Radioligand development for PET imaging of the vesicular acetylcholine transporter (VAChT) in the brain

Abstract

Nowadays, it is general consensus that the cholinergic transmission system in the brain is heavily involved in the development, progress, and therapy of certain neurodegenerative diseases. In particular cholinergic presynaptic components such as the acetylcholinesterase (AChE) or the vesicular acetylcholine transporter (VAChT) are considered to be affected by early changes in neuropathological processes as observed, e.g., in Alzheimer's disease (AD). The VAChT is a transmembrane protein located at synaptic vesicles and responsible for the transport and storage of the neurotransmitter acetylcholine (ACh) in the vesicles. Therefore, the VAChT is regarded as a potential target for neuroimaging of cholinergic alterations with positron emission tomography. To date, the development of PET radioligands for this transporter is based on a single known lead compound named vesamicol. A challenge was arising due to the finding that vesamicol also binds to the sigma receptors which are partly co-localized with the VAChT in several brain regions. In the last three decades, a multitude of structural diverse vesamicol analogs has been designed resulting in a considerable number of 11C-and 18F-labeled PET as well as a few 123/125I-labeled SPECT tracers which were mainly preclinically evaluated. However, only very few of them had the potential for translation to human studies. Therefore, a routinely used VAChT PET imaging method could not be established in the clinics so far. However, first results of recently published studies using the potent candidate [18F]FEOBV in patients with neuropathologies are very promising and possibly a breakthrough in this field. This review addresses the efforts in ligand design and PET radioligand development for the VAChT with a special view on the difficulties arising from the lead compound vesamicol and its low selectivity.