Novel HDAC Class III Specific Radiotracers for PET Imaging.

用于 PET 成像的新型 HDAC III 类特异性放射性示踪剂。

基本信息

批准号：
8723140
负责人：
Juri George Gelovani
金额：
$ 64.28万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723140
关键词：
Anilides Animals Applications Grants Autoradiography Basic Science Binding Biodistribution Biopsy Blood Brain Cell Line Cells Characteristics Clinic Clinical Clinical Research Comparative Study Development Disease Dose Drug Kinetics Enzymes Epigenetic Process Evaluation Gender Goals Heart Hepatocyte Histone Deacetylase Histone Deacetylase Inhibitor Human Image Immune In Situ In Vitro Individual Injection of therapeutic agent Knockout Mice Label Lead Left Libraries Longevity Macaca Macaca mulatta Magnetic Resonance Imaging Malignant Epithelial Cell Malignant Neoplasms Metabolism Monitor Morbidity - disease rate Mus National Institute of Drug Abuse Nature Normal tissue morphology Organ PET/CT scan Pancreatic carcinoma Papio Pharmacodynamics Physiology Positron-Emission Tomography Principal Investigator Protein Isoforms Radiolabeled Radiometry Rattus Recombinants Research Research Personnel Resveratrol Rodent Series Side Sirtuins Specificity Substrate Specificity Time Tissues Translations Treatment Efficacy Tumor Cell Line Vorinostat X-Ray Computed Tomography base design improved in vivo in vivo imaging inhibitor/antagonist neoplastic cell non-invasive imaging non-invasive monitor nonhuman primate novel pancreatic neoplasm pharmacokinetic model pre-clinical research programs radiotracer sirtinol subcutaneous tumor tumor xenograft uptake

项目摘要

The availability of novel HDAC class- and isoform-specific PET radiotracers will have a significant positive impact on the pace or research in the field of epigenetics. SIRTs-specific PET imaging agents will enable non- invasive and repetitive in vivo imaging of SIRTs expression and activity in the brain and different organs and tissues (including cancer) and help to understand the mechanisms of SIRTs involvement in normal physiology and in the mechanisms of different diseases, enable non-invasive monitoring of pharmacodynamics and therapeutic efficacy of novel SIRTs-specific inhibitors (or activators) in experimental animals and in humans, and facilitate their translation into clinic. Therefore, the overall aim of this grant application is to conduct a series of comprehensive in vivo imaging studies in rodents and non-human primates to further assess the efficacy of 18F-PhFAHA for non-invasive imaging of SIRTs in the brain and other organs and tissues. To further improve substrate selectivity and binding to SIRTs, we will synthesize and evaluate 42 potential SIRTs-specific substrates different 18F-labeled acyl "leaving" groups and two different side chains in the "cap" region. The substrate efficiency of compounds in the focused library will be in a panel of recombinant HDACs 1-11 and SIRTs 1-7. Three best substrates will be radiolabeled with F-18 and evaluated further in vitro and in vivo. Then, In vitro radiotracer accumulation studies will be performed with 18F-PhAHA and three novel 18F-labeled radiotracers in tumor cell lines with high, moderate, and low levels of SIRT1 expression; we will determine the radiolabeled metabolites in the primary cultures of human hepatocytes. By conducting these in vitro studies we will select three best novel radiotracers for subsequent microPET/CT imaging and autoradiography studies in mice to assess their efficacy and specificity for imaging SIRTs expression-activity. We will perform in situ immunohistochemical comparative studies to validate PET/CT imaging results. Also, PET/CT imaging studies will be performed in tumor-bearing mice at: a) baseline; b) pre-treatment with resveratrol (SIRTs activator); c) pre-treatment with sirtinol (SIRTs inhibitor) to assess the feasibility of pharmacodynamic imaging. The best radiotracer will be selected for subsequent studies in non-human primates to assess: a) the time-course of biodistribution, uptake, retention, and efflux from different organs and tissues; b) whole body and individual organ radiation dosimetry; and d) the time-course of 18F-labeled metabolites in blood. Also, we will assess the feasibility of PET/CT/MRI with the selected novel radiotracer (or 18F-PhAHA) for monitoring pharmacodynamic (PD) effects of SIRTs activators and inhibitors (resveratrol and sirtinol) in the same animals. Through the proposed studies we will select SIRTs-specific 18F-labeled radiotracer with optimal pharmacokinetic and radiation dosimetry characteristics and sensitivity for PET/CT/MRI imaging of SIRTs expression-activity in vivo.

新型HDAC类和同工型特异性PET放射性示例的可用性将具有明显的阳性对表观遗传学领域的速度或研究的影响。特定于SIRTS的PET成像剂将使非 SIRT在大脑和不同器官中的表达和活性的体内成像的侵入性和重复性成像组织（包括癌症），并有助于了解正常生理学的SIRT的机制以及在不同疾病的机制中，能够对药效学和新型SIRTS特异性抑制剂（或激活剂）在实验动物和人类中的治疗功效，并促进他们翻译成诊所。因此，本赠款申请的总体目的是进行啮齿动物和非人类灵长类动物的一系列全面体内成像研究，以进一步评估 18f-phfaha对大脑以及其他器官和组织中SIRT的非侵入性成像的功效。进一步提高底物的选择性并与SIRT结合，我们将合成并评估42个潜在SIRTS特异性底物不同的18F标记的酰基“离开”基团和“ CAP”区域的两个不同的侧链。这重点库中化合物的底物效率将在重组HDACS 1-11和 SIRTS 1-7。三个最佳底物将用F-18进行放射性标记，并在体外和体内进行进一步评估。然后，体外放射性示意剂积累研究将使用18F-Phaha和三个新型18F标记 SIRT1表达的肿瘤细胞系中的放射性示例；我们将确定人类肝细胞原发性培养物中的放射性标记的代谢物。通过进行这些体外研究我们将选择三个最佳新型放射性示例，用于随后的Micropet/CT成像和放射自显影研究小鼠评估其成像SIRT表达活性的功效和特异性。我们将原地表演免疫组织化学比较研究以验证PET/CT成像结果。另外，PET/CT成像研究将在肿瘤的小鼠中进行：a）基线； b）用白藜芦醇（SIRTS激活剂）进行预处理； c）用Sirtinol（SIRTS抑制剂）进行预处理，以评估药效成像的可行性。最好的将选择radiotracer进行非人类灵长类动物的后续研究以评估：a）来自不同器官和组织的生物分布，摄取，保留和外排； b）全身和个人器官辐射剂量测定； d）血液中18F标记的代谢产物的时间顺序。另外，我们将评估 PET/CT/MRI的可行性与选定的新型放射性示例（或18F-PHAHA）用于监测药效学（PD）同一动物中SIRTS激活剂和抑制剂（白藜芦醇和Sirtinol）的作用。通过拟议的研究我们将选择具有最佳药代动力学和最佳药代动力学和 SIRTS表达活性在体内的PET/CT/MRI成像的辐射剂量法和敏感性。