Development of Vesicular Acetylcholine Transporter Ligands: Molecular Probes for Alzheimer's Disease

The Vesicular Acetylcholine Transporter (VAChT) is found throughout the cholinergic nervous system and is responsible for transporting Acetylcholine (ACh) into synaptic vesicles for storage. Deterioration of cholinergic neurotransmission is a known pathophysiological hallmark of Alzheimer's disease (AD). Ligands that bind to VAChT - particularly in the brain and CNS where cholinergic neurotransmission is vital for memory and cognitive function - may facilitate the study of cholinergic pathway regulation in the CNS and serve as useful diagnostic agents for AD. Vesamicol was the first VAChT ligand identified, however its poor selectivity has prompted the search for more potent and selective compounds. Numerous structural modifications to the vesamicol scaffold have been explored and several classes of VAChT ligands are highlighted in this review. The affinity and selectivity of these ligands for VAChT and σ-receptors are discussed.