Evaluation of 18F-nifene binding to α4β2 nicotinic receptors in the rat brain using microPET imaging

Abstract

MicroPET imaging studies using 18F-nifene, a new positron emission tomography (PET) radiotracer for nicotinic acetylcholinergic receptors (nAChR) α4β2 receptors in rats, have been carried out. Rats were imaged for 90 min after intravenous injection of 18F-nifene (0.8 to 1 mCi), and binding potential (BPND) was measured. 18F-Nifene binding to thalamic and extrathalamic brain regions was consistent with the α4β2 nAChR distribution in the rat brain. Using the cerebellum as a reference, the values for the thalamus varied less than 5% (BPND = 1.30, n = 3), confirming reproducibility of 18F-nifene binding. 18F-Nifene microPET imaging was also used to evaluate effects of nicotine in a group of Sprague-Dawley rats under isoflurane anesthesia. Nicotine challenge postadministration of 18F-nifene demonstrated reversibility of 18F-nifene binding in vivo. For α4β2 nAChR receptor occupancy (nAChROCC), various doses of nicotine (0, 0.02, 0.1, 0.25, and 0.50 mg/kg nicotine free base) 15 min prior to 18F-nifene were administered. Low-dose nicotine (0.02 mg) reached > 80% nAChROCC while at higher doses (0.25 mg) > 90% nAChROCC was measured. The small amount of 18F-nifene binding with reference to the cerebellum affects an accurate evaluation of nAChROCC. Efforts are underway to identify alternate reference regions for 18F-nifene microPET studies in rodents.

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

“…Normal lung distribution and kinetics of 18 F-Nifene in mice was characterized by us in a previous work [33]. Binding of 18 F-Nifene in rat brain correlates very well with the known distribution of α 4 β 2 receptors, as defined by 125 I-iodoepibatidine [30, 34, 35] and confirmed in the studies with β 2-knockout mice (36). The goal of this study was to evaluate utility of 18 F-Nifene as an imaging probe in the early diagnosis of lung cancer.…”

“…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.…”

“…We have developed and validated an imaging probe, 18 F-Nifene (Figure 1), which is suitable for non-invasive visualization of α 4 β 2 nAChRs using PET [30–32]. Normal lung distribution and kinetics of 18 F-Nifene in mice was characterized by us in a previous work [33].…”

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

“…In PET studies, radioligands are used to image nAChRs (reviewed by Horti et al, 2010), with the recent introduction of 18 F-nifene proving effective for imaging α4β2* nAChRs (asterisk indicates presence of additional subunits) with significantly shorter scan times than existing radioligands (e.g., 40–60 min vs. several hours) (Easwaramoorthy et al, 2007; Hillmer et al, 2011; Kant et al, 2011; Pichika et al, 2006). Results across binding studies are largely consistent with the distribution of α4β2* nAChRs in earlier studies.…”

Neural nAChRs PET imaging probes

“…Time-activity curves showed that the ratio of TH/CB peaked at 35 min, suggesting a significantly rapid attainment of pseudoequilibrium compared with 2-[ 18 F]FA, although brain region-cerebellum ratios measured with [ 18 F]Nifene were lower than those reported for 2-[ 18 F]FA because of its lower binding affinity [66]. Another study [68] conducted to evaluate [ 18 F]Nifene binding to a 4 b 2 -nAChRs in thalamic and extrathalamic brain regions of rodents using microPET imaging also validated the faster binding profile of [ 18 F]Nifene, thus providing shorter scan times. Besides, other researches also confirmed the specific regional binding of [ 18 F] Nifene and fast kinetic properties [69,70].…”