Human brain imaging of nicotinic acetylcholine ?4?2* receptors using [18 F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways.
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ABSTRACT: 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 [18 F]Nifene, a fast acting PET imaging agent for ?4?2* nAChRs. Nifene had subnanomolar affinities for h?2?2 (0.34 nM), h?3?2 (0.80 nM) and h?4?2 (0.83 nM) nAChR but weaker (27-219 nM) for h?4 nAChR subtypes and 169 nM for h?7 nAChR. In functional assays, Nifene (100 ?M) 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 ?g/kg/day (278 ?g/m2 /day). In human PET studies, [18 F]Nifene (185 MBq; <0.10 ?g) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18 F]Nifene in white matter thalamic radiations were ?1.6 (anterior) and ?1.5 (superior longitudinal fasciculus). Habenula known to contain ?3?2 nAChR exhibited low levels of [18 F]Nifene binding while the red nucleus with ?2?2 nAChR had DVR ?1.6-1.7. Females had higher [18 F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18 F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18 F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18 F]Nifene PET may be used to study ?4?2* nAChRs in various CNS disorders and for translational research.
SUBMITTER: Mukherjee J
PROVIDER: S-EPMC5788574 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
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