PET Imaging of nAChR Radioligands [¹⁸F]Nifene and [¹⁸F]ASEM to measure effects of Vagus Nerve Stimulation on the Acetylcholine System

Background: Stimulation of the vagus nerve is known to effect release of the neurotransmitter acetylcholine (ACh) which is an agonist of the nicotinic acetylcholine receptor (nAChR). These nAChRs are located in both pre and post-synaptic regions, and show increased cation permeability after binding of endogenous ACh. Of nAChR subtypes, the α₄β₂* (including α₂β₂, α₃β₂, and α₄β₂ receptors) and α₇ are most abundant and widely distributed throughout the central nervous system (CNS). Objective: This work implements the α₄β₂* nAChR radioligand [¹⁸F]nifene and α₇ nAChR radioligand [¹⁸F]ASEM, with bolus plus constant infusion methods in the rhesus macaque primate to investigate the ACh system changes due to vagus nerve stimulation (VNS) in the brain. Methods: One subject was anesthetized with propofol and received one baseline and two stimulus 90-minute bolus plus constant infusion [¹⁸F]nifene PET/CT scans. Additionally, N=2 awake subjects received one baseline and one stimulus 90-minute bolus plus constant infusion [¹⁸F]ASEM PET/CT scan, with the first subject receiving a second stimulus scan. [¹⁸F]Nifene scans were performed with an average bolus injection of 1.11 ± 0.11 mCi and infused activity of 4.51 ± 0.26 mCi (K_bol=22 min) over 89 minutes. [¹⁸F]ASEM scans were conducted with an average bolus injection of 2.12 ± 0.21 mCi and infused activity of 2.92 ± 0.60 mCi (K_bol=67 min) over 89 minutes. 90 minute baseline scans were implemented without stimulus to confirm equilibrium of both radiotracers and determine if adjustments to scan protocol were necessary. Stimulus scan protocol allowed for a 45-minute equilibrium period followed by application of VNS once per minute for 30 minutes, stimulus was then followed by 15 minutes of scan time for observation of post-stimulus dynamics. Pre and post-stimulus data were summed and normalized to the average uptake within the corpus callosum to form two SUVR images for each stimulus scan. These images are subtracted and normalized to the pre-stimulus SUVR image. Results: [¹⁸F]Nifene data shows increase in post-stimulus SUVR within the thalamus region by 12%. While [¹⁸F]ASEM data in the same region shows decreases by 2%, which is within test-retest variability of PET scans. This suggests studies performed with [¹⁸F]nifene show increases in binding within the thalamus post-stimulus, an observation that is not seen in current [¹⁸F]ASEM scans. Figure 1 shows a comparison of equilibrium binding distributions for [¹⁸F]nifene and [¹⁸F]ASEM. Discussion: With currently limited sample size, further experiments are necessary to draw conclusions on changes in radioligand binding due to VNS. Effects of higher in vivo K_D values for [¹⁸F]ASEM compared to [¹⁸F]Nifene on displaceability by ACh, spatiotemporal differences in binding of ACh to α₄β₂* and α₇ receptors, and impact of anesthesia on ACh production are areas requiring further investigation.

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