In vivo imaging agents targeting Tau aggregates

靶向 Tau 聚集体的体内成像剂

• 批准号: 7329991
• 负责人: Hank F Kung
• 金额: $ 20.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329991
• 关键词: Address; Affect; Affinity; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Area; Autopsy; Autoradiography; Binding; Binding Sites; Biodistribution; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Brain region; Cerebellum; Clinical; Dementia; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Disease Progression; Drug Kinetics; Drug Monitoring; Early Diagnosis; Emission-Computed Tomography; Future; Healthcare; Human; Image; Impaired cognition; In Vitro; Incidence; Label; Laboratories; Lead; Life; Ligands; Link; Location; Maps; Measurement; Measures; Medical; Memory Loss; Methods; Monitor; Mus; Naphthalene; Naphthalenes; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Older Population; Paralysed; Pathology; Patients; Photons; Physiology; Positron-Emission Tomography; Progressive Supranuclear Palsy; Radiolabeled; Risk; Role; Sampling; Screening procedure; Signal Transduction; Societies; Specificity; Stratification; Structure; Symptoms; Tauopathies; Testing; Therapeutic; Tissue Sample; Tissues; X-Ray Computed Tomography; base; brain cell; brain tissue; corticobasal degeneration; density; hyperphosphorylated tau; improved; in vivo; innovation; molecular imaging; older patient; protein aggregate; radiotracer; single photon emission computed tomography; success; tau Proteins; tau aggregation; tau-1; tool

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease of the brain, symptoms include dementia, cognitive impairment and memory loss. The disease has a very significant medical importance because it is affecting millions of older population with increasing incidence. Formation and accumulation of aggregates of ¿-amyloid aggregates (A¿ plaques) and tau (tangles) in the brain are distinctive hallmarks of this insidious disease. Both are protein aggregates that contain parallel ¿-sheet structures. The aggregates are likely to be linked to the patho-physiology of neurodegeneration of brain cells. Currently, early appraisal of clinical symptoms for diagnosis of AD is often difficult and unreliable. Therefore, there is an urgent need for in vivo imaging agents, which can specifically demonstrate the location and density of tangles and plaques in the brain. The objective of this project is to develop potential F-18 and I-123 labeled diagnostic imaging agents, which specifically detect tangles (tau aggregates) in the brain using positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively. Imaging tau (tangles), a biomarker for AD, may lead to improve understanding of disease progression and it may potentially be useful for monitoring drug treatment targeting the formation of hyperphosphorylated tau in the brain cells. Based on recent success from our laboratory on developing A¿ plaque-targeting imaging agents, we believe that it is feasible to expand into the area of developing new selective probes for tangles. It is generally accepted that brain samples of corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) patients contain predominately tangles (consisting mainly tau aggregates). Using postmortem brain tissue samples of CBD and PSP for homogenate binding assay and tissue section labeling, we hope to selectively detect tau binding. Three specific aims are proposed: I). In vitro binding assay for specific binding of tau aggregates. II). Synthesis of new compounds. III). In vitro autoradiography of brain sections. IV). Selected compounds will be labeled and evaluated further by in vivo biodistribution study using normal mice. The proposed specific aims are innovative and carefully crafted to meet the stringent requirements for selecting tau-specific imaging agents. We believe that tau-selective imaging agents can be successfully developed and they will serve an unmet need as diagnostic tools for early detection of AD. Alzheimer's disease and other Tauopathies are neurodegenerative diseases of the brain. They are becoming increasingly significant medical problems in our aging society. In order to address the enormous future healthcare burdens that they pose, we need to find effective diagnostic tools and therapeutics for neurodegenerative diseases now. The most significant anatomical hallmarks of these diseases are the presence of ¿-amyloid (A¿) plaques, and neurofibrillary tangles, which contain highly phosphorylated Tau proteins. The objective of this project is to develop F and I labeled molecular imaging agents that can selectively detect 18 123 Tau aggregates in the living human brain. In conjunction with PET (positron emission tomography) or SPECT (single photon computed tomography) these agents will be critically important tools that will be able to visualize and quantify the accumulation of Tau aggregates in the brain of patients with neurodegenerative diseases. The critical objective of this project is to find a F or I compound with a high binding affinity to Tau 18 123 aggregates which can deliver sufficient signal correlated with Tau aggregates in the living human brain. The potential benefits of developing these imaging agents include: a) More precise diagnosis and monitoring of the progression of AD or Tauopathies in symptomatic patients; b) Improved risk stratification of asymptomatic elderly patients prior to AD or other Tauopathy related disorders; c) Better understanding the role of Tau aggregate accumulation in progression of MCI and AD patients; d) Catalyzation of the development of anti-Tau therapies.

