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Quantification of ¹¹C-MADAM Binding to the Serotonin Transporter in the Human Brain

¹ Department of Clinical Neuroscience, Section of Psychiatry, Karolinska Institutet, Stockholm, Sweden
² Department of Sensory and Integrative Medicine, Division of Functional Imaging, Niigata University Graduate School of Medicine and Dental Sciences, Asahimachi-dori Niigata, Japan

¹¹C-N,N-Dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (¹¹C-MADAM) is a newly synthesized radioligand with high selectivity and specificity for the serotonin transporter (5-HTT) in a monkey model. The purpose of this study in humans was to examine the suitability and potential of ¹¹C-MADAM for quantitative PET studies of 5-HTT in applied clinical studies on the pathophysiology and treatment of neuropsychiatric disorders. Methods: PET examination was performed on each of 9 male subjects after intravenous injection of ¹¹C-MADAM with high specific radioactivity. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. A metabolite-corrected arterial input function was used in kinetic 2- and 3-compartment analyses. Cerebellum was used as the reference region in a cross-validation of 6 reference tissue approaches. Results: The highest radioactivity concentration was detected in the raphe nuclei, followed consecutively by the striatum, hippocampal complex, cingulate cortex, neocortex, and cerebellum. The time–activity curve for the fraction of unchanged ¹¹C-MADAM in plasma was best described by a sigmoid function. After 50 min, the fraction was 40%. The labeled metabolites were more polar than the mother compound. The compartment model approaches converged, and could describe the time–activity curves in all regions. The total volume of distribution (V_t) was similar to the regional distribution volumes obtained by the linear graphic analysis. The binding potentials (BPs) for 6 different approaches yielded similar values in all regions but the raphe nuclei, where the 2 equilibrium methods provided lower values. Conclusion: The regional binding distribution of ¹¹C-MADAM is consistent with postmortem data acquired with ³H-MADAM as well as with that of other reference ligands in vitro. The time–activity curves were well described by current major quantitative approaches. The suitability of the cerebellum as a reference region for nonspecific ¹¹C-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model, for applied clinical studies.

Key Words: brain • humans • serotonin transporter • serotonin • PET

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