RT Journal Article
SR Electronic
T1 Pharmacological and Genetic Characterization of Two Selective Serotonin Transporter Ligands: 2-[2-(Dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (AFM) and 3-Amino-4-[2-(dimethylaminomethyl-phenylthio)]benzonitrile (DASB)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 481
OP 486
DO 10.1124/jpet.103.058636
VO 308
IS 2
A1 Qian Li
A1 Li Ma
A1 Robert B. Innis
A1 Nicholas Seneca
A1 Masanori Ichise
A1 Henry Huang
A1 Marc Laruelle
A1 Dennis L. Murphy
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/481.abstract
AB The expression and function of the serotonin transporter (SERT) is important in the regulation of mood and emotion. Determination of SERT alterations in physiological and pathological states is essential for understanding the role of SERT in mood regulation, and in the etiology and therapy of psychiatric disorders. Two SERT ligands, AFM ([3H]2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine) and DASB ([3H]3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile), have recently been developed for positron emission tomography (PET) imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of AFM or DASB binding was compared in the brains of mice with genetically normal, diminished, or absent SERT. In addition, the pharmacodynamic profile of [3H]AFM was examined in the mouse brain. The distribution of [3H]AFM and [3H]DASB binding in the normal brains was consistent with that of previously studied serotonin reuptake inhibitors. Both ligands had negligible binding in the brain of SERT knockout mice, and binding was reduced approximately 50% in heterozygote SERT mice. The Kd of [3H]AFM binding in the cortex and midbrain was 1.6 and 1.0 nM, respectively. Competition studies showed that [3H]AFM has very low affinity for norepinephrine and dopamine transporters as well as 5-HT receptors, including 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors. In addition, fenfluramine showed a low capability to compete with [3H]AFM. The present results suggest that both AFM and DASB are highly selective SERT ligands potentially suitable for use in human PET studies of SERT. The American Society for Pharmacology and Experimental Therapeutics