Abstract
Alzheimer disease and related dementias are major challenges, demanding urgent needs for earliest possible diagnosis to optimize the success rate in finding effective therapeutic interventions. Mounting solid scientific premises point at the core acetylcholine-biosynthesizing cholinergic enzyme, ChAT as a legitimate in vivo target for developing positron emission tomography biomarker for early diagnosis and/or monitoring therapeutic responses in the neurodegenerative dementias. Up-to-date, no PET tracer ligands for ChAT are available. Here we report for the first time a novel hierarchical virtual screening approach on a commercial library of ~300,000 compounds, followed by in vitro screening of the hits by a new High-Throughput ChAT assay. We report detailed pharmacodynamic data for three identified selective novel ChAT ligands with IC50 and Ki values ranging from ~7 to 26 µM. In addition, several novel selective inhibitors of the acetylcholine-degrading enzymes, AChE and BuChE were identified, with one of the compounds showing an IC50-value of ~6 µM for AChE. In conclusion, this report provides an excellent starting platform for designing and optimizing potent and selective ChAT ligands, with high potential as PET-imaging probe for early diagnosis of AD, and related dementias, such as Down’s syndrome and Lewy body disorders.
Highlights
At present, dementia is the major cause of death affecting approximately 47.5 million people worldwide and this figure is projected to be double by 20301
Choline acetyltransferase (ChAT) (EC: 2.3.1.6; Choline O-acetyltransferase) is an important enzyme catalyzing the transfer of acetyl group from Acetyl-Coenzyme A (CoA) to choline for synthesis of acetylcholine (ACh), which is a major neurotransmitter in the brain
A positron emission tomography (PET) tracer that can bind to ChAT and help to monitor the health of cholinergic neurons will provide an important tool for early prognosis of Alzheimer’s disease (AD)
Summary
Dementia is the major cause of death affecting approximately 47.5 million people worldwide and this figure is projected to be double by 20301. In vitro positron emission tomography (PET) imaging is gaining immense clinical impact and is an invaluable scientific tool for understanding the early pathological events in neurodegenerative disorders. It is essential for effective monitoring of novel therapies and early diagnosis of neurodegeneration in AD3. Choline acetyltransferase (ChAT) (EC: 2.3.1.6; Choline O-acetyltransferase) is an important enzyme catalyzing the transfer of acetyl group from Acetyl-CoA to choline for synthesis of acetylcholine (ACh), which is a major neurotransmitter in the brain. To be an effective ChAT inhibitor, the compound should be highly potent, permeable to blood-brain barrier (BBB), and selective to ChAT as compared to other enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The major limitation of the potent compounds till now is quaternary ammonium characteristics, which makes them impermeable to BBB and poses limited applicability
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