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: 10369664
• 负责人: Nashaat Turkman
• 金额: $ 79.7万
• 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/10369664
• 关键词: Address; Affinity; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Applications Grants; Autopsy; Autoradiography; Binding; Biochemical; Biological Markers; Brain; Brain Diseases; Brain region; Central Nervous System Diseases; Characteristics; Clinical Data; Cognitive; Data; Defect; Dementia; Disease; Disease Progression; Drug Kinetics; Early Diagnosis; Early Intervention; Enzymes; Epigenetic Process; Evaluation; Family; Glare; HDAC1 gene; HDAC4 gene; HDAC5 gene; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Huntington Disease; Image; 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; Patients; Play; Positron-Emission Tomography; Radiolabeled; Rattus; Reporting; Research; Rest; Rodent; Role; Route; Sampling; Series; Structure; Synaptic plasticity; Tissues; Tracer; Traumatic Brain Injury; Vorinostat; X-Ray Computed Tomography; advanced disease; base; course development; design; frontal lobe; gray matter; human disease; human imaging; imaging probe; imaging study; in vivo; in vivo imaging; inhibitor; member; metabolic profile; molecular imaging; nonhuman primate; novel; overexpression; quantitative imaging; 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 an attempt to delineate the role of Histone Deacetylases (HDACs) in memory function. As such, HDAC blockade with panHDAC inhibitors have been perused to alleviate the memory decline in the AD brain. However, two recent and independent human imaging studies reported that class-I HDAC levels decrease as AD advances, which emphasizes 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, and (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 is of great relevance to other diseases, such as Huntington’s disease, ischemic stroke, traumatic brain injuries, and cancer.

摘要。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。阿尔茨海默氏症与进行性痴呆和认知能力下降有关，这突出了迫切需要新的基于生物标志物的工具来准确检测早期阿尔茨海默氏症并选择患者进行靶向治疗。表观遗传机制的发现及其对阿尔茨海默病认知能力下降的重大贡献激发了广泛的研究，试图描述组蛋白去乙酰化酶（hdac）在记忆功能中的作用。因此，用panHDAC抑制剂阻断HDAC已被用于减轻AD大脑的记忆衰退。然而，最近两项独立的人类影像学研究报告称，随着阿尔茨海默病的进展，i类HDAC水平下降，这强调了在阿尔茨海默病大脑中特异性靶向HDAC的必要性。iia类HDAC成员HDAC4和HDAC5在神经元突触可塑性和记忆形成中起关键作用。Anderson KW等人的一项定量研究发现，AD患者额叶皮层iia类HDAC5表达增加47%，而AD患者额叶皮层i类HDAC5表达下调（hdac1,2减少32%），这与近期使用11c -马诺酸酯获得的临床数据一致。这些发现为我们量化人类AD大脑中iia类HDAC表达变化的方法提供了强有力的证据，并验证了iia类HDAC作为AD的治疗靶点；这将对AD患者产生显著的积极影响。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，以无创和定量地绘制整个大脑中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了所提出研究的适用性和可行性，其中一种示踪剂（18F-26）显示了一种有用的CNS PET示踪剂的特性。18F-26表现出优异的药代动力学和成像特性，因为大脑摄取在灰质区域高，导致高质量的PET图像；组织动力学适用于18F示踪剂，并且通过自我阻断和与SAHA （panHDAC抑制剂）结合，证明了iia类HDAC的特异性结合。因此，我们提出了三个具体目标：(1)合成和筛选30个候选抑制剂的集中库；(2)使用我们的新放射合成途径和其他已建立的放射化学方法对aim1中选定的候选示踪剂（N=6）进行放射性标记；(3)验证用于健康大鼠大脑中iia类HDAC表达的体内PET/CT成像的最佳三种放射性示踪剂。我们将使用我们的铅示踪剂进行定量体外放射自显影，以测量死于AD的患者死后脑切片中iia类HDAC的表达，并将这些样本与健康对照（无AD）的脑组织进行比较。通过iia类HDAC PET成像早期发现AD，将允许使用iia类HDAC抑制剂进行早期干预，以减缓或停止疾病进展。此外，iia类HDAC PET成像与其他疾病有很大的相关性，如亨廷顿病、缺血性中风、外伤性脑损伤和癌症。