Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2

Psychopharmacology (Berl). 2006 Sep;188(1):119-27. doi: 10.1007/s00213-006-0483-3. Epub 2006 Aug 4.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / blood
  • Adrenergic Uptake Inhibitors / pharmacokinetics*
  • Animals
  • Atomoxetine Hydrochloride
  • Binding, Competitive
  • Brain / metabolism*
  • Dose-Response Relationship, Drug
  • Fluorine Radioisotopes
  • Macaca fascicularis
  • Morpholines
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Positron-Emission Tomography*
  • Propylamines / administration & dosage
  • Propylamines / blood
  • Propylamines / pharmacokinetics*
  • Protein Binding


  • 2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine
  • Adrenergic Uptake Inhibitors
  • Fluorine Radioisotopes
  • Morpholines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Propylamines
  • Atomoxetine Hydrochloride