HDAC Class IIa specific PET radiotracers for PET imaging of CNS

用于中枢神经系统 PET 成像的 HDAC IIa 类特异性 PET 放射性示踪剂

基本信息

批准号：
7941746
负责人：
Juri George Gelovani
金额：
$ 167.24万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7941746
关键词：
Acetylation Acetylesterase Acids Acute Address Affinity Applications Grants Area Autoradiography Behavior Behavioral Biodistribution Biopsy Blood Brain Cell Nucleus Chemical Structure Chronic Client Clinic Clinical Research Cocaine Development Dose Drug Addiction Drug Kinetics Drug abuse Enzymes Epigenetic Process Exhibits Experimental Animal Model Exposure to Funding Future Genes Grant HDAC4 gene HDAC5 gene Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Image Immunohistochemistry In Situ In Vitro Individual Institution Knockout Mice Label Lead Libraries Longitudinal Studies Macaca Macaca mulatta Measures Metabolism Monitor Mono-S Morbidity - disease rate Mus National Institute of Drug Abuse National Institute on Alcohol Abuse and Alcoholism Nucleus Accumbens Patients Pharmaceutical Preparations Pharmacodynamics Phase Positron-Emission Tomography Protein Isoforms Proteins Radiolabeled Radiometry Rattus Recombinants Research Research Personnel Research Project Grants Rodent Role Series Specificity Structure Technology Time Toxicology Tracer Translations United States National Institutes of Health Validation Vorinostat Withdrawal addiction analog base brain tissue chromatin remodeling drug addict drug addiction therapy economic impact health care economics imaging modality in vivo inhibitor/antagonist intravenous injection molecular imaging next generation nonhuman primate novel pharmacokinetic model pre-clinical psychostimulant public health relevance radiotracer response socioeconomics tool uptake

项目摘要

DESCRIPTION (provided by applicant): This grant application addresses one of the top priority areas identified by the National institute for Drug Abuse (NIDA) for "Grand Opportunities" RC2 grants: EPIGENETICS; and specific area identified as: Technologies enabling in vivo imaging of epigenetic markers, modifying enzymes, or effector molecules in the brain. With the recent advances in epigenetic research and improvement in our understanding of various epigenetic mechanisms involved in the development of drug addiction behavior, histone deacetylase (HDAC) Class IIa enzymes HDAC4 and HDAC5 have emerged as important targets for the development of novel therapies for drug addiction. However, for studies on the involvement of different HDACs in the mechanisms of addicted behavior development, the utilization of invasive biopsies of brain tissue is prohibitive in humans due to obvious reasons of traumatism and morbidity. Therefore, in this grant application we propose series of comprehensive in vivo imaging studies in rodents and non-human primates to further assess the efficacy of HDAC Class-IIa specific radiotracers 18F-DFAHA and 18F-TFAHA for non-invasive PET imaging of HDAC4 and HDAC5 activity in the brain in comparison with previously developed, but less specific radiotracer 18F- FAHA. Also, we propose to synthesize potentially even more specific and potent 18F-labeled substrate- radiotracers for PET imaging of HDAC4 and HDAC5 activity in the brain. These novel HDAC Class-IIa specific PET radiotracers can be widely distributed to academic institutions for pre-clinical and clinical research, and which can be integrated with other NIH and privately funded research projects and initiatives within the reasonable timeframe (after completion of this project). The availability of HDAC class and isotype-specific PET radiotracers will facilitate the development of novel HDAC inhibitors by providing the tools for non- invasive, repetitive, and quantitative imaging of expression-activity of different HDAC enzymes in various structures (nuclei) of the brain both in experimental animal models and in human patients. Novel molecular imaging methods and targeted therapies of addiction should generate a significant healthcare-economic and socio-economic impact. PUBLIC HEALTH RELEVANCE: In this grant application we propose series of comprehensive imaging studies in rodents and non-human primates to assess the efficacy of novel radiolabeled agents non-invasive PET imaging of Class-IIa histone deacetylase enzymes in the brain, which have been implicated in the mechanism of development of drug addiction. The availability of HDAC class and isotype-specific PET radiotracers will facilitate the development of novel HDAC inhibitors by providing the tools for non-invasive, repetitive, and quantitative imaging of expression-activity of different HDAC enzymes in various structures (nuclei) of the brain both in experimental animal models and in human patients. Novel molecular imaging methods and targeted therapies of addiction should generate a significant healthcare-economic and socio-economic impact.

描述（由申请人提供）：本赠款申请介绍了美国国家药物滥用研究所（NIDA）确定的“大机会” RC2赠款：表观遗传学的首要优先级领域之一；和特定区域被识别为：实现体内表观遗传标记，修饰酶或大脑效应分子的技术。随着表观遗传研究的最新进展和对吸毒行为发展的各种表观遗传机制的理解，组蛋白脱乙酰基酶（HDAC）IIA酶HDAC4和HDAC5作为新颖的吸毒疗法发展的重要靶标。但是，对于关于不同HDAC在上瘾行为发展机制中涉及的研究，由于创伤和发病率的明显原因，人类对脑组织的侵入性活检的利用变得过于敏锐。因此，在此赠款应用中，我们提出了一系列在啮齿动物和非人类灵长类动物中的全面体内成像研究，以进一步评估HDAC类-IIA类特异性放射性示踪剂18F-DFAHA和18F-TFAHA对HDAC4和HDAC5与先前开发的特定特定radiotrace相比，对大脑中HDAC4和HDAC5活性的非侵入性PET成像的功效。另外，我们建议将可能更具体，有效的18F标记的底物辐射剂合成用于大脑中HDAC4和HDAC5活性的PET成像的底物。这些新型的HDAC类IIA特定于IIA的PET放射性示踪剂可以广泛分配给学术机构进行临床前和临床研究，并可以与其他NIH和私人资助的研究项目和计划在合理的时间段（完成此项目完成后）集成。 HDAC类和同种型特异性PET放射性示踪剂的可用性将通过为在实验动物模型和人类患者中脑中各种大脑中不同结构（核）中不同HDAC酶的表达活性提供非侵入性，重复性和定量成像的工具来促进新型HDAC抑制剂的发展。新颖的分子成像方法和成瘾的靶向疗法应产生重大的医疗经济和社会经济影响。公共卫生相关性：在此赠款应用中，我们提出了一系列在啮齿动物和非人类灵长类动物中的综合成像研究，以评估新型放射性标记剂对大脑中IIA组蛋白脱乙酰基酶的非侵入性PET成像的功效，这与药物成瘾的发展机制有关。 HDAC类和同种型特异性PET放射性示踪剂的可用性将通过为在实验性动物模型和人类患者中的各种脑（核）中不同HDAC酶（核）中不同HDAC酶的表达活性提供非侵入性，重复性和定量成像的工具来促进新型HDAC抑制剂的发展。新颖的分子成像方法和成瘾的靶向疗法应产生重大的医疗经济和社会经济影响。