Evaluation of [ 11C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates

[ 11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [ 11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [ 11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [ 11C]MRB volume of distribution was observed after correction for [ 11C]MRB plasma free fraction. ATX IC 50 was estimated to be 31 ± 10 ng/mL plasma. This corresponds to an effective dose ( ED 50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5 mg/kg). [ 11C]MRB binding potential BP ND in the thalamus was estimated to be 1.8 ± 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21 ± 3 ng/mL (using caudate as the reference region). This study demonstrated that [ 11C]MRB is suitable for drug occupancy studies of NET. ► Atomoxetine induced a dose-dependent decrease of [11C]MRB binding. ► Atomoxetine IC50 was estimated to be 31 ± 10 ng/mL plasma. ► [11C]MRB binding potential (BPND) in the thalamus was estimated to be 1.8 ± 0.3. ► [11C]MRB is suitable for drug occupancy studies.