描述（申请人提供）：阿尔茨海默病（AD）是一种大脑神经退行性疾病，症状包括痴呆、认知障碍和记忆丧失。该疾病具有非常重要的医学重要性，因为它影响着数百万老年人，且发病率不断上升。大脑中 ¿-淀粉样蛋白聚集体（A¿ 斑块）和 tau 蛋白（缠结）的形成和积累是这种隐匿疾病的独特标志。两者都是含有平行 ¿-片层结构的蛋白质聚集体。这些聚集物可能与脑细胞神经变性的病理生理学有关。目前，通过早期评估临床症状来诊断 AD 通常很困难且不可靠。因此，迫切需要体内成像剂，能够特异性地显示大脑中缠结和斑块的位置和密度。该项目的目标是开发潜在的 F-18 和 I-123 标记诊断成像剂，分别使用正电子发射断层扫描 (PET) 和单光子发射计算机断层扫描 (SPECT) 专门检测大脑中的缠结（tau 聚集体）。 tau（缠结）是 AD 的一种生物标志物，对其进行成像可能有助于提高对疾病进展的了解，并且可能有助于监测针对脑细胞中过度磷酸化 tau 形成的药物治疗。基于我们实验室最近在开发 A 斑块靶向成像剂方面取得的成功，我们相信扩展到开发新的缠结选择性探针领域是可行的。人们普遍认为，皮质基底节变性 (CBD) 或进行性核上性麻痹 (PSP) 患者的大脑样本主要含有缠结（主要由 tau 蛋白聚集体组成）。使用 CBD 和 PSP 的死后脑组织样本进行匀浆结合测定和组织切片标记，我们希望选择性地检测 tau 结合。提出了三个具体目标：I)。 tau 聚集体特异性结合的体外结合测定。二）。新化合物的合成。三）。脑切片的体外放射自显影。四）。选定的化合物将被标记并通过使用正常小鼠的体内生物分布研究进一步评估。所提出的具体目标是创新且精心设计的，以满足选择 tau 特异性显像剂的严格要求。我们相信 tau 选择性显像剂可以成功开发，并且它们将满足作为早期检测 AD 的诊断工具的未满足的需求。阿尔茨海默病和其他 Tau蛋白病是大脑的神经退行性疾病。在我们的老龄化社会中，它们正成为日益重要的医疗问题。为了解决它们未来带来的巨大医疗负担，我们现在需要找到针对神经退行性疾病的有效诊断工具和治疗方法。这些疾病最显着的解剖学特征是存在 β-淀粉样蛋白 (A¿) 斑块和神经原纤维缠结，其中含有高度磷酸化的 Tau 蛋白。该项目的目标是开发 F 和 I 标记的分子成像剂，可以选择性地检测活人大脑中的 18 123 个 Tau 聚集体。与 PET（正电子发射断层扫描）或 SPECT（单光子计算机断层扫描）相结合，这些试剂将成为至关重要的工具，能够可视化和量化神经退行性疾病患者大脑中 Tau 聚集体的积累。该项目的关键目标是找到对 Tau 18 123 聚集体具有高结合亲和力的 F 或 I 化合物，该化合物可以传递与活体人脑中的 Tau 聚集体相关的足够信号。开发这些显像剂的潜在好处包括： a) 更精确地诊断和监测有症状患者的 AD 或 Tau 病进展； b) 改善 AD 或其他 Tau 蛋白病相关疾病之前无症状老年患者的风险分层； c) 更好地了解 Tau 聚集体积累在 MCI 和 AD 患者进展中的作用； d) 催化抗-Tau 疗法的发展。