Nicotinic acetylcholine receptors in rat forebrain that bind ¹⁸F‐nifene: Relating PET imaging, autoradiography, and behavior

Abstract

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study we used the novel compound 18F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of 18F-nifene in mice lacking the β2 nAChR subunit, consistent with previous findings that 18F-nifene binds to α4β2* nAChRs. We then examined the distribution of 18F-nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, 18F-nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, 18F-nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related 18F-nifene binding in several forebrain regions to each animal’s performance on an auditory-cued, active avoidance task. The strongest correlations with performance after 14 days training were found for 18F-nifene binding in the temporal subcortical white matter, subiculum and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory-cognitive function.

Development of novel approach to diagnostic imaging of lung cancer with 18F-Nifene PET/CT using A/J Mice treated with NNK

“…Greater brown adipose tissue uptake of 18 F-FDG in NNK-treated mice was in keeping with the reports on the effects of nicotine on this tissue (46). While 18 F-Nifene was excreted into the kidney and urinary bladder, 18 F-Nifene was also retained in the brain, particularly in the nAChR-rich thalamus [36]. Control mice showed little uptake of 18 F-FDG in the lung, which was in agreement with the 18 F-FDG PET/CT scan (Figure 7A–D).…”

“…Previous works have established that 18 F-Nifene is a highly specific radioligand of α 4 β 2 nAChR [30–32, 34–36]. Herein, we tested the hypothesis that 18 F-Nifene can visualize α 4-made nAChRs in the lung tumors of NNK-treated A/J mice, thus enabling early diagnosis of lung cancer.…”

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions

“…Nicotine activates nicotinic acetylcholine receptors (nAChRs), which are present throughout the auditory system (Clarke et al, 1985; Morley and Happe, 2000; Dani and Bertrand, 2007; Bieszczad et al, 2012). These nAChRs normally are activated by endogenous ACh, which is a key neuromodulator of cognitive and sensory processes (Himmelheber et al, 2000; Hasselmo and Sarter, 2011; Klinkenberg et al, 2011).…”

Nicotinic α4β2 receptor imaging agents. Part IV. Synthesis and Biological Evaluation of 3-(2-(S)-3,4-dehydropyrrolinyl methoxy)-5-(3′-18F-Fluoropropyl)pyridine (18F-Nifrolene) using PET

“…Nifene, which contains a 3,4-dehydroproline ring system, exhibited selective binding to the receptors in the rat brain and was displaced by nicotine in vivo [23]. The selectivity of 18 F-nifene binding was further confirmed in β2-knock out mice [24]. In the rhesus monkeys, 18 F-Nifene demonstrated rapid uptake, fast kinetics in receptor-rich regions (≤60 mins) and cleared rapidly from the various brain regions [25].…”