1. ¹Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK
2. ²Icon Development Solutions, Manchester, UK
3. ³Manchester Academic Health Science Centre, Stopford Building, The University of Manchester, Manchester, UK
4. ⁴Manchester Academic Health Science Centre, Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK

Correspondence: Dr PS Talbot, Wolfson Molecular Imaging Centre, The University of Manchester, 27 Palatine Road, Withington, Manchester, Greater Manchester, M20 3LJ, UK, Tel: +440 161 275 0015, Fax: +440 161 275 0003, E-mail: peter.talbot@manchester.ac.uk

Received 30 July 2009; Revised 2 October 2009; Accepted 6 October 2009; Published online 4 November 2009.

Abstract

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. ¹¹C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP_ND) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 3010%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25–46%). However, several subjects with occupancy (36–39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.