Radiolabeled benzoxazinoles - a unique beta-amyloid PET-tracer class allowing the dichotomous detection of parenchymal and vascular beta-amyloid deposits

放射性标记苯并恶嗪 - 一种独特的 β-淀粉样蛋白 PET 示踪剂类别，可对实质和血管 β-淀粉样蛋白沉积物进行二分检测

• 批准号: 325375587
• 负责人: Professor Dr. Bernd Pichler
• 金额: --
• 依托单位: Abteilung für Präklinische Bildgebung und Radiopharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/325375587?language=en
• 关键词: Radiolabeled; benzoxazinoles; unique; beta; amyloid

Alzheimer disease (AD) is an insidious, fatal disorder of the central nervous system (CNS) affecting 2/3 out of the estimated 35 mio people worldwide living with dementia. Key hallmarks of AD are the formation and accumulation of extracellular deposits through enzymatic cleavage of the amyloid precursor protein (APP), resulting in the formation of diverse and distinctly different amyloid deposits, depending on posttranslational peptide modifications and mutation status of the host. In patients with a genetic predisposition for AD, thus affected by a hereditary form of the disease, these processes take place already decades before first clinical symptoms are recognized. Only recently, it was discovered that the fragment length of the amyloid peptide, between 40 and 42 amino acids, predetermines the site of deposition in the transgenic mouse brain (parenchymal or vascular deposition). Thus, as the primary deposition site of amyloid species can be very different, it is well conceivable that the role in the development of the pathophysiological condition present in the diseased AD brain is distinctly divergent for cerebral amyloid angiopathy (CAA) and parenchymal amyloidosis (PEA). To unravel potentially differing pathogenic mechanisms of both amyloid deposits, it is crucial to develop a non-invasive screening method (in this proposal based on Positron Emission Tomography, PET) allowing for a quantitative and dichotomous detection of PEA and CAA, this is, however, so far not available. The strength of a non-invasive, in vivo diagnosis of mixed PEA/CAA states with PET or PET/MRI is the ability for 3D volume quantitation and a fully translational character of this technique. Moreover, to date no specific CAA PET-tracer is available and previously published CAA-imaging conceptual studies are unconvincing. Currently, we see a pressing need for a specific CAA tracer, as we have recently identified CAA as the major determinant behind quantitative loss of perfusion during the course of AD; thus CAA could have an important and, yet, underestimated impact on the progression of AD. As it turned out in the past decade, most of the published amyloid PET tracers are promiscuous amyloid imaging agents targeting several diffuse and dense deposits of both, APP and of non-APP nature. Therefore, there is still an urgent need for the development of improved diagnostic PET-tracers to image the disease progress in a reliable, comparable and amyloid-species differentiating manner. The hitherto neglected class of benzoxazinoles are characterized by the unique property of selective PEA or CAA affinity, depending on the lead structure design - a property that none of the other amyloid tracer classes is offering. Thus, the primary goal of this research proposal is to identify a structure design for a specific PEA and a specific CAA PET-tracer allowing their separate detection in the same subject.

阿尔茨海默病（Alzheimer disease，AD）是一种潜在的、致命的中枢神经系统（CNS）疾病，在全世界估计的3500万痴呆患者中，有2/3的人患有AD。AD的关键特征是通过淀粉样前体蛋白（APP）的酶促裂解形成和积累细胞外沉积物，导致形成多种和明显不同的淀粉样沉积物，这取决于宿主的翻译后肽修饰和突变状态。在具有AD遗传易感性的患者中，因此受到疾病的遗传形式的影响，这些过程在首次临床症状被识别之前已经发生了几十年。仅在最近，发现淀粉样肽的片段长度在40和42个氨基酸之间，预先决定了在转基因小鼠脑中的沉积位点（实质或血管沉积）。因此，由于淀粉样物质的主要沉积部位可能非常不同，因此很可能在患病AD脑中存在的病理生理学状况的发展中的作用对于脑淀粉样血管病（CAA）和实质淀粉样变性（PEA）明显不同。为了揭示两种淀粉样蛋白沉积物的潜在不同致病机制，关键是开发一种非侵入性筛查方法（在该提议中基于正电子发射断层扫描，PET），其允许PEA和CAA的定量和二分检测，然而，这是迄今为止不可用的。用PET或PET/MRI对混合PEA/CAA状态进行非侵入性体内诊断的优势在于3D体积定量的能力和该技术的完全转化特征。此外，迄今为止，没有具体的CAA PET示踪剂是可用的，以前发表的CAA成像概念研究是没有说服力的。目前，我们迫切需要一种特定的CAA示踪剂，因为我们最近发现CAA是AD过程中灌注定量损失的主要决定因素;因此CAA可能对AD的进展产生重要但被低估的影响。在过去的十年中，大多数已发表的淀粉样蛋白PET示踪剂是混杂的淀粉样蛋白成像剂，靶向APP和非APP性质的几种弥漫性和致密沉积物。因此，仍然迫切需要开发改进的诊断PET示踪剂，以可靠、可比和淀粉样蛋白种类区分的方式对疾病进展进行成像。迄今为止被忽视的一类苯并恶嗪醇的特征在于选择性PEA或CAA亲和力的独特性质，这取决于先导结构设计-其他淀粉样蛋白示踪剂类别都没有提供的性质。因此，本研究提案的主要目标是确定特定PEA和特定CAA PET示踪剂的结构设计，允许在同一受试者中分别检测它们。