In vivo imaging agents targeting Tau aggregates

描述(申请人提供)：阿尔茨海默病(AD)是一种脑部神经退行性疾病，症状包括痴呆症、认知障碍和记忆丧失。这种疾病具有非常重要的医学意义，因为它正在影响数以百万计的老年人口，发病率不断上升。大脑中淀粉样蛋白聚集体(A斑块)和tau(缠结)的形成和积累是这种潜伏性疾病的显著特征。两者都是含有平行片状结构的蛋白质聚集体。这些聚集体很可能与脑细胞神经退化的病理生理学有关。目前，对阿尔茨海默病临床症状的早期评估往往是困难和不可靠的。因此，迫切需要体内显像剂，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标记的诊断显像剂，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)来特异性地检测大脑中的缠结(tau聚集体)。成像tau(Tangles)是AD的一个生物标志物，可能有助于更好地了解疾病的进展，并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斑块靶向显像剂方面取得的成功，我们相信扩展到开发新的选择性缠结探针领域是可行的。人们普遍认为，皮质基底性变性(CBD)或进行性核上性麻痹(PSP)患者的大脑样本中主要含有缠结(主要由tau聚集体组成)。利用死后CBD和PSP脑组织标本进行匀浆结合分析和组织切片标记，我们希望有选择地检测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试验。Ii)。新化合物的合成。三)。脑切片的体外放射自显影。四)。选定的化合物将通过正常小鼠的体内生物分布研究进行标记和进一步评估。建议的具体目标是创新和精心制作的，以满足选择tau特定显像剂的严格要求。我们相信，tau选择性显像剂可以成功开发，它们将作为AD早期检测的诊断工具，服务于尚未满足的需求。阿尔茨海默病和其他神经退行性疾病是大脑的神经退行性疾病。在我们老龄化的社会中，它们正成为日益严重的医疗问题。为了应对它们构成的巨大未来医疗负担，我们现在需要为神经退行性疾病找到有效的诊断工具和治疗方法。这些疾病最显著的解剖学特征是存在淀粉样斑块和神经原纤维缠结，其中含有高度磷酸化的Tau蛋白。本项目的目标是开发F和I标记的分子显像剂，可以选择性地检测活体人脑中的18个123 Tau聚集体。与正电子发射断层扫描(PET)或单光子计算机断层扫描(SPECT)相结合，这些试剂将成为重要的工具，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。这个项目的关键目标是寻找一种与Tau 18123聚集体具有高结合亲和力的F或I化合物，以便在活体人脑中传递与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)更准确地诊断和监测有症状患者的AD或肌萎缩侧索硬化症的进展；b)改善无症状老年患者在AD或其他与肌萎缩侧索硬化症相关的疾病之前的风险分层；c)更好地了解Tau聚集在MCI和AD患者进展中的作用；d)促进抗Tau疗法的发展。

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.