding nortropanes with 11C]methyl iodide in approximately 30% radiochemical yield (decay-corrected to end of bombardment, EOB). High specific activity 123I]ZIET was synthesized in 33% radiochemical yield (decay-corrected) by treating the 2beta-carbomethoxy-3beta-4'-((Z)-2-trimethylstannylethenyl)phenyl]tropane (3) with no carrier-added sodium 123I]iodide and hydrogen peroxide in ethanolic HCl. Biodistribution studies in rats indicated that 123I]ZIET enters the brain readily and accumulates in SERT-rich regions. Blocking studies performed in rats demonstrated that 123I]ZIET was selective and specific for SERT-rich regions (e.g. thalamus, brainstem, and striatum). MicroPET brain imaging studies in monkeys demonstrated that 11C]ZIET and 11C]ZBrET uptakes were selectivity localized in the putamen, midbrain, caudate, thalamus, pons, and medulla. Radioactivity in the regions of high SERT density of monkey brain was displaceable with citalopram except in the putamen and caudate. Radioactivity uptake in these DAT-rich regions was significantly displaceable either by preadministration of citalopram followed by injection of RTI-113 (or vice-versa) or by administration of a mixture of DAT and SERT ligands. In conclusion, the high yield, high specific activity, one-step radiolabeling method, high selectivity and favorable kinetics, and the good results obtained with 123I]ZIET in rats support the candidacy of 11C]ZIET for in vivo visualization and quantification of brain SERT.