Viloxazine occupies the 5-HT2C receptor in the macaca fascicularis brain in vivo: A [11C]CIMBI-36 positron emission tomography study

Abstract

Efficacy of viloxazine ER (extended-release capsules; Qelbree®) for attention-deficit/hyperactivity disorder (ADHD) is attributed to its ability to increase extracellular norepinephrine and dopamine in the medial prefrontal cortex by inhibiting norepinephrine transporters (NET); however, studies also suggest potentially relevant activity at serotonin (5-HT) receptors. This positron emission tomography (PET) study in macaca fascicularis monkeys measured viloxazine binding to 5-HT2C/5-HT2A receptors based on displacement of the 5-HT2C/5-HT2A radioligand agonist [11C]CIMBI-36. Here viloxazine displaced [11C]CIMBI-36 at 5-HT2C receptors at a concentration 10- to 20-fold lower than at 5-HT2A receptors (EC50: 4.1 vs 45.1 μM, respectively), mirroring previously measured receptor binding affinities (Ki: 0.64 vs 16.3 μM, respectively). Monkey unbound viloxazine plasma concentrations during scans were compared to human unbound concentrations at doses used to treat ADHD. At these clinically relevant concentrations, receptor occupancy calculations (based on [11C]CIMBI-36 displacement) suggested relevant viloxazine occupancy at 5-HT2C (66.0-97.5%). Overall, results demonstrate that (in addition to NET inhibition) viloxazine acts on 5-HT2C receptors at concentrations clinically relevant for ADHD treatment, and these effects could therefore contribute to therapeutic activity.