Selective PET imaging probes targeting BD1 of N-terminal bromodomains

项目摘要 溴域蛋白是表观遗传的“读取器”，在基因的表观遗传调控中起关键作用。 通过与组蛋白尾部的乙酰化赖氨酸残基(Ac-K)结合而转录。BET蛋白有两个保守的 N-末端溴域(Bd1和BD2)。溴结构域和末端外域(BET)抑制剂具有 在过去的几年里，它在肿瘤治疗方面得到了广泛的研究。最近，BET抑制剂已有报道 在大脑功能中发挥关键作用，如学习和记忆，也显示出治疗物质的潜力 虐待。BET蛋白在调节组织特异性转录程序中有不同的作用，因此，靶向 对特定的BET结构域的研究对于研究潜在疗法的安全性将是重要的。 不幸的是，目前还没有合适的非侵入性成像工具来研究BET的表达和活性 无论是动物还是人类。体内特定BET结构域可视化技术的发展是一个关键 了解BET在大脑中的正常功能和病理生理学。此外，这些技术 将加速发现选择性地与特定BET相互作用的小分子疗法 域名。该项目旨在为BET的BD2结构域开发新型的PET成像探针。我们将修改 我们的先导化合物的结构和用氟-18标记BET抑制剂并评估它们的潜力 通过成像研究F-18分子在人体内的分布和药代动力学 在啮齿动物和非人灵长类动物身上。

Project Summary Bromodomain proteins function as epigenetic “readers” and play a key role in epigenetic regulation of gene transcription by binding to acetylated lysine residues (Ac-K) on histone tails. BET proteins have two conserved N-terminal bromodomains (BD1 and BD2). The bromodomain and extra-terminal domain (BET) inhibitors have been extensive studied for tumors treatment in the past few years. Recently, BET inhibitors have been reported to play a key role in brain functions, such as learning and memory, also show a therapeutic potential for substance abuse. BET proteins have diverse roles in regulating tissue-specific transcriptional programs, therefore, targeting of specific BET domains will be important for investigating the safety of potential therapeutics. Unfortunately, there are no suitable non-invasive imaging tools for investigating BET expression and activity in animals or in man. The development of techniques for visualizing specific BET domains in vivo represents a key step in understanding both the normal function and pathophysiology of BET in brain. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with the specific BET domains. The project is designed to develop novel PET imaging probes for BD2 domain of BET. We will modify the structure of our lead compounds and label BET inhibitors with fluorine-18 and evaluate the potential of these molecules to serve as F-18 radiotracers for BET in humans by imaging their distribution and pharmacokinetics in rodents and non-human primates.