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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 10, 2003; DOI: 10.1124/jpet.103.058636

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Received for publication August 14, 2003.
Revised October 18, 2003.
Accepted for publication October 28, 2003.

Pharmacologic and Genetic Characterization of Two Selective Serotonin Transporter Ligands: 2-[2- (dimethylaminomethylphenylthio)]-5- fluoromethylphenylamine (AFM) and 3-amino-4-[2- (dimethylaminomethylphenylthio)]benzonitrile (DASB)

Qian Li 1*, Li Ma 2, Robert B. Innis 3, Nicholas Seneca 3, Masanori Ichise 3, Henry Huang 4, Marc Laruelle 4, Dennis L. Murphy 3

1 University of Texas Medical Branch 2 National institute of Mental Health, NIH 3 National Institute of Mental Health, NIH 4 Columbia University

* Address correspondence to: E-mail: qili{at}utmb.edu

Abstract

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 and DASB, have recently been developed for PET imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of 3H-AFM or 3H- DASB binding was compared in the brains of mice with genetically normal, diminished or absent 5-HT transporters. 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 (SRIs). 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.


Key words: autoradiography, competition study, fenfluramine, knockout mice, serotonin receptors, serotonin reuptake inhibitors


This article has been cited by other articles:


Home page
 Mol. Interv.Home page
D. L. Murphy, A. Lerner, G. Rudnick, and K.-P. Lesch
Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics
Mol. Interv., April 1, 2004; 4(2): 109 - 123.
[Abstract] [Full Text] [PDF]


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