PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

Abstract

As a neuromodulator, the neurotransmitter acetylcholine plays an important role in cognitive, mood, locomotor, sleep/wake, and olfactory functions. In the pathophysiology of most neurodegenerative diseases, such as Alzheimer disease (AD) or Lewy body disorder (LBD), cholinergic receptors, transporters, or enzymes are involved and relevant as imaging targets. The aim of this review is to summarize current knowledge on PET imaging of cholinergic neurotransmission in neurodegenerative diseases. For PET imaging of presynaptic vesicular acetylcholine transporters (VAChT), (2)-18 F-fluoroethoxybenzovesamicol ( 18 F-FEOBV) was the first PET ligand that could be successfully translated to clinical application. Since then, the number of 18 F-FEOBV PET investigations on patients with AD or LBD has grown rapidly and provided novel, important findings concerning the pathophysiology of AD and LBD. Regarding the a4b2 nicotinic acetylcholine receptors (nAChRs), various second-generation PET ligands, such as 18 F-nifene, 18

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

“…Positron emission tomography ligands specific to NSS and blood oxygenation level-dependent imaging 50 may provide further information about NSS function and integrity. 51,52 Novel neuroimaging methods must leverage effective data sharing and granular post mortem validation to improve standardization, reproducibility, and understanding of biological correlations.…”

“…Expanding adoption of 7T ultra‐high‐field magnetic resonance imaging and approaches to address noise, such as multi‐echo functional sequences 46,47 and multiband imaging, 48,49 may offer solutions. Positron emission tomography ligands specific to NSS and blood oxygenation level–dependent imaging 50 may provide further information about NSS function and integrity 51,52 . Novel neuroimaging methods must leverage effective data sharing and granular post mortem validation to improve standardization, reproducibility, and understanding of biological correlations.…”

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography

“…A structurally similar compound BIBN99 was reported to have moderate affinity for M2 receptors (pK i = 7.6 nM) and improved selectivity toward M1 receptors (K i (M1)/K i (M2) = 33). [ 11 C]BIBN99 (26) was obtained with a decay-corrected yield of 26% from [ 11 C]ethyl iodide, but to date, no studies have been conducted to investigate its potential use as a PET imaging agent. 99 Despite sharing similar chemical structures with several reported M1selective PET ligands, such as [ 11 C]xanomeline (18) and [ 11 C]butylthio-TZTP (19), [ 18 F]FP-TZTP (27) proved to exhibit higher binding affinity for M2 receptors (K i = 2.2 nM) in comparison to M1 receptors (K i = 7.4 nM).…”

“…Positron emission tomography (PET) is a cutting-edge noninvasive imaging modality that has gained widespread use in recent years, particularly in the assessment of biochemical processes and disease staging in real time. − Compared to other imaging technologies, PET offers several advantages, such as superior tissue penetration, increased quantification capabilities, and feasibility for clinical translation. The development of a diverse range of PET tracers tailored to visualize specific subunits of cholinergic receptors under normal and pathological conditions has significantly contributed to the advancement of our understanding of the roles and mechanisms of cholinergic receptors in various biological processes, particularly in CNS disorders. − …”

Assessment of Purity, Functionality, Stability, and Lipid Composition of Cyclofos-nAChR-Detergent Complexes from Torpedo californica Using Lipid Matrix and Macroscopic Electrophysiology

“…The nAChRs are widely distributed in different tissues in mammals and other animal species and have been implicated in various neurological diseases. These include but are not limited to congenital myasthenic syndromes, tobacco addiction, Alzheimer’s disease, Parkinson’s disease, schizophrenia, epilepsy, Turret’s syndrome, inflammation, and more recently COVID-19 infection, (Gotti and Clementi 2004 ; Zoli et al 2015 ; Lucatch et al 2018 ; Farsalinos et al 2020 ; Mashimo et al 2020 ; Bekdash 2021 ; Hollenhorst and Krasteva-Christ 2021 ; Recio-Barbero et al 2021 ; Jankauskaite et al 2022 ; Tiepolt et al 2022 ).…”