Due to the lack of tools for early diagnosis of Alzheimer's disease (AD), the patients were usually diagnosed with AD after exhibiting significant clinical symptoms and it is extremely difficult to develop new drugs for AD. Histone deacetylase inhibitors (HDACIs) are potential agents to enhance the memory, learning ability, and cognitive function of patients with neurodegenerative diseases, such as AD. Hence, molecular imaging agents for noninvasive real-time in vivo visualization and quantification of the contents and activity of HDAC in human brains would be valuable for the determination of the roles HDAC plays in AD. In this study, a series of fluoroalkyl-substituted benzamide derivatives was designed and synthesized as novel HDACIs with potential blood-brain barrier (BBB) permeability. In the series, most ligands demonstrated potent inhibition against HDAC1 and HDAC2, whereas these compounds had negligible ability to inhibit other subtypes of HDAC. Several compounds exhibited high potency and selectivity for HDAC1 (IC50 = 50-100 nM), and other ligands showed similar potency for both HDAC1 and HDAC2 (IC50 = 60-200 nM). In PAMPA assay, several probes demonstrated high potential to penetrate through BBB. A fluoropropyl-substituted derivative was radiolabeled and this 18F-labeled HDACI was evaluated in vivo as a potential positron emission tomography (PET) imaging agent for study of AD and other CNS applications.

Design and synthesis of novel [F18]-labeled histone deacetylase inhibitors as potential molecular imaging agents for Alzheimer's disease

254th National Meeting (2017)

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