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

• Published in: Psychopharmacologia Vol. 188; no. 1; pp. 119 - 127
• Main Authors: Seneca, Nicholas, Gulyás, Balázs, Varrone, Andrea, Schou, Magnus, Airaksinen, Anu, Tauscher, Johannes, Vandenhende, Francois, Kielbasa, William, Farde, Lars, Innis, Robert B., Halldin, Christer
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.09.2006; Springer Nature B.V
• Subjects: Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - blood; Adrenergic Uptake Inhibitors - pharmacokinetics; Animals; Atomoxetine Hydrochloride; Binding, Competitive; Biological and medical sciences; Brain; Brain - metabolism; Dose-Response Relationship, Drug; Fluorine Radioisotopes; Inhibitor drugs; Macaca fascicularis; Measurement techniques; Medical sciences; Morpholines; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Pharmacology; Positron-Emission Tomography; Primates; Propylamines - administration & dosage; Propylamines - blood; Propylamines - pharmacokinetics; Protein Binding; Tomography; Psychotropic; Central nervous system; Monkey; Atomoxetine, Norepinephrine transporter occupancy; Catecholamine; Reuptake inhibitor; Encephalon; Dose activity relation; (S,S)-[18F]FMeNER-D2; Vertebrata; Mammalia; Atomoxetine; Animal; Neurotransmitter; Primates; Nonhuman primate brain; Norepinephrine; PET; Emission tomography
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-006-0483-3

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.