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

Nowadays, it is general consensus that the cholinergic transmission system in 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) into 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 cholinergic brain regions. In the last three decades a multitude of structural diverse vesamicol analogs have 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 could not be established in the clinics so far. However, just recently published studies using the potent candidate [18F]FEOBV in patients with neuropathologies are very promising and probably a breakthrough within this field.
This review addresses the efforts in ligand design and PET radioligand developments for the VAChT with a special view on the difficulties arising from the lead compound vesamicol and its low selectivity.