Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[(18)F]FMeNER-D (2).
OBJECTIVE
In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner.


METHODS
Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[(18)F]FMeNER-D(2) under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP(ND) obtained with the simplified reference tissue model.


RESULTS
NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml.


CONCLUSIONS
The results indicate that clinical doses of atomoxetine would occupy NET almost completely.
Takano
Akihiro
A
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, S-171 76, Stockholm, Sweden. Akihiro.takano@ki.se
Gulyás
Balázs
B
Varrone
Andrea
A
Maguire
Ralph Paul
RP
Halldin
Christer
C
D018685:Anesthetics, Inhalation; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D011851:Radioactivity; D014018:Tissue Distribution
C506462:2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine; D018685:Anesthetics, Inhalation; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride