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

基本信息

批准号：
9379945
负责人：
STEPHEN J HAGGARTY
金额：
$ 45.87万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/9379945
关键词：
Acetylation Address Affinity Animal Experimentation Animal Model Antidepressive Agents Behavior Binding Biochemical Biochemistry Biological Assay Blood Blood - brain barrier anatomy 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 Kinetics Knockout Mice Knowledge Label Laboratories Lead Libraries Malignant Neoplasms Maps Measures Memory Mental Depression Methods Modeling Mood Disorders Moods Morphology Names Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathology Patients Penetrance Penetration Pharmacology Phenotype Plant Roots Positioning Attribute Positron Positron-Emission Tomography Property Protein Isoforms Proteomics Radiolabeled Recombinants Rodent Series Sex Characteristics Structure-Activity Relationship Tail Therapeutic Translations Work Zinc Fingers age difference alpha Tubulin base brain tissue density design dosimetry drug development human imaging human stem cells imaging study in vivo in vivo imaging inhibitor/antagonist innovation nanomolar 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

项目摘要

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 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.

项目概要异构体选择性组蛋白脱乙酰酶 (HDAC) 放射性示踪剂的开发将填补关键的知识空白我们对人脑 HDAC 功能的理解中存在的 HDAC6 是主要的亚型。迄今为止，HDAC 已表现出强大的治疗潜力。用于治疗抑郁症和神经退行性疾病的 HDAC6 抑制和转化工具作为针对 HDAC6 的正电子发射断层扫描放射性示踪剂，我们将能够评估 HDAC6 在人脑中的临床前发现并不是通过从组蛋白中去除乙酰基来发挥作用。可能表明，而是通过调节包括 α- 在内的几种非组蛋白的乙酰化状态微管蛋白、cortactin、tau、HSP90 和 catenin 选择性地与其他 10 种 HDAC6 结合的抑制剂。 HDAC 亚型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 HDAC6 抑制剂支架，我们将设计并合成一个库。 HDAC6 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。文库将经过严格的理化和生化分析，包括评估 HDAC- 培养的人类神经元中异构体的选择性和功效，并预测血脑屏障的渗透。通过这些测定确定优先顺序的化合物将被放射性标记，并在啮齿类动物中评估其大脑吸收情况，将使用体内成像结果来验证药代动力学和特异性（可饱和）结合。 HDAC6 敲除小鼠成像最终为转化为人类 HDAC6 成像（我们的）奠定了基础。团队已完成 I 类 HDAC 成像），我们将评估非人类化合物的优先级灵长类动物使用完全代谢物校正的动脉血输入函数来确定区域脑结合在资助项目期结束时，我们的团队将准备好测量人脑中 HDAC6 在自然异质性过程中的密度分布（例如年龄和性别）差异）以及患有 HDAC6 相关脑部疾病的患者。