Brain Serotonin Transporter Occupancy by Oral Sibutramine Dosed to Steady State: A PET Study Using super(11)C-DASB in Healthy Humans

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 15mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. super(11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP sub(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30 plus or minus 10%), 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