Design and Development of Choline Acetyltransferase Fluorescence Imaging Probes (21419)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which commonly affects the elderly. Despite the arduous effort in developing an effecting treatment for AD, there is still no cure for this disease. Treatment at early stages of AD has been postulated to deliver better pathological benefits as neuropathological changes start taking place about two decades prior to the appearance of clinical symptoms. Bioimaging has been proposed to be a better alternative to the conventional behavior-based clinical diagnosis. The attractive advantages of fluorescence imaging, such as its non-radioactive nature, have made fluorescent probes an indispensable tool for bioimaging. This study aims to develop novel choline acetyltransferase (ChAT) ligands which can be used as fluorescence imaging probes for early-AD detection. ChAT is the enzyme that catalyzes the biosynthesis of acetylcholine neurotransmitter, and acetylcholine deficiency manifests as cognitive and non-cognitive dysfunctions. Hence, its activity can be used to document the health of cholinergic neurons. Following in silico structure-based screening of a known chemical database, 20 compounds were developed and structurally characterized. N1-DMA has been identified as the lead compound, demonstrating high binding affinity towards ChAT (Ki = 1.89 μM), selectivity over anti-targets; acetylcholinesterase and butyrylcholinesterase (>14-fold), intrinsic fluorescence (ϕ = 59%), no significant neurotoxicity towards SH-SY5Y cells (at 50 μM), predicted blood-brain barrier permeation and cellular binding to target protein ChAT. As one of the most potent ChAT ligands reported to date, these favorable characteristics of N1-DMA highlight its potential to be developed into a fluorescence imaging probe for early-AD detection.