Development of class-IIa HDAC targeting PET probes for molecular imaging of disorders of the CNS

开发用于中枢神经系统疾病分子成像的 IIa 类 HDAC 靶向 PET 探针

基本信息

批准号：
10807881
负责人：
Nashaat Turkman
金额：
$ 58.7万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10807881
关键词：
Address Affinity Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Autopsy Autoradiography Binding Biochemical Biodistribution Biological Markers Brain Brain region Central Nervous System Diseases Characteristics Classification Clinical Data Cognitive Data Defect Dementia Disease Disease Progression Drug Kinetics Early Diagnosis Early Intervention Enzymes Epigenetic Process Evaluation Family HDAC1 gene HDAC4 gene HDAC5 gene HDAC9 gene Health Histone Deacetylase Histone Deacetylase Inhibitor Human Huntington Disease Image Imaging Device Impaired cognition In Vitro Individual Ischemic Stroke Kinetics Knowledge Label Lead Learning Libraries Link Malignant Neoplasms Maps Measures Memory Memory Loss Metabolic Methods Molecular Probes Monitor Neurodegenerative Disorders Neurons Partition Coefficient Patient Selection Patients Play Positron-Emission Tomography Preparation Radiolabeled Rattus Reporting Research Rest Role Route Sampling Series Synaptic plasticity Tissues Tracer Traumatic Brain Injury Vorinostat X-Ray Computed Tomography candidate selection clinical translation course development design frontal lobe gray matter human disease imaging study improved in vivo in vivo imaging inhibitor lipophilicity member metabolic profile molecular imaging nonhuman primate novel novel strategies novel therapeutics overexpression radiochemical radiotracer success targeted treatment therapeutic target tool treatment response uptake

项目摘要

ABSTRACT. Alzheimer's diseases (AD) is a devastating brain neurodegenerative disease with no cure currently available. AD is associated with progressive dementia and cognitive decline which highlight the glaring need for new biomarker-based tools to accurately detect early AD and select patients for targeted therapies. The discovery of epigenetic mechanisms and their substantial contribution to cognitive decline in AD inspired extensive research in attempt to delineate the role of Histone Deacetylases (HDACs) in memory function. As such, HDAC blockade with panHDAC inhibitors have been extensively perused to alleviate the memory decline in the AD brain. However, two recent and independent imaging studies in humans reported that class-I HDAC levels decrease as AD advances, which highlights the need for specific targeting of HDACs in the AD brain. The class-IIa HDAC members, HDAC4 and HDAC5, play a key role in neuronal synaptic plasticity and memory formation. A quantitative study by Anderson KW, et al. found a 47% increase in the class-IIa HDAC5 expression in the AD human frontal cortex, while class-I HDACs were downregulated in AD (HDAC1,2 decreased 32%) which is consistent with recent clinical data obtained with 11C-Martinostate. These findings establish strong evidence for our approach to quantitate changes in class-IIa HDAC expression in the human AD brain and validate class-IIa HDACs as a therapeutic target in AD; this will have a significant positive impact for AD patients. Therefore, we aim to develop and validate radiotracers for positron emission tomography (PET) to non-invasively and quantitatively map the expression and localization of class-IIa HDACs in the brain in its entirety, thus providing a contrast view of the whole healthy brain versus the AD brain. Our preliminary results support the suitability and feasibility of the proposed studies, with one tracer (18F-26) demonstrating the characteristics of a useful CNS PET tracer. 18F-26 displays excellent pharmacokinetic and imaging characteristics, since brain uptake is high in gray matter regions, leading to high-quality PET images; tissue kinetics are appropriate for an 18F tracer, and specific binding for class-IIa HDAC is demonstrated by self-blockade and with SAHA (panHDAC inhibitor). Therefore, we propose these three specific aims: (1) To synthesize and screen a focused library of 30 candidate inhibitors. (2) To radiolabel the selected tracer candidates (N=6) from aim1 using our novel radiosynthetic route and other established radiochemical methods. (3) To validate the best three radiotracers for in vivo PET/CT imaging of class-IIa HDAC expression in the brain of healthy rats. We will perform quantitative in vitro autoradiography with our lead tracer to measure class-IIa HDAC expression in postmortem brain sections from patients who died with AD and compare those samples with sections obtained from healthy controls (sans AD).Early detection of AD by class-IIa HDAC PET imaging will allow early intervention to slow or halt disease progression with class-IIa HDAC inhibitors. Further, class-IIa HDAC PET imaging can also find vast applications while investigating and monitoring other diseases, such as Huntington's diseases, ischemic stroke, traumatic brain injuries, and cancer.

