In vivo characterization of the PET pharmacokinetic properties of T807 in humans

 描述(由申请人提供)：AD的公共卫生负担正在增加，在国际基础上进行了毁灭性的预测。虽然最近关于AD疾病过程的许多知识已经获得，由于PET Aü成像结合MRI海马区体积、FDG PET、Aü和tau脑脊液(CSF)浓度和认知能力-仍有许多需要了解，特别是当该领域从终末期疾病进一步转移到临床前AD时。Jack和Holtzmann(2013)的结论是，5种AD生物标志物已被充分验证，可纳入临床诊断标准和治疗试验使用，分为两大类：(1)A？沉积(A？PET、CSF A？)和(2)神经变性(FDG？PET、MRI？HV、CSF？tau)。[18F]T807(也称为[18F]AV-1451)等有前景的tau特异性PET试剂的开发，可能会导致一个新的体内脑内局部聚集tau水平的第6 AD生物标志物。第一项人类T807 PET研究显示，有望在体内检测聚集的tau负荷，但组织比率数据(即SUVR)表明，相对T807摄取动力学可能随观察到的体内结合水平的不同而不同，对于对照组和轻度结合组，SUVR平台在不同区域提前且稳定地开始，对于中等结合组，接近平台的方法具有更大的可变性，而对于高结合组，则几乎稳定积累。这引起了人们的关注，即在注射后100分钟的PET扫描间隔(通常使用)内在固定时间间隔内确定的区域T807组织比率可能不能作为跨受试者组和区域的可靠的结合措施。这项拟议的研究是朝着“充分验证”这一生物标志物迈出的重要一步，其目的是表征T807在体内的PET动力学，并验证有效和一致的横断面和纵向数据收集和解释的可行方法。这项研究将主要集中在AD疾病谱上，并对30名受试者进行[11C]PIB(PIB)筛查：15名PIB(-)对照[5名年轻人，10名老年人]和15名PIB(+)受试者[5名老年对照，5名轻度认知障碍，5名AD]。我们还将通过探索：(1)T807在一小群进行性核上性麻痹受试者中的动力学，以及(2)体内T807PET与tau负荷的神经病理学测量和其他神经病理学测量之间的关系来加强这一特征。很有可能[18F]T807将成为使用最广泛的PET tau显像剂，至少在初期是这样。几个地点的研究正在进行中或正在启动(例如，无症状阿尔茨海默病的抗淀粉样蛋白治疗(A4)研究)。在这项新技术的早期使用期间，有必要在AD研究人群中仔细系统地评估T807动力学。

 DESCRIPTION (provided by applicant): The public health burden of 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 PET Aß imaging in combination with MRI Hippocampal volume, FDG PET, Aß and tau cerebrospinal fluid (CSF) concentrations and cognitive performance - there is still much to be understood, particularly as the field moves further from end-stage disease to preclinical AD. Jack and Holtzmann (2013) concluded that 5 AD biomarkers were sufficiently validated for inclusion into clinical diagnostic criteria and therapeutic trial use that fall into 2 broad measures: (1) Aß deposition (Aß PET, CSF Aß) and (2) neurodegeneration (FDG PET, MRI HV, CSF tau). The development of promising tau-specific PET agents, such as [18F]T807 (also named [18F]AV-1451), could lead to a new 6th AD biomarker for regional brain aggregated tau levels in vivo. The first human T807 PET studies show promise for the in vivo detection of aggregated tau load but tissue ratio data (i.e., SUVR) suggest that the relative T807 uptake kinetics may vary across observed levels of in vivo binding, with early and stable onset of the SUVR plateau across regions for controls and mild binders, more variability in the approach to plateau for moderate binders and nearly steady accumulation for high binders. This raises concern that regional T807 tissue ratios determined at a fixed time interval within the 100 min post-injection PET scan interval (commonly used) may not serve as robust binding measures, across subject groups and regions. The proposed research is an essential step toward "sufficient validation" of such a biomarker in its aim to characterize the in vivo PET kinetics of T807 and verify feasible methods for valid and consistent cross-sectional and longitudinal data collection and interpretation. This research will primarily focus on the AD disease spectrum and study 30 subjects screened with [11C]PiB (PiB): 15 PiB(-) controls [5 young, 10 elderly] and 15 PiB(+) subjects [5 elderly controls, 5 mild cognitive impairment, 5 AD]. We will augment this characterization by also exploring: (1) T807 kinetics in a small group of subjects with Progressive Supranuclear Palsy and (2) relationships between in vivo T807 PET and neuropathology measures of tau load and other neuropathology measures. It is very likely that [18F]T807 will be the most widely used PET tau imaging agent, at least initially. Studies are ongoing or being initiated at several sites (e.g., Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study). There is a need for a careful systematic evaluation of T807 kinetics in an AD research population, during the early use of this new technology.