SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study

Abstract

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressants which have high affinity to both serotonin transporter (SERT) and norepinephrine transporter (NET). In studies in vitro, SNRIs have been reported to show a large variability in the affinity ratio between SERT and NET. For instance, the reported affinity ratio is about 30 for venlafaxine and 1.6 for milnacipran. In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran. PET measurements with [(11)C]MADAM and [(18)F]FMeNER-D(2) were performed in two female cynomolgus monkeys at baseline and after pretreatment with venlafaxine and milnacipran, respectively. Relationships between dose, plasma concentration, and transporter occupancy were evaluated by saturation analysis using a hyperbolic function. Binding affinity (Kd(plasma)) was expressed by the dose or plasma concentration at which 50% of the transporter was occupied. SERT and NET occupancy by venlafaxine and milnacipran increased in a dose and plasma concentration-dependent manner. The Kd(plasma) ratio of SERT to NET was 1.9 for venlafaxine and 0.6 for milnacipran. In this nonhuman primate PET study, the affinity in vivo for SERT and NET, respectively, was shown to be at a similar level for venlafaxine and milnacipran. Both drugs were found to produce balanced inhibition of SERT and NET binding. This observation is not consistent with previous in vitro binding data and illustrates the need to characterize antidepressants at in vivo condition.