FlipADAM: a potential new SPECT imaging agent for the serotonin transporter

Abstract

Single photon emission computed tomography (SPECT) imaging of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiological functions and disease states involving the serotonergic system. The goal of this study was to develop an improved SPECT radiotracer with faster kinetics than the current leading SPECT tracer, [(123)I]ADAM, for selective SERT imaging. The in vitro binding affinities of (2-(2'-((dimethylamino)methyl)-4'-iodophenylthio)benzenamine) (FlipADAM) (1c), were determined using Hampshire pig kidney cells stably overexpressing the serotonin, norepinephrine (NET) or dopamine transporter (DAT). Localization of [(125)I]FlipADAM (1c) was evaluated through biodistribution and autoradiography in male Sprague Dawley rats, and the specificity of binding was assessed by injecting selective SERT or NET inhibitors prior to [(125)I]FlipADAM (1c). FlipADAM (1c) displayed a high binding affinity for SERT (K(i)=1.0 nM) and good selectivity over NET and DAT binding (43-fold and 257-fold, respectively). [(125)I]FlipADAM (1c) successfully penetrated the blood brain barrier, as evidenced by the brain uptake at 2 min (1.75% dose/g). [(125)I]FlipADAM(1c) also had a good target to non-target (hypothalamus/cerebellum) ratio of 3.35 at 60 min post-injection. In autoradiography studies, [(125)I]FlipADAM (1c) showed selective localization in SERT-rich brain regions such as the thalamic nuclei, amygdala, dorsal raphe nuclei and other areas. [(125)I]FlipADAM (1c) exhibited faster clearance from the brain and time to binding equilibrium when compared to [(125)I]2-(2'-((dimethylamino)methyl)-phenylthio)-5-iodophenylamine [(125)I]ADAM (1b) and a higher target to non-target ratio when compared to [(125)I]5-iodo-2-(2'-((dimethylamino)methyl)-phenylthio)benzyl alcohol [(125)I]IDAM (1a). Therefore, [(123)I]FlipADAM (1c) may be an improved SPECT tracer for imaging SERT.