Imaging AD Amyloidosis Pathology by Novel Multi-modal NIR/PET/19F MRI Probes

描述（由申请人提供）：针对A2物种的新型分子成像探针，包括可溶性A2低聚物，不溶性原纤维和斑块，对于准确和早期检测AD病理，以及药物开发和治疗监测是必不可少的。NIR（近红外成像），MRI（磁共振成像）和PET（正电子发射断层扫描）是目前提供A2物种成像能力的成像方式。每种模式都有自己的优点和缺点；多模态成像是一种新兴的方法，它结合了来自多个模态的信息，为以下方面提供了根本性的改进：1)准确检测，允许早期诊断和空间定位；2)关于靶标分子活性的明确信息；3)易于从动物研究到临床试验的转化。迄今为止，多模态成像的研究主要集中在两个方面：1)通过构建混合成像系统或使用复杂的配准算法来实现更好的协同配准，从而实现精确的空间定位；2)通过开发多模态成像探针，获得更精确的目标分子水平信息。这种探针将特别适合于检测和监测阿尔茨海默病和其他神经退行性疾病。姜黄素是印度咖喱中的主要类姜黄素，已被用于淀粉样蛋白沉积物的体外检测。然而，其快速的代谢和有限的穿透血脑屏障（BBB）不允许其作为体内显像剂使用。在本申请中，我们建议建立一个具有近红外特性的姜黄素衍生物的小文库，用于体外和体内初步筛选，并使用PET和19F MR成像报告器对选定的候选物进行修饰，用于近红外/MRI/PET成像。我们将进一步在体内对转基因动物进行AD病理的NIR/PET/19F MRI多模态成像。最后，我们将尝试使用合成探针对AD治疗进行有限的诊断研究，以监测治疗结果。此外，几种非常有前途的PET探针，如PiB（匹兹堡化合物B）和AV-45，主要用于成像不溶性A2斑块；然而，我们仍然缺乏一种探针来成像可溶性A2物种，这可能是AD早期病理阶段的有毒物种。由于我们在初步研究中合成的姜黄素衍生物显示出与单体物种的明显结合，我们将在本应用中进一步研究这一现象。如果成功的话，我们将拥有一系列检测不溶性斑块和可溶性A2的探针，我们相信最终我们将能够监测阿尔茨海默病淀粉样变病理的整个过程。

DESCRIPTION (provided by applicant): New molecular imaging probes specific to A2 species including soluble A2 oligomers, insoluble fibrils and plaques, are indispensable for accurate and early detection of AD pathology, as well as for drug development and treatment monitoring. NIR (near infrared imaging), MRI (magnetic resonance imaging) and PET (positron emission tomography) are the imaging modalities that currently provide capabilities for imaging A2 species. Each of these modalities has its own advantages and weaknesses; multi-modality imaging, an emerging approach that combines information from more than one modality, provides fundamental improvements for 1) accurate detection to permit early diagnosis and spatial localization; 2) unambiguous information about molecular activities of a target; 3) easy translation from animal study to clinical trial. To date, multi-modality imaging efforts have been focused primarily on two objectives: 1) to achieve better co-registration for accurate spatial location by constructing hybrid imaging systems or using complicated registration algorithms; 2) to achieve more accurate molecular-level information of the target by developing multi-modal imaging probes. Such probes would be particularly suitable for detection and monitoring of AD and other neurodegenerative diseases. Curcumin, the principal curcuminoid of the Indian curry, has been used for ex vivo detection of amyloid deposits. However, its rapid metabolism and limited penetration across blood-brain barrier (BBB) do not allow for its use as an in vivo imaging agent. In this application we propose to create a small library of curcumin derivatives with NIR properties for in vitro and in vivo preliminary screening, and adapt the selected candidates for modification with PET and 19F MR imaging reporters for NIR/MRI/PET imaging. We will further perform NIR/PET/19F MRI multi-modality imaging of AD pathology in transgenic animals in vivo. Finally, we will attempt to conduct a limited theragnostic study with AD therapeutics using the synthesized probes for monitoring of the therapeutic outcome. In addition, several very promising PET probes such as PiB (Pittsburg compound B) and AV-45 have displayed efficacy primarily for imaging insoluble A2 plaques; however, we still fall short of a probe for imaging the soluble A2 species, the likely toxic species at early AD pathological stage. Since curcumin derivatives synthesized in our preliminary studies showed appreciable binding to monomeric species, we will investigate this phenomenon further in this application. If successful, with an arsenal of probes for detection of both insoluble plaques and soluble A2 species, we believe that eventually we will be able to monitor the full course of amyloidosis pathology of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposed research will be beneficial for the preclinical animal study and the drug development for Alzheimer's Disease, and will have potential capability for the early and accurate clinical diagnosis of Alzheimer's Disease.