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.

项目概要 亨廷顿病 (HD) 是一种常染色体显性遗传的神经退行性疾病，其特征是不自主的 运动功能障碍以及认知和精神症状，最终导致死亡。 诊断测试可用于 HD，但仍然迫切需要客观的临床标志物来表征 疾病的发生和进展，以开发有效的治疗方法来支持早期干预和治疗。 为了防止衰退，我们需要了解疾病时活体大脑中发生的早期生物学变化 正电子发射断层扫描 (PET) 成像有助于体内纵向测量 然而，迄今为止，尚未产生 PET 配体。 最近的研究表明，神经胶质细胞的激活可以预测疾病的转化或帮助预后。 在 HD 患者出现症状时或症状出现之前检测到，从而引发了发展的潜力 此外，来自神经退行性疾病模型的新证据表明，小胶质细胞， 大脑的常驻免疫细胞在一些最早的病理事件中发挥着重要作用，包括 我们的初步数据显示 HD 患者和 HD 患者中环氧合酶 2 (COX-2) 蛋白均增加。 HD 小鼠模型大脑（尸检）表明它有望成为一种新型临床前模型。 在小胶质细胞介导的突触消除期间表现出 COX-2 升高，这是病理学早期的一个事件 此外，我们发现 COX-2 在小胶质细胞中特异性增加。 人类HD死后脑组织中受疾病影响的区域是真正了解其作用的唯一方法。 COX-2在HD中的作用是检查它在整个过程中在人脑中的存在和动态。 因此，我们建议开发一种用于体内 PET 成像的选择性放射性示踪剂来研究 COX-2。 活体大脑中的失调，并对小胶质细胞中 COX-2 功能进行离体机制研究。 将合成新型 COX-2 选择性配体，并针对亲和力、靶点选择性、高脑摄取和 易于用碳 11 或氟 18 进行放射性标记。这些配体将经过严格的物理化学处理。 和生化分析，包括评估 COX-2-亚型选择性和预测血脑的测定 屏障渗透性将被放射性标记并使用体外放射自显影进行评估。 人类 HD 死后脑组织以评估特异性和可饱和结合，随后将进行体内结合。 同时，我们对啮齿类动物进行 PET 成像，以评估大脑摄取、放射性示踪剂动力学和放射性代谢物。 将阐明HD小鼠模型中小胶质细胞中COX-2的生化机制，并研究其作用 COX-2 在改变小胶质细胞功能方面发挥作用，到资助项目期结束时，我们的团队将有能力。 使用转化成像工具研究活体大脑中的 COX-2，从而提高对 HD 的理解 病理生理学和加速新疗法的开发。