Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; and.
Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Leipzig, Germany.
J Nucl Med. 2022 Jun;63(Suppl 1):33S-44S. doi: 10.2967/jnumed.121.263198.
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), (-)-F-fluoroethoxybenzovesamicol (F-FEOBV) was the first PET ligand that could be successfully translated to clinical application. Since then, the number of 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 α4β2 nicotinic acetylcholine receptors (nAChRs), various second-generation PET ligands, such as F-nifene, F-AZAN, F-XTRA, (-)-F-flubatine, and (+)-F-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, F-ASEM and C-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 (C-LSN3172176), M2 (F-FP-TZTP), and M4 (C-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 C-PMP and C-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.
作为一种神经调质，神经递质乙酰胆碱在认知、情绪、运动、睡眠/觉醒和嗅觉功能中发挥着重要作用。在大多数神经退行性疾病的病理生理学中，如阿尔茨海默病（AD）或路易体病（LBD），涉及到胆碱能受体、转运体或酶，并将其作为成像靶点。本综述的目的是总结神经退行性疾病中单胺能神经传递的正电子发射断层扫描（PET）成像的最新知识。对于前突触囊泡乙酰胆碱转运体（VAChT）的 PET 成像，（-）-F-氟乙氧基苯并 Vesamicol（F-FEOBV）是第一个成功转化为临床应用的 PET 配体。此后，AD 或 LBD 患者的 F-FEOBV PET 研究数量迅速增加，并提供了有关 AD 和 LBD 病理生理学的新的、重要的发现。关于α4β2 烟碱型乙酰胆碱受体（nAChRs），已经开发出各种第二代 PET 配体，如 F-尼芬、F-AZAN、F-XTRA、（-）-F-氟烷和（+）-F-氟烷，并已成功应用于人体。在 AD 和 LBD 等神经退行性疾病中，α4β2 nAChRs 的 PET 成像对于监测疾病进展和针对α4β2 nAChRs 的药物具有特殊价值。对于α7 nAChR 的 PET，F-ASEM 和 C-MeQAA 分别成功应用于轻度认知障碍和 AD。α7 nAChR PET 的最大潜力在于分期、评估疾病进展和治疗监测。选择性毒蕈碱乙酰胆碱受体（mAChRs）的 PET 仍处于早期阶段，因为亚型选择性放射性配体的开发很复杂。用于成像 mAChR 亚型 M1（C-LSN3172176）、M2（F-FP-TZTP）和 M4（C-MK-6884）的有前途的放射性配体已被开发并成功应用于人体。mAChRs 的 PET 成像对于 AD 和 LBD 的评估和治疗监测具有重要意义。乙酰胆碱酯酶活性的 PET 研究自 20 世纪 90 年代以来一直在进行。许多使用 C-PMP 和 C-MP4A 的 PET 研究表明，AD 和 LBD 相关的痴呆与皮质胆碱能功能障碍有关。最近的研究表明，在 LBD 中，皮质和皮质下胆碱能功能障碍与非认知功能障碍（如平衡和步态）之间存在密切关系。综上所述，胆碱能神经传递的不同成分的 PET 成像对于诊断、疾病监测和治疗监测以及深入了解不同神经退行性疾病的病理生理学具有重要意义。
