PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

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), (-)-¹⁸F-fluoroethoxybenzovesamicol (¹⁸F-FEOBV) was the first PET ligand that could be successfully translated to clinical application. Since then, the number of ¹⁸F-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 α4β2 nicotinic acetylcholine receptors (nAChRs), various second-generation PET ligands, such as ¹⁸F-nifene, ¹⁸F-AZAN, ¹⁸F-XTRA, (-)-¹⁸F-flubatine, and (+)-¹⁸F-flubatine, were developed and successfully translated to human application. In neurodegenerative diseases such as AD and LBD, PET imaging of α4β2 nAChRs is of special value for monitoring disease progression and drugs directed to α4β2 nAChRs. For PET of α7 nAChR, ¹⁸F-ASEM and ¹¹C-MeQAA were successfully applied in mild cognitive impairment and AD, respectively. The highest potential for α7 nAChR PET is seen in staging, in evaluating disease progression, and in therapy monitoring. PET of selective muscarinic acetylcholine receptors (mAChRs) is still in an early stage, as the development of subtype-selective radioligands is complicated. Promising radioligands to image mAChR subtypes M1 (¹¹C-LSN3172176), M2 (¹⁸F-FP-TZTP), and M4 (¹¹C-MK-6884) were developed and successfully translated to humans. PET imaging of mAChRs is relevant for the assessment and monitoring of therapies in AD and LBD. PET of acetylcholine esterase activity has been investigated since the 1990s. Many PET studies with ¹¹C-PMP and ¹¹C-MP4A demonstrated cortical cholinergic dysfunction in dementia associated with AD and LBD. Recent studies indicated a solid relationship between subcortical and cortical cholinergic dysfunction and noncognitive dysfunctions such as balance and gait in LBD. Taken together, PET of distinct components of cholinergic neurotransmission is of great interest for diagnosis, disease monitoring, and therapy monitoring and to gain insight into the pathophysiology of different neurodegenerative disorders.