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

阿尔茨海默病(AD)是一种潜伏的、致命的中枢神经系统(CNS)疾病，全世界估计有3500万痴呆症患者，其中三分之二受到影响。阿尔茨海默病的关键特征是通过对淀粉样前体蛋白(APP)的酶解形成和积累细胞外沉积，导致不同和截然不同的淀粉样沉积的形成，这取决于宿主的翻译后多肽修饰和突变状态。对于具有阿尔茨海默病遗传易感性的患者，因此受到这种疾病的遗传形式的影响，这些过程在第一临床症状被识别之前就已经发生了几十年。就在最近，人们发现淀粉样肽的片段长度在40到42个氨基酸之间，预先决定了转基因小鼠大脑中的沉积位置(实质或血管沉积)。因此，由于淀粉样蛋白的主要沉积部位可能非常不同，可以很好地想象，在阿尔茨海默病患者大脑中存在的病理生理状况的发展中，大脑淀粉样血管病(CAA)和实质淀粉样变性(PEA)的作用明显不同。为了揭示这两种淀粉样蛋白沉积潜在的不同致病机制，关键是开发一种非侵入性筛查方法(在本提案中基于正电子发射断层扫描，PET)，允许对PEA和CAA进行定量和二分法检测，然而，到目前为止，这还不是可用的。PET或PET/MRI对混合PEA/CAA状态的无创活体诊断的优势在于3D体积定量的能力和该技术的完全平移特性。此外，到目前为止还没有特定的CAA PET示踪剂可用，以前发表的CAA成像概念性研究也不能令人信服。目前，我们认为迫切需要一种特定的CAA示踪剂，因为我们最近发现CAA是AD过程中定量灌注丧失的主要决定因素；因此，CAA可能对AD的进展具有重要的、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示踪剂都是混杂的淀粉样蛋白显像剂，目标是APP和非APP性质的几种弥漫和致密的沉积物。因此，仍迫切需要开发改进的诊断PET示踪剂，以可靠、可比较和淀粉样蛋白种类区分的方式成像疾病进展。迄今为止被忽视的苯并恶唑类化合物具有选择性PEA或CAA亲和力的独特性质，这取决于铅的结构设计--这是其他淀粉样示踪剂类都不具备的特性。因此，这项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，从而允许在同一对象中分别检测它们。

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.