2-(2′-((Dimethylamino)methyl)-4′-(fluoroalkoxy)-phenylthio)benzenamine Derivatives as Serotonin Transporter Imaging Agents

Abstract

A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4′-position on phenyl ring B of 2-(2′-((dimethylamino)methyl)-4′-(fluoroalkoxy)phenylthio)benzenamine (4′-2-fluoroethoxy derivatives 28–31 and 4′-3-fluoropropoxy derivatives 40–42) were prepared and tested as serotonin transporter (SERT) imaging agents. The new ligands displayed high binding affinities to SERT (K_i ranging from 0.03 to 1.4 nM). The corresponding ¹⁸F labeled compounds, which can be prepared readily, showed excellent brain uptake and retention after iv injection in rats. The hypothalamus region showed high uptake values between 0.74% and 2.2% dose/g at 120 min after iv injection. Significantly, the hypothalamus to cerebellum ratios (target to nontarget ratios) at 120 min were 7.8 and 7.7 for [¹⁸F]28 and [¹⁸F]40, respectively. The selective uptake and retention in the hypothalamus, which has a high concentration of SERT binding sites, demonstrated that [¹⁸F]28 and [¹⁸F]40 are promising positron emission computed tomography imaging agents for mapping SERT binding sites in the brain.