Design of Class-specific HDAC Imaging Probes for Positron Emission Tomography

特定类别HDAC成像探头的设计 用于正电子发射断层扫描 项目总结 已经确定了许多酶催化的过程来修饰DNA分子及其 相关的染色质。这些表观遗传过程调节基因的表达。表观遗传学的关联性 人类疾病的功能障碍已经从详细的分子和化学生物学在细胞和 亚细胞水平。在某些情况下，这些关联导致了新的治疗药物，这可以 调节表观遗传过程，潜在地“挽救”患病组织的表观遗传状态。尽管 在分子水平上的表观遗传状态与人类疾病和治疗之间的联系日益密切，有一种 令人惊讶的是，允许研究人员直接探测体内表观遗传过程的工具数量有限。新的 可以报告催化表观遗传的酶的人类分子成像技术 变革将彻底改变我们将基础研究转化为人类疗法的能力。要解决这个问题 迫切需要，我们的目标是开发正电子发射断层扫描(PET)的放射性示踪剂，可以提供 分子水平的表观遗传信息。虽然我们最终将开发一系列放射性示踪剂 对于表观遗传靶点，我们在这里提出的研究将导致一种体内显像剂与许多 人类疾病，包括癌症、中枢神经系统疾病、心脏病和 发炎。具体地说，我们将系统地开发和优化用于I类成像的PET放射性示踪剂 组蛋白脱乙酰酶(HDAC)。我们将通过以下方式实现这一目标：1)开发和应用独特的 迭代精化模型用于识别特定类别的HDAC抑制剂，这些抑制剂设计为包含功能性的 适合于PET放射性同位素掺入且符合一定物理化学标准的基团；2)标记 适当的前体化合物并详细评估其在啮齿动物体内的成像潜力；以及3) 优化首选放射性示踪剂，进行非人类灵长类成像，并评估其潜力 用来翻译给人类。这一建议的一个关键特征是研究战略，可以很容易地适应 解决其他类别的HDAC制剂和其他表观遗传靶点。这项研究的结果将是 体内成像表观遗传过程的新技术，既可用于临床前研究，也可用于 人体研究。

DESIGN OF CLASS-SPECIFIC HDAC IMAGING PROBES FOR POSITRON EMISSION TOMOGRAPHY PROJECT SUMMARY A number of enzyme catalyzed processes have been identified which modify the DNA molecule and its associated chromatin. These epigenetic processes modulate gene expression. The association of epigenetic dysfunction with human disease has grown out of detailed molecular and chemical biology at the cellular and sub-cellular level. In some cases, these associations have led to new therapeutics agents, which can modulate epigenetic processes and potentially "rescue" the epigenetic status in diseased tissue. Despite the increasing link between epigenetic status at a molecular level and human disease and treatment, there are a surprisingly limited number of tools that allow researchers to directly probe epigenetic processes in vivo. New technologies for human molecular imaging that can report on enzymes which catalyze epigenetic transformations will revolutionize our ability to translate basic research to human therapy. To address this critical need, we aim to develop radiotracers for positron emission tomography (PET) that can provide molecular-level epigenetic information. While we will ultimately develop a series of radiotracers for a number of epigenetic targets, here we propose studies that will lead to an in vivo imaging agent relevant across many human diseases including, among others, cancer, central nervous system disorders, heart disease, and inflammation. Specifically, we will systematically develop and optimize a PET radiotracer for imaging class-I histone deacetylases (HDACs). We will accomplish this goal by: 1) developing and applying a distinct iterative refinement model to identifying class-specific HDAC inhibitors that, by design, contain a functional group suitable for PET radioisotope incorporation and which meet certain physiochemical criteria; 2) Labeling appropriate precursor compounds and evaluating their in vivo imaging potential in detail in rodents; and 3) Optimizing top radiotracer candidates, performing non-human primate imaging, and assessing their potential for translation to humans. A key feature of this proposal is a research strategy that can be easily adapted to address other classes of HDAC agents and other epigenetic targets. The outcome of this research will be a new technology for imaging epigenetic processes in vivo that can be used in both preclinical research and human studies.