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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' 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

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.

摘要。阿尔茨海默病（Alzheimer's diseases，AD）是一种严重的脑神经退行性疾病，目前尚无治愈方法 available. AD与进行性痴呆和认知能力下降有关，这突出了对AD治疗的迫切需要。 新的基于生物标志物的工具，以准确地检测早期AD和选择患者进行靶向治疗。的 表观遗传机制的发现及其对AD认知能力下降的实质性贡献 广泛的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，用泛HDAC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，最近两项独立的人体成像研究报告，I类HDAC 随着AD的进展，HDAC水平降低，这突出了在AD脑中特异性靶向HDAC的需要。的 IIa类HDAC成员HDAC 4和HDAC 5在神经元突触可塑性和记忆中起关键作用 阵安德森KW等人的定量研究发现，IIa类HDAC 5表达增加了47 在AD人类额叶皮层中，而I类HDAC在AD中下调（HDAC 1，2降低32%） 这与最近用11 C-马替诺酯获得的临床数据一致。这些发现有力地证明了 证据表明我们的方法定量的变化，在IIa类HDAC表达在人类AD的大脑， 验证IIa类HDAC作为AD的治疗靶点;这将对AD患者产生重大积极影响。 因此，我们的目标是开发和验证放射性示踪剂的正电子发射断层扫描（PET），以非侵入性 并定量绘制IIa类HDAC在整个脑中的表达和定位， 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 建议的研究的适用性和可行性，一个示踪剂（18F-26）证明了一个 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征，因为脑 在灰质区域摄取高，导致高质量的PET图像;组织动力学适用于 18F示踪剂，并且通过自阻断和与SAHA（panHDAC）的特异性结合证明了对IIa类HDAC的特异性结合 抑制剂）。因此，我们提出了以下三个具体目标：（1）合成并筛选30个 候选抑制剂。(2)为了使用我们的新的放射性标记来自aim 1的所选示踪剂候选物（N=6）， 放射合成途径和其他已建立的放射化学方法。(3)验证三种最佳放射性示踪剂， 健康大鼠脑中IIa类HDAC表达的体内PET/CT成像。我们将进行定量分析 体外放射自显影与我们的铅示踪剂测量IIa类HDAC表达在死后脑切片 并将这些样本与健康对照组（sans 通过IIa类HDAC PET成像早期检测AD将允许早期干预以减缓或停止疾病 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，如亨廷顿病、缺血性中风、创伤性 脑损伤和癌症