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

项目摘要 表观遗传学是指不涉及DNA序列变化的基因组功能修饰。 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”与多种功能有关 并与多种人类疾病如阿尔茨海默病（AD）相关。布罗莫结构域和额外的- 蛋白质末端结构域（BET）家族含有与乙酰化组蛋白结合串联溴结构域。四 BET成员（BRD 2、BRD 3、BRD 4和BRDT）在人类中发现，各自含有两个溴结构域（N-溴结构域）。 末端布罗莫结构域（BD 1）或C-末端布罗莫结构域（BD 2））。最近，已经报道了BET抑制剂 对大脑功能产生关键影响，包括学习和记忆。我们的总体目标是开发PET 放射性示踪剂靶向脑中的BET-BD 1，用于与疾病状态进行比较并用于体内评估BET-BD 1 与BET药物治疗靶向接合。此外，这些技术将加速发现小 选择性地与特异性BET-BD 1结构域相互作用的分子治疗剂。目前，没有PET 可用于脑中BET-BD 1成像的示踪剂，尽管几种BET抑制剂或选择性BET-BD 1 抑制剂已被报道或放射性标记。该项目的目的是进行IND使能研究， BET BD 1结构域的新型PET成像探针。

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.