title: Evaluation of [(11)C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates.
abstract: [(11)C]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 [(11)C]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. [(11)C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [(11)C]MRB volume of distribution was observed after correction for [(11)C]MRB plasma free fraction. ATX IC(50) was estimated to be 31 ± 10ng/mL plasma. This corresponds to an effective dose (ED(50)) of 0.13mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0-1.5mg/kg). [(11)C]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 ± 3ng/mL (using caudate as the reference region). This study demonstrated that [(11)C]MRB is suitable for drug occupancy studies of NET.
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT 06520, USA. jean-dominique.gallezot@yale.edu
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.forename: David
authors.initials: D
authors.lastname: Weinzimmer
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.forename: Krista
authors.initials: K
authors.lastname: Fowles
authors.forename: Christine
authors.initials: C
authors.lastname: Sandiego
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McCarthy
authors.forename: R Paul
authors.initials: RP
authors.lastname: Maguire
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D018759:Adrenergic Uptake Inhibitors; D002250:Carbon Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D019275:Radiopharmaceuticals; D000069445:Atomoxetine Hydrochloride