Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter.

The tricyclic tropane analogues (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane, 1, and (1S,3S,6R,10S)-(Z)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane-10-carboxylic acid methyl ester, 2, have been shown to be potent and selective serotonin transporter (SERT) ligands. They possess nanomolar affinity for the SERT (Ki = 0.06 nM and 1.8 nM respectively) and are suitable for radiolabelling using iodine-123. In the present study we prepared [(123)I]1 and [(123)I]2 from the appropriate tributylstannane precursors using acidic media with chloramine-T as the oxidising agent. The radiochemical yield obtained for [(123)I]1 varied between 50-60% while for [(123)I]2 the range was 65-80%. Both radioligands were obtained with radiochemical purity > 97% and specific activity estimated to be > 185 GBq/micromol. The biodistribution of [(123)I]1 demonstrated low degree of brain penetration at 5 min (0.14%ID/g) with a homogeneous distribution. The radioactivity cleared quickly from all brain regions with no preferential localization. In comparison, [(123)I]2 demonstrated on average a higher brain uptake at 5 min (0.5%ID/g). However the distribution of radioactivity was homogeneous and cleared to levels similar to [(123)I]1 at 1 hr post-injection. Pre-administration of citalopram failed to show any significant inhibition of [(123)I]2 uptake in the rat brain. The high lipophilicity of 1 and 2 (HPLC-derived log P(7.4) values of 6.41 and 4.25 respectively) and in vivo metabolism, seen by high thyroid uptake would explain the absence of any specific binding observed in the rat brain. In view of these results [(123)I]1 and [(123)I]2 do not appear to be suitable radioligands for in vivo studies of the SERT.