The neurotransmitter acetylcholine (ACh) plays a ubiquitous role in cognitive functions including learning and memory with widespread innervation in the cortex, subcortical structures, and the cerebellum. Cholinergic receptors, transporters, or enzymes associated with many neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are potential imaging targets. In the present study, we have developed 2D-quantitative structure–activity relationship (2D-QSAR) models for 19 positron emission tomography (PET) imaging agents targeted against presynaptic vesicular acetylcholine transporter (VAChT). VAChT assists in the transport of ACh into the presynaptic storage vesicles, and it becomes one of the main targets for the diagnosis of various neurodegenerative diseases. In our work, we aimed to understand the important structural features of the PET imaging agents required for their binding with VAChT. This was done by feature selection using a Genetic Algorithm followed by the Best Subset Selection method and developing a Partial Least Squares- based 2D-QSAR model using the best feature combination. The developed QSAR model showed significant statistical performance and reliability. Using the features selected in the 2D-QSAR analysis, we have also performed similarity-based chemical read-across predictions and obtained encouraging external validation statistics. Further, we have also performed molecular docking analysis to understand the molecular interactions occurring between the PET imaging agents and the VAChT receptor. The molecular docking results were correlated with the QSAR features for a better understanding of the molecular interactions. This research serves to fulfill the experimental data gap, highlighting the applicability of computational methods in the PET imaging agents’ binding affinity prediction.

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