title: Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, S-17176, Stockholm, Sweden. Nicholasseneca@mail.nih.gov
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.forename: Anu
authors.initials: A
authors.lastname: Airaksinen
authors.forename: Johannes
authors.initials: J
authors.lastname: Tauscher
authors.forename: Francois
authors.initials: F
authors.lastname: Vandenhende
authors.forename: William
authors.initials: W
authors.lastname: Kielbasa
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D008252:Macaca fascicularis; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding
chemical_list: C506462:2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine; D018759:Adrenergic Uptake Inhibitors; D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride