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

正电子发射断层扫描专用 HDAC 成像探头的设计

• 批准号: 8663851
• 负责人: Jacob M. Hooker
• 金额: $ 41.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663851
• 关键词: Acetylation; Address; Animal Model; Applications Grants; Autoradiography; Basic Science; Binding; Biodistribution; Biological Assay; Biology; Brain; Carbon; Cells; Central Nervous System Diseases; Chemicals; Chromatin; Communities; DNA; Data; Deacetylation; Development; Disease; Drug Formulations; Drug Kinetics; Environmental Risk Factor; Enzymes; Epigenetic Process; Exhibits; Female; Fluorine; Functional disorder; Gene Expression; General Hospitals; Goals; Heart; Heart Diseases; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Homeostasis; Human; Image; Image Analysis; Imaging technology; In Vitro; Inflammation; Institutes; Intravenous; Isotopes; Kinetics; Label; Laboratories; Lead; Link; Malignant Neoplasms; Massachusetts; Medical Research; Metabolic; Metabolism; Methods; Modeling; Molecular; Monitor; Organ; Outcomes Research; Papio; Papio anubis; Pharmaceutical Chemistry; Plasma; Plasma Proteins; Play; Positron-Emission Tomography; Process; Protein Isoforms; Radiochemistry; Radioisotopes; Radiolabeled; Regulation; Reporting; Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Series; Signal Pathway; Solubility; Stimulus; Structure-Activity Relationship; Targeted Research; Technology; Therapeutic Agents; Tissues; Transferase; Translating; Translations; Work; base; bioimaging; bone; cancer therapy; chemical property; design; disease diagnosis; dosimetry; functional group; human disease; human tissue; imaging probe; in vivo; in vivo imaging; inhibitor/antagonist; lipophilicity; meetings; molecular imaging; new technology; non-invasive imaging; nonhuman primate; novel therapeutics; pre-clinical research; radiochemical; radiotracer; screening; small molecule; tool

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.

特定类HDAC成像探针的设计 正电子发射断层扫描 项目摘要 已经鉴定出许多酶催化的过程，这些过程改变了DNA分子及其 相关的染色质。这些表观遗传过程调节基因表达。表观遗传学的关联 人类疾病功能障碍已从细胞和 亚细胞水平。在某些情况下，这些关联导致了新的治疗剂，这可以 调节表观遗传过程，并可能“营救”患病组织中的表观遗传状况。尽管有 在分子水平上的表观遗传状况与人类疾病和治疗之间增加了联系，有一个 令人惊讶的是，有限的工具使研究人员可以直接在体内探测表观遗传过程。新的 人类分子成像的技术，可以报告催化表观遗传的酶 转型将彻底改变我们将基础研究转化为人类治疗的能力。解决这个问题 急需的需求，我们旨在开发可以提供正电子发射断层扫描（PET）的放射性示例剂 分子水平的表观遗传信息。虽然我们最终将为一个数字开发一系列的放射性示例 在表观遗传靶标的中，我们在这里提出的研究将导致许多与许多相关的体内成像剂 人类疾病包括癌症，中枢神经系统疾病，心脏病和 炎。具体而言，我们将系统地开发和优化用于成像I类的PET radiotracer 组蛋白脱乙酰基酶（HDACS）。我们将通过：1）开发和应用独特的目标来实现这一目标 迭代改进模型，以识别特定于类的HDAC抑制剂，该抑制剂通过设计包含功能 适用于PET放射性同位素掺入并符合某些生理化学标准的组； 2）标签 适当的前体化合物并在啮齿动物中详细评估其体内成像的潜力； 3） 优化顶级放射性示意剂候选者，进行非人类灵长类动物成像并评估其潜力 转化为人类。该提案的一个关键特征是一项研究策略，可以轻松适应 解决其他类别的HDAC剂和其他表观遗传靶标。这项研究的结果将是 在临床前研究和 人类研究。