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: 8144799
• 负责人: Jacob M. Hooker
• 金额: $ 44.55万
• 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/8144799
• 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; public health relevance; radiochemical; radiotracer; small molecule; tool

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.

描述（由申请人提供）： 用于正电子发射断层扫描的类别特异性HDAC成像探针的设计项目概述已经鉴定了许多修饰DNA分子及其相关染色质的酶催化过程。这些表观遗传过程调节基因表达。表观遗传功能障碍与人类疾病的关联已经从细胞和亚细胞水平的详细分子和化学生物学中发展出来。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越来越多，但令人惊讶的是，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。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。为了满足这一关键需求，我们的目标是开发用于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。虽然我们最终将为许多表观遗传靶点开发一系列放射性示踪剂，但我们在这里提出的研究将导致与许多人类疾病相关的体内成像剂，包括癌症，中枢神经系统疾病，心脏病和炎症。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来鉴定类别特异性HDAC抑制剂，所述类别特异性HDAC抑制剂通过设计包含适合PET放射性同位素掺入的官能团并且满足某些生理化学标准; 2）标记适当的前体化合物并且详细评估它们在啮齿动物中的体内成像潜力;和3）优化最佳放射性示踪剂候选物，进行非人灵长类动物成像，并评估其转化为人类的潜力。该提案的一个关键特征是一种研究策略，可以很容易地适应于解决其他类别的HDAC代理和其他表观遗传目标。这项研究的成果将是一种新的技术，用于成像表观遗传过程在体内，可用于临床前研究和人类研究。 公共卫生相关性： 用于正电子发射断层扫描的类特异性HDAC成像探针的设计叙述性证据表明，环境因素在调节基因表达中起着关键作用，这为基因表达与疾病之间的关系提供了一个新的视角。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测组蛋白脱乙酰酶（HDAC），这是一种调节基因表达的关键酶，一直是与开发癌症，中枢神经系统疾病，心脏病和炎症新疗法相关的研究目标。为了实现这一目标，我们将选择和合成小分子HDAC抑制剂，这些抑制剂可以用同位素标记用于正电子发射断层扫描成像，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。这些工具将用于加速表观遗传学研究，并最终转化为人类PET成像和临床医生诊断疾病和监测治疗。