Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD Y.-S. Ding a,d, ⁎, M. Naganawa a , J.-D. Gallezot a , N. Nabulsi a , S.-F. Lin a , J. Ropchan a , D. Weinzimmer a , T.J. McCarthy b , R.E. Carson a , Y. Huang a , M. Laruelle c a Department of Diagnostic Radiology, Yale University, New Haven, CT, USA b Pfizer Global R&D, Groton, CT, USA c New Medicines, UCB Pharma S.A., Brussels, Belgium d Department of Psychiatry and Radiology, New York University, New York, NY, USA abstract article info Article history: Accepted 1 August 2013 Available online 9 August 2013 Keywords: Atomoxetine Attention deficit hyperactivity disorder Depression Norepinephrine transporter Serotonin transporter Positron emission tomography Background: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepi- nephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [ 11 C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [ 11 C]MRB (a NET ligand) and [ 11 C]AFM (a SERT ligand) to evaluate in vivo IC 50 values of ATX in monkeys. Methods: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2 h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01–0.12 mg/kg/h and 0.045–1.054 mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (V T ) and IC 50 values were estimated. Results: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC 50 of 31 ± 10 and 99 ± 21 ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0–1.8 mg/kg, approx. 300–600 ng/mL plasma), ATX would occupy N 90% of NET and N 85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. Conclusion: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET. © 2013 Published by Elsevier Inc. Introduction Atomoxetine (ATX, Strattera) is the first non-stimulant drug that was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) (Arnsten, 2006; Bymaster et al., 2002; Chamberlain et al., 2007a; Del Campo et al., 2011; Michelson et al., 2001; Swanson et al., 2006; Volkow et al., 2001). It has also been used to improve responses to treatment of depression (Dell'Osso et al., 2010; O'Sullivan et al., 2009). The majority of medications currently used in the treatment of ADHD or depression act to increase brain catecholamine levels; e.g., do- pamine (DA), norepinephrine (NE) and serotonin. However, the precise mechanisms that are responsible for the therapeutic effects of these medications remain elusive. For example, based on the current literature, the therapeutic effects of methylphenidate, the most common treatment for ADHD, are due mostly to its dopamine transporter (DAT) inhibition. However, our recent in vivo PET imaging study demonstrated, for the first time in humans, that oral methylphenidate significantly occupies norepinephrine transporter (NET) at clinically relevant doses with an ED 50 of 0.14 mg/kg, which is lower than that for DAT (0.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in ADHD (Hannestad et al., 2010). ATX is another effective drug for the treatment of ADHD, belonging to a different structural class than methylphenidate (being a distant relative of tricyclics). It is thought that ATX acts via blockade of the presynaptic norepinephrine transporter (NET) in the brain; however, our previous study showed that it had a blocking effect similar to fluoxetine (a selec- tive serotonin transporter [SERT] inhibitor) on binding of [ 11 C]DASB (Ding and Fowler, 2005), a selective SERT ligand with a Ki value of 1.77 nM (Houle et al., 2000). These results suggested that ATX not only binds to NET, but also binds to SERT with high affinity. To date, whether the therapeutic effects of ATX in the treatment of either ADHD or depres- sion are due to inhibitory effects on one (NET) or two transporters (NET NeuroImage 86 (2014) 164–171 ⁎ Corresponding author at: New York University School of Medicine, 660 First Avenue, 4th Floor, New York, NY 10016, USA. Fax: +1 212 263 7541. E-mail addresses: yu-shin.ding@nyumc.org, yushin.ding@nyu.edu (Y.-S. Ding). 1053-8119/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.neuroimage.2013.08.001 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg