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

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 a4b2* nAChRs. Nifene had subnanomolar affinities for ha2b2 (0.34 nM), ha3b2 (0.80 nM) and ha4b2 (0.83 nM) nAChR but weaker (27-219 nM) for hb4 nAChR subtypes and 169 nM for ha7 nAChR. In functional assays, Nifene (100 lM) 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

[18F]FDG PET/CT Studies in Transgenic Hualpha-Syn (A53T) Parkinson’s Disease Mouse Model of α-Synucleinopathy

“…Nicotinic α4β2 receptors play a role in cognitive impairment and may be targets for neuroprotection in PD ( Perez-Lloret and Barrantes, 2016 ). Our goal is to use [ 18 F]nifene ( Mukherjee et al, 2018 ) and [ 18 F]nifrolene ( Pichika et al, 2013 ) to understand changes in nicotinic acetylcholinergic mechanisms in the A53T PD mice. Our previous work on dopamine D2/D3 receptors in the MPTP mice model of PD found exercise-induced increases in the receptor ( Vuckovic et al, 2010 ).…”

[18F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson’s Disease

“…[ 18 F]Nifrolene was found most suitable with PET scan times of 90 min to equilibrate and good target to nontarget ratios in brain regions. [ 18 F]Nifene 4 which lacks the fluoropropyl group, is more nicotine-like and has more agonist like properties [ 4 , 5 ]. Imaging of α4β2* nAChRs by SPECT is made possible by inclusion of iodine-123 at the 5-position in [ 123 I]niodene [ 6 ].…”

Enhanced Sensory–Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors

“…19,20 Enhanced sensory thalamocortical transmission also may involve nAChRs located in the subcortical white matter, where they act to enhance the speed and synchrony of axonal propagation. 17,21,22 Postsynaptic nAChRs also occur throughout cortex and act to increase excitability. 16,[23][24][25][26] However, actions of nAChRs to excite inhibitory interneurons are particularly prominent in studies of hippocampus and sensory cortex, and can both inhibit pyramidal (principal) neurons as well as increase responsiveness of pyramidal neurons by inhibiting other interneurons that mediate feed-forward inhibition.…”