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

项目摘要 表观遗传学是指在不涉及DNA序列变化的情况下对基因组进行功能性修改。 越来越多的证据表明，调节表观遗传过程可能是一种新的治疗方法 适用于大多数人类疾病。表观遗传的“读者”被认为具有多种功能 并与各种人类疾病有关，如阿尔茨海默病(AD)。溴域和额外的- 末端结构域(BET)蛋白家族含有与乙酰化组蛋白结合的串联溴结构域。四 末端溴域(Bd1)或C-末端溴域(BD2))。最近，BET抑制剂已有报道 对大脑功能产生关键影响，包括学习和记忆。我们的总体目标是发展PET 靶向脑内BET-BD1的放射性示踪剂用于与疾病状态的比较和体内BET-BD1的评估 目标参与BET药物治疗。此外，这些技术将加速发现小的 可用于脑内BET-BD1成像的示踪剂，尽管几种BET抑制剂或选择性BET-BD1 已有报道或放射性标记的抑制剂。该项目的设计目的是为一个

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.