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

描述(由申请人提供)： 类特异性HDAC成像探针的设计用于正电子发射断层扫描项目摘要已经确定了一些酶催化的过程，它们可以修饰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。表观遗传功能障碍与人类疾病的联系源于细胞和亚细胞水平的详细分子和化学生物学。在某些情况下，这些关联导致了新的治疗药物，这些药物可以调节表观遗传过程，并潜在地“挽救”疾病组织的表观遗传状态。尽管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越来越大，但令人惊讶的是，允许研究人员直接探索体内表观遗传过程的工具数量有限。人类分子成像的新技术可以报告催化表观遗传转化的酶，这将彻底改变我们将基础研究转化为人类治疗的能力。为了解决这一关键需求，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，以提供分子水平的表观遗传学信息。虽然我们最终将为一些表观遗传靶点开发一系列放射性示踪剂，但在这里，我们建议进行研究，以获得一种与许多人类疾病相关的体内显像剂，其中包括癌症、中枢神经系统疾病、心脏病和炎症。具体地说，我们将系统地开发和优化一种用于I类组蛋白脱乙酰酶(HDAC)成像的PET放射性示踪剂。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来确定特定类别的HDAC抑制剂，该模型在设计上包含适合PET放射性同位素掺入的官能团，并且满足某些物理化学标准；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候选化合物，进行非人类灵长类成像，并评估它们转换到人类的潜力。这一建议的一个关键特点是一种研究战略，可以很容易地调整，以解决其他类别的HDAC制剂和其他表观遗传目标。这项研究的结果将是一种可用于临床前研究和人体研究的体内表观遗传过程成像的新技术。 公共卫生相关性： 为正电子发射断层扫描项目设计特定类别的HDAC成像探针叙述性证据表明，环境因素在调节基因表达方面发挥了关键作用，这为基因表达与疾病之间的关系引入了一个新的视角。在这项拨款申请中，我们建议开发一种新的体内成像技术，使研究人员能够直接探针组蛋白脱乙酰酶(HDAC)，这是一种调节基因表达的关键酶，一直是与开发治疗癌症、中枢神经系统疾病、心脏病和炎症相关的新疗法的研究目标。为了实现这一目标，我们将选择和合成可以用同位素标记的小分子HDAC抑制剂，用于正电子发射断层成像，并使用动物模型评估这些探针定量HDAC表达水平和活性的能力。这些工具将被用于加速表观遗传学研究，并最终将被转化为人类PET成像和临床医生，用于诊断疾病和监测治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: DESIGN OF CLASS-SPECIFIC HDAC IMAGING PROBES FOR POSITRON EMISSION TOMOGRAPHY PROJECT NARRATIVE Evidence that environmental factors play a key role in regulating gene expression has introduced a new perspective on the relationships between gene expression and disease. In this grant application, we propose to develop a new in vivo imaging technology that will allow researchers to directly probe histone deacetylase (HDAC), a key enzyme regulating gene expression that has been the target of research related to developing new therapies for cancer, central nervous system disorders, heart disease, and inflammation. To accomplish this, we will select and synthesize small-molecule HDAC inhibitors that can be labeled with isotopes for use in positron emission tomography imaging and evaluate the ability of these probes to quantify HDAC expression level and activity using animal models. These tools will be use to accelerate epigenetic research and will ultimately be translated to human PET imaging and clinicians for diagnosing disease and monitoring treatment.