Epigenetic Radiotracers for PET Imaging: Isoform-SelectiveHDAC Probes

用于 PET 成像的表观遗传放射性示踪剂：异构体选择性 HDAC 探针

• 批准号: 9915983
• 负责人: STEPHEN J HAGGARTY
• 金额: $ 46.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915983
• 关键词: Acetylation; Address; Affinity; Animal Experimentation; Animal Model; Antidepressive Agents; Behavior; Binding; Biochemical; Biochemistry; Biological Assay; Blood; Brain; Brain Diseases; C-terminal; Carbon; Catalytic Domain; Cells; Chemicals; Chromatin; Clinical Research; Collaborations; Data; Deacetylase; Development; Disease; Dose; Drug Kinetics; EMS1 gene; Epigenetic Process; Exhibits; Fluorine; Foundations; Gene Expression; Goals; Grant; HDAC6 gene; Health; Heat-Shock Proteins 90; Heterogeneity; Histone Acetylation; Histone Deacetylase; Histone H3; Histone H4; Histones; Human; Image; In Vitro; Interdisciplinary Study; Isotopes; Knockout Mice; Knowledge; Label; Laboratories; Lead; Libraries; Malignant Neoplasms; Maps; Measures; Memory; Mental Depression; Methods; Modeling; Mood Disorders; Moods; Morphology; N-terminal; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathology; Patients; Penetrance; Pharmacology; Phenotype; Plant Roots; Positioning Attribute; Positron; Positron-Emission Tomography; Property; Protein Isoforms; Proteomics; Radiolabeled; Recombinants; Rodent; Series; Sex Differences; Structure-Activity Relationship; Tail; Therapeutic; Translations; Work; Zinc Fingers; age difference; alpha Tubulin; base; beta catenin; blood-brain barrier penetration; brain tissue; density; design; dosimetry; drug development; human imaging; human stem cells; imaging study; in vivo; in vivo imaging; inhibitor/antagonist; innovation; kinetic model; nanomolar; neural circuit; non-histone protein; nonhuman primate; normal aging; novel; pre-clinical; radiochemical; radiotracer; response; scaffold; success; tau Proteins; therapeutic target; therapy development; tool; translation to humans; uptake

Project Summary The development of isoform-selective histone deacetylase (HDAC) radiotracers will fill critical knowledge gaps that exist in our understanding of HDAC function in the human brain. HDAC6 is primary among the isoforms of HDAC that, to date, have exhibited strong therapeutic potential. Compelling preclinical evidence supports HDAC6 inhibition for the treatment of depression and neurodegenerative diseases and translational tools such as a positron emission tomography radiotracer targeting HDAC6 will allow us to assess the relevance of preclinical findings in the human brain. HDAC6 acts not by removing acetyl groups from histones as its name might suggest, but instead by regulating the acetylation state of several non-histone proteins including α- tubulin, cortactin, tau, HSP90 and β-catenin. Inhibitors that selectively engage HDAC6 over the other ten isoforms of HDAC have been developed by our team and by others in the field and provide the foundation for PET radiotracer development. Using known HDAC6 inhibitor scaffolds, we will design and synthesize a library of HDAC6 inhibitors that can be readily labeled with a positron-emitting isotope (carbon-11 or fluorine-18). The library will undergo rigorous physiochemical and biochemical profiling including assays that evaluate HDAC- isoform selectivity and efficacy in cultured human neurons and that predict blood-brain barrier penetration. Compounds prioritized through these assays will be radiolabeled and evaluated in rodents for brain uptake, pharmacokinetics and specific (saturable) binding. Promising in vivo imaging results will be validated using HDAC6 knock-out mouse imaging. Finally to set the stage for translation to human HDAC6 imaging (which our team has accomplished for class-I HDAC imaging), we will evaluate priority compounds in non-human primates to determine regional brain binding using full metabolite-corrected arterial blood input function correction and kinetic modeling. By the end of the grant project period, our team will be poised to measure the density-distribution of HDAC6 in the human brain over the course of natural heterogeneity (e.g. age and sex differences) and in patients with HDAC6-implicated brain disorders.

项目摘要 异构体选择性组蛋白去乙酰化酶（HDAC）放射性示踪剂的开发将填补关键的知识空白 存在于我们对人类大脑HDAC功能的理解中。HDAC 6是主要的同种型， 迄今为止，HDAC已经表现出强大的治疗潜力。令人信服的临床前证据支持 用于治疗抑郁症和神经退行性疾病的HDAC 6抑制和翻译工具 作为靶向HDAC 6的正电子发射断层扫描放射性示踪剂， 人类大脑的临床前发现。HDAC 6的作用并不像它的名字那样通过从组蛋白上去除乙酰基来实现 可能表明，而是通过调节几种非组蛋白蛋白的乙酰化状态，包括α- 微管蛋白、coronin、tau、HSP 90和β-连环蛋白。抑制剂选择性地参与HDAC 6超过其他十个 HDAC的同种型已经由我们的团队和该领域的其他人开发，并为 PET放射性示踪剂开发。使用已知的HDAC 6抑制剂支架，我们将设计和合成一个文库， HDAC 6抑制剂可以很容易地用正电子发射同位素（碳-11或氟-18）标记。的 文库将进行严格的生理化学和生物化学分析，包括评估HDAC的测定。 在培养人神经元中的同种型选择性和功效以及预测血脑屏障穿透。 通过这些测定优先的化合物将被放射性标记并在啮齿动物中评价脑摄取， 药代动力学和特异性（可饱和）结合。有希望的体内成像结果将通过使用 HDAC 6敲除小鼠成像。最后，为人类HDAC 6成像的翻译奠定基础（我们的 团队已经完成了I类HDAC成像），我们将在非人类中评估优先化合物 灵长类动物使用完全代谢物校正的动脉血输入函数确定局部脑结合 校正和动力学建模。在资助项目结束时，我们的团队将准备好测量 在自然异质性（例如年龄和性别）过程中人脑中HDAC 6的密度分布 差异）和HDAC 6相关脑疾病患者。