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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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Abstract

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 [11C]MeNER.

Objectives

To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 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)-[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.

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)-[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.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, S-17176, Stockholm, Sweden

    Nicholas Seneca, Balázs Gulyás, Magnus Schou, Anu Airaksinen, Lars Farde & Christer Halldin

  2. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Nicholas Seneca & Robert B. Innis

  3. Biostructure and Bioimaging Institute, National Research Council, Napoli, Italy

    Andrea Varrone

  4. Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN, USA

    Johannes Tauscher & William Kielbasa

  5. Lilly Research Laboratories, Mont-Saint-Guibert, Belguim

    Francois Vandenhende

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  1. Nicholas Seneca
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Correspondence to Nicholas Seneca.

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Seneca, N., Gulyás, B., Varrone, A. et al. Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2 . Psychopharmacology 188, 119–127 (2006). https://doi.org/10.1007/s00213-006-0483-3

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

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