抽象的。阿尔茨海默病（AD）是一种毁灭性的脑神经退行性疾病，目前尚无治愈方法可用的。 AD 与进行性痴呆和认知能力下降有关，这凸显了对基于新生物标记的工具可准确检测早期 AD 并选择患者进行靶向治疗。这表观遗传机制的发现及其对 AD 认知能力下降的重大贡献启发大量研究试图阐明组蛋白脱乙酰酶 (HDAC) 在记忆功能中的作用。作为因此，使用 panHDAC 抑制剂阻断 HDAC 已被广泛用于缓解记忆力下降在 AD 大脑中。然而，最近两项独立的人类成像研究报告称，I 类 HDAC 随着 AD 的进展，HDAC 水平会降低，这凸显了在 AD 大脑中针对 HDAC 进行特异性靶向治疗的必要性。这 IIa 类 HDAC 成员 HDAC4 和 HDAC5 在神经元突触可塑性和记忆中发挥关键作用形成。 Anderson KW 等人的定量研究。发现 IIa 类 HDAC5 表达增加了 47% 在 AD 人类额叶皮层中，而 I 类 HDAC 在 AD 中下调（HDAC1,2 下降 32%）这与最近使用 11C-Martinostate 获得的临床数据一致。这些发现有力地证明了我们定量人类 AD 大脑中 IIa 类 HDAC 表达变化的方法的证据验证 IIa 类 HDAC 作为 AD 的治疗靶点；这将对 AD 患者产生显着的积极影响。因此，我们的目标是开发和验证用于正电子发射断层扫描（PET）的放射性示踪剂，以非侵入性并定量绘制整个大脑中 IIa 类 HDAC 的表达和定位，从而提供整个健康大脑与 AD 大脑的对比视图。我们的初步结果支持拟议研究的适用性和可行性，其中一种示踪剂（18F-26）展示了有用的 CNS PET 示踪剂。 18F-26 显示出优异的药代动力学和成像特性，因为脑灰质区域的吸收率很高，从而获得高质量的 PET 图像；组织动力学适用于 18F示踪剂和IIa类HDAC的特异性结合通过自我阻断和SAHA（panHDAC 抑制剂）。因此，我们提出以下三个具体目标：（1）合成和筛选包含 30 个的重点库候选抑制剂。 (2)使用我们的小说对来自aim1的选定示踪剂候选物(N=6)进行放射性标记放射合成途径和其他已建立的放射化学方法。 (3) 验证最佳的三种放射性示踪剂健康大鼠大脑中 IIa 类 HDAC 表达的体内 PET/CT 成像。我们将进行定量使用我们的先导示踪剂进行体外放射自显影，测量死后脑切片中 IIa 类 HDAC 的表达来自死于 AD 的患者，并将这些样本与从健康对照获得的切片进行比较（无 AD）。通过 IIa 类 HDAC PET 成像早期检测 AD 将允许早期干预以减缓或阻止疾病 IIa 类 HDAC 抑制剂的进展。此外，IIa 类 HDAC PET 成像也可以找到广泛的应用同时调查和监测其他疾病，如亨廷顿舞蹈病、缺血性中风、创伤性中风脑损伤和癌症。