BET-BD1 Selective Neuroimaging probes for Alzheimer's disease research

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Project Summary Epigenetics refers to functional modifications to the genome that do not involve a change in the DNA sequence. Growing evidence have shown that modulation of epigenetic processes may be a new therapeutic approach applicable across most human diseases. The epigenetic “readers” have been implicated in multiple functions and associated with various human diseases, such as Alzheimer’s disease (AD). The bromodomain and extra- terminal domain (BET) family of proteins contain tandem bromodomains which bind to acetylated histones. Four BET members (BRD2, BRD3, BRD4 and BRDT) are found in humans, contain two bromodomains each (N- terminal bromodomain (BD1) or C-terminal bromodomain (BD2)). Recently, BET inhibitors have been reported to have a key impact on brain function, including learning and memory. Our overall goal is to develop PET radiotracers target BET-BD1 in the brain for comparison to disease states and for assessing in vivo BET-BD1 target engagement with BET drug treatment. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with the specific BET-BD1 domain. Currently, there are no PET tracers available for imaging BET-BD1 in the brain, although several BET inhibitors or selective BET-BD1 inhibitors have been reported or radiolabeled. The project is designed to perform IND-enabling studies for a novel PET imaging probe for BD1 domain of BET.