Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

Nicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27 to 219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14-day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2/day). In human PET studies, [18F]Nifene (185 MBq; 15% than males. No significant aging effect was observed in [18F]Nifene binding over 5 decades. In all species (mice, rats, monkeys and humans) thalamus showed highest [18F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research. This article is protected by copyright. All rights reserved.