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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.

项目总结