PT  - JOURNAL ARTICLE
AU  - Yu-Shin Ding
AU  - Mika Naganawa
AU  - Jean-Dominique  Gallezot
AU  - David Weinzimme
AU  - Paul Maguire
AU  - Henry Huang
AU  - Richard Carson
AU  - Marc Laruelle
TI  - Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transporters (NET and SERT): Implications for treatment of depression and ADHD
DP  - 2009 May 01
TA  - Journal of Nuclear Medicine
PG  - 486--486
VI  - 50
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/50/supplement_2/486.short
4100  - http://jnm.snmjournals.org/content/50/supplement_2/486.full
SO  - J Nucl Med2009 May 01; 50
AB  - 486 Objectives Atomoxetine (ATX), a drug for depression and ADHD, has high affinity for NET; yet, our previous study showed it blocked [11C]DASB binding similar to fluoxetine (SSRI). Whether ATX therapeutic effects are due to inhibition on NET or both NET and SERT is not known. Here we report our comparative PET studies with [11C]MRB (NET ligand) and [11C]AFM (SERT ligand) to evaluate in vivo IC50 of ATX in monkeys. Methods Rhesus monkeys were scanned four times with each tracer (baseline, low, med. & high doses). ATX infusion began 2 h before each scan, lasting until the end of the 2 h scan. Infusion rates ranged 0.01-0.12 mg/kg/h and 0.045-1.054 mg/kg/h for NET and SERT studies, respectively. ATX plasma levels and arterial input functions were measured. Distribution volumes and IC50 values were estimated. Results ATX displayed dose-dependent occupancy with IC50 of 28 ng/mL plasma (infusion 0.015 mg/kg/h) and 167 ng/mL plasma (infusion 0.126 mg/kg/h) for NET and SERT, respectively. Occupancy of 74% NET and 26% SERT occurred at 0.21 mg/kg. At a therapeutic dose (1.8 mg/kg, 600 ng/mL plasma) ATX occupied 80% of SERT. Conclusions Our data shows in vivo ATX IC50 ratio of 6 for SERT to NET, consistent with reported in vitro affinity (Kd) ratio of 4.5 (8.9 and 2 nM for SERT and NET, respectively), suggesting that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, ATX treatment of depression and ADHD may be more complex than selective blockade of NET. Further studies on the mechanisms are needed.