Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[F-18]FMeNER-D-2

: Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, Vandenhende F, Kielbasa W, Farde L, Innis RB, Halldin C

Publisher: SPRINGER

: 2006

: Psychopharmacology

: PSYCHOPHARMACOLOGY

: 188

: 1

: 119

: 127

: 9

: 0033-3158

DOI: https://doi.org/10.1007/s00213-006-0483-3

Rationale Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Previous positron emission tomography (PET) studies had failed to demonstrate the feasibility of measuring a dose-dependent and saturable NET occupancy in human brain using [C-11]MeNER.Objective To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[F-18]FMeNER-D-2 in nonhuman primate brain.Methods A total of eight PET measurements were performed in two cynomolgus monkeys. Each monkey was examined four times with PET: under baseline conditions and after steady-state infusion with 0.03, 0.06, or 0.12 mg/kg/h of atomoxetine. A prolonged intravenous (i.v.) infusion design was developed rather than an i.v. bolus to better mimic an oral absorption profile and to reach plasma steady state.Results During baseline conditions, (S,S)-[F-18]FMeNER-D-2 uptake was highest in the locus coeruleus, thalamus, mesencephalon, and the cingulate gyrus, whereas the radioactivity in the caudate was low. Peak equilibrium measurements were achieved using (S,S)-[F-18]FMeNER-D-2 in contrast to the previously reported data for [C-11]MeNER. After administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET.Conclusions This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[F-18]FMeNER-D-2. Furthermore, an asymptotic relationship between N-desmethylatomoxetine plasma concentration and NET occupancy was established. In total, these data encourage further PET studies using (S,S)-[F-18]FMeNER-D-2 in humans.