Translation of tau-selective PET radiopharmaceuticals in Alzheimers patients

摘要 这是第一次重新提交面向方法学的R01赠款申请。中国的公共卫生负担 阿尔茨海默病(AD)的发病率正在增加，在国际上有破坏性的预测。虽然很多 最近，由于淀粉样蛋白β(Aβ)正电子的作用，人们对阿尔茨海默病的发病过程有了更多的了解。 发射断层扫描(PET)结合MRI、海马体积、FDGPET、淀粉样蛋白和tau的研究 脑脊液浓度和认知表现--仍有许多需要了解，特别是 随着该领域从终末期疾病进一步发展到临床前AD。十年前，AD的临床研究是 当有可能在体内具体检测到一种决定性的病理变化时，这种变化就发生了 AD，Aβ斑块使用正电子发射计算机断层扫描。然而，淀粉样蛋白沉积本身并不与临床状态密切相关， 认知表现，或进展阶段。相比之下，tau病理的模式，另一种定义AD的模式 病变与AD表型的关系比Aβ病理更密切。第一代tau-PET放射性示踪剂， [18F]T807(也称为[18F]AV-1451；Flortaucipir)，作为一种很有前途的人类tau成像工具出现，是 迄今为止最广泛的使用，开创性的研究源于我们在马萨诸塞州的实验室 综合医院。仍然迫切需要在3个方面改进tau-PET示踪剂，以便及早改善 疾病检测并实现疾病修正治疗试验所需的多个纵向跟踪： 1)减少了脱靶结合，例如，在邻近海马体的结构中；2)在体内得到了改善 Kinetics确保从低到高粘结剂的tau负载的稳定量化；以及3)更高的信噪比 阿尔茨海默病症状前的末端。我们最近共同开发了一种新的第二代tau- 宠物示踪剂，[18F]MK-6240，与默克研究实验室合作。总体目标是 全面评估[18F]MK-6240，使用纵向研究设计显示改进的量化 整个大脑中都有tau的含量。我们的研究将解决确保成功所需的其余关键障碍 [18F]MK-6240在AD临床研究中的应用具体来说，我们的目标是：a)履行 基于动脉的全定量动力学评估[18F]MK-6240动力学；B)测量 [18F]MK-6240在脑内，基线和一年(YR)随访；c)开发一种高产的放射性合成 [18F]MK-6240使用我们先进的放射性氟化技术，从而便于广泛分发和 多中心试验；以及D)和探索性目标，以检查区域和底物特定的放射自显影 [18F]MK-6240的结合及其与其他淀粉样蛋白和非淀粉样蛋白的脱靶结合。严谨的 这种新型、高特异性、灵敏度更高的tau-PET示踪剂在体内测量tau的评价 迫切需要对疾病分期进行病理学和监测。这种新的放射性药物被设想为 以实现更小的样本量、更短的机制验证时间线，并促进最佳患者选择 用于AD治疗的开发。

ABSTRACT This is the first resubmission of a methodology oriented R01 grant application. The public health burden of Alzheimer's disease (AD) is increasing with devastating projections on an international basis. Although much knowledge has been gained recently about the AD disease process, as a result of amyloid-β (Aβ) positron- emission tomography (PET) imaging in combination with MRI hippocampal volume, FDG PET, amyloid and tau cerebrospinal fluid concentrations and cognitive performance - there is still much to be understood, particularly as the field moves further from end-stage disease to preclinical AD. A decade ago, AD clinical research was transformed when it became possible to specifically detect in vivo one of the defining pathologic changes of AD, Aβ plaques using PET. However, amyloid deposition is not itself robustly associated with clinical status, cognitive performance, or stage of progression. In contrast, the pattern of tau pathology, the other AD-defining lesion, is more closely related to the AD phenotype than Aβ pathology. A first generation tau-PET radiotracer, [18F]T807 (a.k.a. [18F]AV-1451; Flortaucipir), emerged as a promising tool for human tau imaging and is the most widely used to date, with pioneering studies originating from our laboratories at the Massachusetts General Hospital. There remains a critical need to improve tau-PET tracers in 3 areas in order to improve early disease detection and enable multiple longitudinal follow-ups required for disease-modifying therapeutic trials: 1) reduction of off-target binding in, for example, structures adjacent to hippocampus; 2) improved in vivo kinetics to ensure stable quantification of tau load across low-to-high binders; and 3) greater signal-to-noise at the pre-symptomatic end of the AD spectrum. We have recently co-developed a novel second generation tau- PET tracer, [18F]MK-6240, in collaboration with Merck Research Laboratories. The overall goal is to comprehensively evaluate [18F]MK-6240, using a longitudinal study design to show improved quantification of tau load throughout brain. Our study will address remaining key obstacles needed to ensure successful application of [18F]MK-6240 for clinical research investigations of AD. Specifically our aims are: A) To perform a fully quantitative arterial-based kinetic evaluation of [18F]MK-6240 kinetics; B) To measure the distribution of [18F]MK-6240 in brain, at baseline and at 1-year (yr) follow-up; C) To develop a high yield radiosynthesis of [18F]MK-6240 using our advanced radiofluorination technology thereby facilitating widespread distribution and multi-center trials; and D) and exploratory aim to examine region- and substrate-specific autoradiographic binding of [18F]MK-6240 and its off-target binding to other amyloid and non-amyloid proteins. The rigorous evaluation of this novel, highly specific tau-PET tracer with greater sensitivity for in vivo measurement of tau pathology and monitoring of disease staging is critically needed. This new radiopharmaceutical is envisioned to enable smaller sample sizes, shorter proof-of-mechanism timelines, and facilitate optimal patient selection for AD treatment development.