Synthesis and Characterization of Iodine-123 Labeled 2β-Carbomethoxy-3β-(4‘-((Z)-2-iodoethenyl)phenyl)nortropane. A Ligand for in Vivo Imaging of Serotonin Transporters by Single-Photon-Emission Tomography

Abstract

2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [(123)I]ZIENT and [(123)I]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield (decay-corrected to end of bombardment (EOB)), respectively, by preparation of the precursor carbomethoxy-3beta-(4'-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [(123)I]iodide and hydrogen peroxide in ethanolic HCl. Competition binding in cells stably expressing the transfected human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET) using [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively, demonstrated the following order of SERT affinity (K(i) in nM): ZIENT (0.05) > nor-CIT (0.12) >> EIENT (1.15) > fluvoxamine (1.46). The affinity of ZIENT and EIENT for DAT was 69 and 1.6-fold lower, respectively, than for SERT. In vivo biodistribution and blocking studies were performed in male rats and demonstrated that the brain uptake of [(123)I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [(123)I]ZIENT in a cynomolgus monkey, radioactivity was reduced by 39% in the diencephalon at 101 min following injection of citalopram. The high specific activity one-step radiolabeling preparation and high selectivity of [(123)I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.

Effects of Dopamine Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys: Relationship to Transporter Occupancy Determined by Positron Emission Tomography Neuroimaging

“…Both ZIENT and FECNT are nortropane derivatives that exhibit similar physiochemical properties appropriate for PET imaging of transporter occupancy. ZIENT is a potent ligand for imaging the SERT (K i ϭ 0.05 nM) with high selectivity over DAT and NET (Goodman et al, 2003). The kinetic analysis was performed using the same programs and methods that were used to analyze the [ 18 F]FECNT data Votaw et al, 2002).…”

Development of SPECT imaging agents for the norepinephrine transporters: [123I]INER

“…Research on quantitative mapping of dopamine transporter (DAT) and serotonin transporter (SERT) related to various CNS disorders has benefited from the availability of suitable radioligands (e.g., β-CIT as DAT radioligand, 13,14 and DASB or ZIENT as SERT radioligands 15,16 ). In contrast, brain imaging of NET has been hampered by lack of a suitable radioligand.…”

Radiotracers for SPECT imaging: current scenario and future prospects

“…This high selectivity using trilalkyltin derivatives facilitates the introduction of the iodine-123 to label alkenes with retention of configuration across the double bond [27] as seen in Fig. 5.…”