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Serotonin transporter (SERT) occupancy by oral sibutramine in the living human brain using 11C-DASB PET

¹ University of Manchester, Wolfson Molecular Imaging Centre, Manchester, United Kingdom ² University of Manchester, Division of Imaging Science & Biomedical Engineering, Manchester, United Kingdom ³ Icon Development Solutions, Manchester, United Kingdom

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Objectives: We present the first PET study of central SERT inhibition by the appetite suppressant drug sibutramine (SIB) in humans.

Methods: 12 healthy males completed a double-blind, placebo-controlled, within-subject crossover investigation of central SERT occupancy (using ¹¹C-DASB) by 15 mg/day of SIB at steady state. Correlations were measured between occupancy and i) plasma concentrations of SIB and its active metabolites M1 and M2; ii) food intake. PET scans were performed on the HRRT. Binding potentials (BP_ND) on placebo and SIB were calculated by Logan reference tissue (cerebellum) method.

Results: Baseline (placebo) BP_ND values were: brainstem 0.60±0.09; caudate 0.82±0.24; putamen 1.22±0.32; thalamus 1.25±0.31. Mean SERT occupancy was 30.0%±10.2% (range ~ 10%-50%). Occupancy was positively correlated (p=0.09) with plasma concentration of M2, but not with SIB or M1. All subjects with significant appetite suppression (n = 5) had occupancy in the upper range (~ 25-50%). Non-responders (n = 7) had occupancy across the whole range.

Conclusions: Our data support that: i) SERT occupancy by clinical doses of SIB can be measured accurately by ¹¹C-DASB PET and is of modest magnitude; ii) SERT occupancy is predominantly mediated by M2 in humans; iii) SERT occupancy may be necessary but not sufficient for SIB's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and norepinephrine transporters.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Talbot, P. Articles by Matthews, J. PubMed Articles by Talbot, P. Articles by Matthews, J.