COX-2-selective PET imaging as an onset marker of Huntington's disease

COX-2 选择性 PET 成像作为亨廷顿病的发病标志物

• 批准号: 10308680
• 负责人: Jacob M. Hooker
• 金额: $ 64.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308680
• 关键词: Acute; Affect; Affinity; Automobile Driving; Autopsy; Autoradiography; Basal Ganglia; Binding; Binding Proteins; Biochemical; Biochemistry; Biological; Biological Assay; Brain; Brain Diseases; Carbon; Cells; Central Nervous System Diseases; Cessation of life; Clinical Markers; Coxibs; Data; Degenerative Disorder; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Disease model; Drug Kinetics; Early Intervention; Enzymes; Event; Evoked Potentials; Exhibits; Fluorine; Functional disorder; Generations; Genes; Globus Pallidus; Goals; Grant; Human; Huntington Disease; Huntington gene; Image; Imaging Device; Immune; Immunohistochemistry; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inherited; Interdisciplinary Study; Involuntary Movements; Kinetics; Lead; Ligands; Link; Measurement; Measures; Mediating; Microglia; Molecular; Monitor; Neurobehavioral Manifestations; Neurodegenerative Disorders; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Play; Positron-Emission Tomography; Pre-Clinical Model; Process; Prognosis; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Proteins; Radiolabeled; Research; Rodent; Role; Signal Transduction; Symptoms; Synapses; Tissues; Treatment Efficacy; Up-Regulation; blood-brain barrier penetration; brain tissue; cyclooxygenase 1; cyclooxygenase 2; cytokine; density; design; disease mechanisms study; genetic testing; glial activation; imaging agent; immune activation; improved; in vivo; in vivo Model; in vivo imaging; insight; motor disorder; mouse model; nanomolar; neuroinflammation; neuron loss; novel; novel therapeutics; paralogous gene; prevent; psychiatric symptom; radiochemical; radiotracer; response; success; synaptic pruning; therapeutically effective; tool; treatment strategy; uptake

Project Summary Huntington’s Disease (HD) is an autosomal dominant, neurodegenerative disease characterized by involuntary movement dysfunction, and cognitive and psychiatric symptoms, ultimately resulting in death. Although diagnostic testing is available for HD, there remains a critical need for an objective clinical marker to characterize both disease onset and progression. In order to develop effective therapeutics to support early intervention and prevent decline, we need to understand the early-stage biological changes in the living brain that occur at disease conversion. Imaging with positron emission tomography (PET) facilitates in vivo longitudinal measurements of molecular changes that manifest with evolving pathology. To date however, no PET ligands have been generated to predict disease conversion or aid prognosis in HD. Recent studies have shown that glial cell activation can be detected either at or just prior to the onset of symptoms in HD patients, evoking potential for the development of such a ligand. In addition, there is emerging evidence from neurodegenerative disease models that microglia, the brain’s resident immune cells, play an important role in some of the earliest pathological events, including synaptic loss. Our preliminary data showing increased cyclooxygenase-2 (COX-2) protein in both HD patient and HD mouse model brains (postmortem), suggest it holds promise as a novel clinical marker. Preclinical models exhibit elevated COX-2 during periods of microglia-mediated synaptic elimination, an event early in the pathology of many neurodegenerative diseases. In addition, we see COX-2 is increased specifically in the microglia of disease-affected regions in human HD post-mortem brain tissue. The only way to truly understand the role that COX-2 plays in HD is to examine its presence and dynamics in the human brain throughout the course of disease. Therefore, we propose to develop a selective radiotracer for in vivo PET imaging to study COX-2 dysregulation in the living brain, and carry out ex vivo mechanistic studies of COX-2 function in microglia. We will synthesize novel COX-2-selective ligands, optimized for affinity, target selectivity, high brain uptake, and amenability to radiolabeling with carbon-11 or fluorine-18. These ligands will undergo rigorous physiochemical and biochemical profiling, including assays that evaluate COX-2-isoform selectivity, and that predict blood-brain barrier penetration. Lead compounds will be radiolabeled and evaluated with in vitro autoradiography using human HD post-mortem brain tissue to evaluate specific and saturable binding. This will be followed by in vivo imaging in rodents with PET to evaluate brain uptake, radiotracer kinetics, and radiometabolites. In parallel, we will elucidate biochemical mechanisms of COX-2 in microglia in HD mouse models, and investigate the role COX-2 plays in altering microglial function. By the end of the grant project period, our team will have the ability to study COX-2 in the living brain with translational imaging tools, enabling improved understanding of HD pathophysiology and accelerating development of novel therapeutics.

项目摘要 亨廷顿氏病（HD）是一种常染色体显性，神经退行性疾病，以非自愿性为特征 运动功能障碍以及认知和精神病符号最终导致死亡。虽然 诊断测试可用于HD，目的是对客观临床标记的表征至关重要的需求 疾病发作和进展。为了开发有效的治疗以支持早期干预和 防止下降，我们需要了解生命大脑中发生的早期生物学变化 转换。与正电子发射断层扫描（PET）成像促进了体内纵向测量 表现出进化病理的分子变化。但是，迄今为止，尚未产生宠物配体 预测疾病的转化或有助于HD的预后。最近的研究表明，神经胶质细胞活化可以是 在高清患者的症状发作之前或之前检测到 这样的配体。此外，还有来自神经退行性疾病模型的新兴证据，这些模型是小胶质细胞， 大脑的居民免疫细胞，在一些最早的病理事件中起着重要作用，包括 突触损失。我们的初步数据显示HD患者和 HD小鼠模型大脑（验尸）表明它具有新颖的临床标记。临床前模型 在小胶质细胞介导的突触紧急事件期间展示了COX-2升高，这是病理早期的事件 许多神经退行性疾病。此外，我们认为Cox-2在小胶质细胞中的特异性增加 人类高清后尸体后脑组织受疾病影响的区域。真正了解角色的唯一方法 在整个过程中 疾病。因此，我们建议开发用于体内PET成像的选择性放射性示例以研究COX-2 活大脑的失调，并对小胶质细胞中COX-2功能进行离体机械研究。我们 将合成新型的Cox-2选择配体，针对亲和力，目标选择性，高脑摄取和 与碳-11或氟-18的放射性标记的不合适性。这些配体将经历严格的理化学 和生化分析，包括评估COX-2-异型选择性的评估，并预测血脑 障碍穿透。铅化合物将使用放射性标记和评估，并使用体外放射自显影术评估 人类高清验尸后脑组织，以评估特定且饱和的结合。接下来是体内 用PET的啮齿动物成像，以评估脑摄取，放射性示意剂动力学和放射性代谢物。并行，我们 将阐明高清小鼠模型中小胶质细胞中COX-2的生化机制，并研究该作用 COX-2在改变小胶质功能方面发挥作用。到赠款项目期结束时，我们的团队将有能力 使用翻译成像工具在活大脑中研究COX-2，从而提高对HD的了解 病理生理学和新型治疗的加速发展。