In Vivo Characterization of a Series of 18F-Diaryl Sulfides (18F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Abstract

PET of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiologic functions as well as disease states involving the serotonergic system. The goal of this study was to further develop and refine a series of 4'-fluoroalkoxy-substituted, (18)F-radiolabeled SERT imaging agents. 2-(2'-((Dimethylamino)methyl)-4'-(4-(18)F-fluorobutoxy)phenylthiol)benzenamine (3) and 2-(2'-((dimethylamino)methyl)-4'-(5-(18)F-fluoropentoxy)phenylthiol)benzenamine (4) were synthesized and evaluated along with 2 previously reported compounds of this series, 2-(2'-((dimethylamino)methyl)-4'-(2-(18)F-fluoroethoxy)phenylthiol)benzenamine (1) and 2-(2'-((dimethylamino)methyl)-4'-(3-(18)F-fluoropropoxy)phenylthiol)benzenamine (2). The in vitro binding affinities of compounds 3 and 4 were determined in monoamine transporter-transfected LLC-PK(1) cell homogenates. In vivo localization of the respective (18)F-labeled compounds was evaluated by biodistribution studies in male Sprague-Dawley rats. Compound 3 was selected for further examination by autoradiographic and PET studies in rats. The corresponding mesylate precursors of 3 and 4 were radiolabeled with (18)F within 75-90 min. Radiochemical yield was 6%-35%, specific activity was 15-170 GBq/mumol, and radiochemical purity was greater than 97% (end of synthesis). The compounds showed subnanomolar binding affinities for SERT (inhibition constants, 0.51 and 0.76 nM, respectively), had brain uptake at 2 min of 1.25 and 0.68 percentage injected dose per gram, respectively, and possessed high target-to-nontarget (hypothalamus-to-cerebellum) ratios at 120 min after injection (6.51 and 5.70, respectively). Autoradiographic studies of (18)F-3 showed selective localization in SERT-rich brain regions. PET studies of (18)F-3 showed clear localization in the midbrain, thalamus, and striatum. This compound series was found to have potential for producing a suitable (18)F-radiolabeled PET radiotracer for SERT. Compound 4, the pentoxy derivative, had the lowest brain uptake and target-to-nontarget ratio. Compound 3, the butoxy derivative, had a lower target-to-nontarget ratio than compounds 1 (ethoxy derivative) and 2 (propoxy derivative). Compounds 1 and 2 both hold promise as SERT radioimaging agents, but because of cost limitations, only compound 2 will be evaluated in further studies.