5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

Two novel ligands with 4′ substitution on the Phenyl Ring B of biphenylthiol, 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine (7) and 2-(2′-((dimethylamino)methyl)-4′-methoxyphenylthio)-5-iodobenzenamine (8), were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (Ki=0.22±0.09 and 0.11±0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (Ki>1000 nM). The corresponding [125I]7 and [125I]8 were successfully prepared from tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after intravenous injection in rats (brain uptake was 1.77% and 0.98% dose/g for [125I]7, and 0.92% and 0.29% dose/g for [125I]8, at 2 and 120 min, respectively). Significantly, [125I]7 showed excellent uptake and prolonged retention in the hypothalamus, where SERT concentration was highest. The hypothalamus/cerebellum (HY/CB) ratios (target/background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 h, respectively. The HY/CB ratios for [125I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 h, respectively. Adding the 4′-iodo group to the Phenyl Ring B of Compound (7) appeared to reduce the rate of clearance from the brain, and kinetics favored uptake and retention in the hypothalamus. The localization of [125I]7 in the hypothalamus region in the rat brain could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), which are all selective SERT ligands (at 2 mg/kg iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 h after intravenous injection of [125I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggest that [123I]7 is a potential lead compound for developing new imaging agents targeting SERT-binding sites with single-photon emission computed tomography.