The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.
Synapse 58:173-183, 2005. (c) 2005 Wiley-Liss, Inc.