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

Abstract

[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 IC50 was estimated to be 31±10 ng/mL plasma. This corresponds to an effective dose (ED50) 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 BPND 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 IC50 estimate obtained using MRTM2 BPND 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.

Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus

“…This is consistent with the known distribution of the NET in brain. 17,21 This PET tracer has been shown to be useful in NET occupancy studies 22,23 of atomoxetine hydrochloride and methylphenidate, which have demonstrated its use in measuring NET availability in vivo.…”

PET imaging evaluation of [18F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates

“…Thus correction for the free fraction of parent in plasma may be critical for accurate quantification of [ 18 F]DBT-10. The use of V T / f P as a more stable outcome measure than V T has been previously reported for PET radioligands in other neurotransmitter systems [26]. Importantly, the [ 18 F]DBT-10 f P values, ranging from 15–22% at baseline, are sufficiently large for reliable measurement, thus the need to correct for f P should not impede the accurate quantification of [ 18 F]DBT-10 binding.…”

Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory

“…ATX is a selective pre-synaptic NET blocker affecting NE and DA in the prefrontal cortex (Bymaster et al 2002) and NE in the thalamus, locus coeruleus and cerebellum, with minimal striatal effects (Gallezot et al 2011).…”