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

T807 在人体内的 PET 药代动力学特性的体内表征

• 批准号: 9129581
• 负责人: Julie C Price
• 金额: $ 52.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129581
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Area; Autopsy; Binding; Biological Markers; Blood flow; Bolus Infusion; Brain; Brain Pathology; Cerebrospinal Fluid; Clinical; Cognitive; Complement; Computer Simulation; Computers; Data; Data Analyses; Data Collection; Deposition; Detection; Development; Diagnostic; Disease; Drug Kinetics; Elderly; Evaluation; Future; Health; Hippocampus (Brain); Human; Image; Impaired cognition; Injection of therapeutic agent; International; Kinetics; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Modeling; Names; Neocortex; Nerve Degeneration; Neurofibrillary Tangles; Pathology; Performance; Plasma; Population Research; Positron-Emission Tomography; Prevalence; Process; Progressive Supranuclear Palsy; Property; Public Health; Quantitative Evaluations; Radiolabeled; Reference Standards; Reporting; Research; Sampling; Site; Synapses; Tauopathies; Temporal Lobe; Testing; Therapeutic Trials; Time; Tissues; Validation; Water; abeta deposition; base; cognitive performance; end stage disease; falls; hyperphosphorylated tau; imaging agent; imaging modality; in vivo; in vivo imaging; innovation; mild cognitive impairment; neurofibrillary tangle formation; neuron loss; neuropathology; new technology; novel marker; pre-clinical; radioligand; radiotracer; statistics; synaptic failure; tau Proteins; tau aggregation; time interval; tool; uptake

 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.

 描述（由申请人提供）：AD的公共卫生负担正在增加，在国际基础上具有破坏性的预测。尽管最近已经获得了关于AD疾病过程的许多知识，但是由于PET Ablast成像与MRI海马体积、FDG PET、Ablast和tau脑脊液（CSF）浓度和认知性能的组合，仍然有许多需要理解的，特别是随着该领域从终末期疾病进一步发展到临床前AD。Jack和Holtzmann（2013）得出结论，5种AD生物标志物已得到充分验证，可纳入临床诊断标准和治疗试验使用，分为2个广泛指标：（1）腺苷酸沉积（腺苷酸PET，CSF腺苷酸）和（2）神经变性（FDG PET，MRI HV，CSF tau）。开发有前景的tau特异性PET试剂，如[18 F]T807（也称为[18 F]AV-1451），可能会导致体内区域脑聚集tau水平的新的第6种AD生物标志物。 第一个人T807 PET研究显示了体内检测聚集的tau负荷的前景，但组织比率数据（即，SUVR）表明，相对T807摄取动力学可能在观察到的体内结合水平之间变化，对于对照和轻度结合者，SUVR平台期在各区域的早期和稳定开始，对于中度结合者，接近平台期的变异性更大，对于高结合者，接近稳定积累。这引起了人们的担忧，即在注射后100分钟PET扫描间隔（常用）内的固定时间间隔测定的区域T807组织比率可能无法作为受试者组和区域的稳健结合指标。拟议的研究是对这种生物标志物进行“充分验证”的重要一步，其目的是表征T807的体内PET动力学，并验证有效和一致的横截面和纵向数据收集和解释的可行方法。本研究将主要关注AD疾病谱，并研究30例接受[11 C]PiB（PiB）筛选的受试者：15例PiB（-）对照[5例年轻，10例老年]和15例PiB（+）受试者[5例老年对照，5例轻度认知障碍，5例AD]。我们还将通过探索以下内容来增强这种表征：（1）一小组进行性核上性麻痹受试者中的T807动力学和（2）体内T807 PET与tau负载的神经病理学测量和其他神经病理学测量之间的关系。 [18F]T807很可能是最广泛使用的PET tau成像剂，至少在最初是这样。研究正在几个研究中心进行或正在启动（例如，无症状阿尔茨海默病中的抗淀粉样蛋白治疗（A4）研究）。有必要在AD研究人群中仔细系统地评价T807的动力学，在早期使用这种新技术。