PET IMAGING OF Abeta PLAQUES IN ALZHEIMER'S DISEASE

阿尔茨海默病 Abeta 斑块的 PET 成像

• 批准号: 6894269
• 负责人: Hank F Kung
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894269
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; autoradiography; baboons; bioimaging /biomedical imaging; biomarker; brain disorder diagnosis; brain imaging /visualization /scanning; chemical binding; chemical synthesis; diagnosis design /evaluation; drug design /synthesis /production; fluorine; genetically modified animals; laboratory mouse; neuritic plaques; pharmacokinetics; positron emission tomography; radiochemistry; radiodiagnosis; radionuclides; radiotracer; species difference

DESCRIPTION (provided by applicant): This application proposes to develop imaging agents targeting beta-amyloid (Abeta) plaques in the brain of patients with Alzheimer's disease (AD). Cognitive decline and behavioral changes related to old age and AD are often very difficult to differentiate. This is an important clinical question with high impact to millions of potential AD patients. Currently, there is no simple and definitive imaging tool available to assist the diagnosis. Recent reports suggest that accelerated accumulation of Abeta plaques in the brain may be a key risk factor associated with AD. Therefore, Abeta plaques in the brain could be useful as a biomarker for differential diagnosis of AD. Imaging the key component, Abeta protein aggregates, may provide pivotal information pertinent to the initiation and progression of AD. A series of F-18 labeled agents with high binding affinity towards Abeta plaques are proposed as positron emission computed tomography (PET) imaging agents. They are potentially useful to directly estimate the Abeta burden relevant to pathological states of AD and evaluate effects of potential therapeutic drugs aimed at reducing the plaques. Five specific aims are proposed: 1) novel candidates with potential of showing high binding affinity towards Abeta aggregates will be synthesized, 2) binding affinity of proposed candidates will be measured with preformed Abeta aggregates, 3) after optimizing the binding affinity selected candidates will be labeled with F-18, 4) in vivo biodistribution in normal mice after an intravenous injection of a F-18 labeled tracer will be performed to investigate the brain penetration. Additional biodistribution studies of promising agents will also be evaluated in a transgenic animal model of AD and normal non-human primates to assess species differences. The transgenic mice specially engineered to produce excess Abeta plaques in the brain will be injected with selected F- 18 imaging agents. Labeling of Abeta plaques in the cortex and hippocampus regions in the living brain of transgenic mice will be confirmed by ex vivo autoradiography, 5) PET imaging studies of these mice with an animal PET scanner will be performed to select final candidates suitable for phase I clinical trial as biomarkers for diagnosis of Alzheimer's disease.

描述（由申请人提供）： 该应用建议开发针对阿尔茨海默氏病（AD）患者大脑中β-淀粉样蛋白（ABETA）斑块的成像剂。与老年和AD相关的认知能力下降和行为变化通常很难区分。这是一个重要的临床问题，对数百万潜在的AD患者产生了很大影响。当前，尚无简单且确定的成像工具来协助诊断。最近的报告表明，大脑中Abeta斑块的积累加速可能是与AD相关的关键危险因素。因此，大脑中的Abeta斑块可作为AD鉴别诊断的生物标志物。成像关键成分ABETA蛋白聚集体可能提供与AD的启动和进展有关的关键信息。提出了一系列对Abeta斑块具有高结合亲和力的F-18标记药物，作为正电子发射计算机断层扫描（PET）成像剂。它们对于直接估计与AD的病理状态相关的ABETA负担并评估旨在减少斑块的潜在治疗药物的作用是有用的。 Five specific aims are proposed: 1) novel candidates with potential of showing high binding affinity towards Abeta aggregates will be synthesized, 2) binding affinity of proposed candidates will be measured with preformed Abeta aggregates, 3) after optimizing the binding affinity selected candidates will be labeled with F-18, 4) in vivo biodistribution in normal mice after an intravenous injection of a F-18将进行标记的示踪剂以研究脑穿透。在AD和正常非人类灵长类动物的转基因动物模型中，还将评估对有希望药物的其他生物分布研究，以评估物种差异。专门设计用于在大脑中产生过量Abeta斑块的转基因小鼠将注入选定的F-18成像剂。 Ex Vivo自显影术将证实在皮质和海马区域的ABETA斑块将确认，5）使用动物宠物扫描仪对这些小鼠进行宠物成像研究，以选择适用于A型I临床标记的最终候选者，以作为Alzheimerers的生物标志物作为生物分类者的诊断。