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: 8267687
• 负责人: Jacob M. Hooker
• 金额: $ 43.68万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267687
• 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; Screening procedure; 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; inhibitor/antagonist; lipophilicity; meetings; molecular imaging; new technology; nonhuman primate; novel therapeutics; pre-clinical research; radiochemical; radiotracer; 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.

特定类别HDAC成像探头的设计 正电子发射断层扫描 项目摘要 已经鉴定了许多酶催化的过程，其修饰DNA分子及其结构。 相关染色质这些表观遗传过程调节基因表达。表观遗传学 功能障碍与人类疾病已经成长出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剂，其可以 调节表观遗传过程并潜在地“拯救”患病组织中的表观遗传状态。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日益增加， 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 用于人类分子成像的技术，可以报告催化表观遗传的酶 变革将彻底改变我们将基础研究转化为人类疗法的能力。为了解决这个 迫切需要，我们的目标是开发放射性示踪剂的正电子发射断层扫描（PET），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， 表观遗传靶点，在这里，我们提出的研究，将导致在体内显像剂相关的许多 人类疾病，尤其包括癌症、中枢神经系统病症、心脏病，以及 炎症具体来说，我们将系统地开发和优化PET放射性示踪剂成像I类 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 迭代细化模型，以识别类别特异性HDAC抑制剂，通过设计， 适用于PET放射性同位素掺入并符合某些理化标准的组; 2）标记 合适的前体化合物，并详细评估其在啮齿动物中的体内成像潜力;以及3） 优化顶级放射性示踪剂候选物，进行非人类灵长类动物成像，并评估其潜力 翻译给人类。该提案的一个主要特点是研究战略，可以很容易地适应 解决其他类别的HDAC剂和其他表观遗传靶点。这项研究的结果将是 用于体内表观遗传过程成像的新技术，可用于临床前研究， 人类研究