Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2
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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 [11C]MeNER.
To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain.
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.
During baseline conditions, (S,S)-[18F]FMeNER-D2 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)-[18F]FMeNER-D2 in contrast to the previously reported data for [11C]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.
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)-[18F]FMeNER-D2. 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)-[18F]FMeNER-D2 in humans.
KeywordsAtomoxetine Norepinephrine transporter occupancy PET Nonhuman primate brain (S,S)-[18F]FMeNER-D2
This study was sponsored by the Eli Lilly and Co., Indianapolis, IN, USA. The authors would like to thank Eli Lilly Research Laboratories for providing the precursor, standard, and atomoxetine. We are appreciative of G. Douglas Ponsler from Eli Lilly Research Laboratories and Heather Coales from SFBC Taylor for their bioanalytical support. We are also grateful to the members of the Karolinska PET psychiatry group for their assistance in the PET experiments. Andrea Varrone was supported by a grant from the “Short-Term Mobility Program” of the National Research Council of Italy. Nicholas Seneca and Magnus Schou are graduate students in the NIH–Karolinska Institutet joint Ph.D. program in neuroscience, and this research was supported in part by the Intramural Research Program of the NIH, National Institute of Mental Health, Bethesda, Maryland, USA.
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