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

通过新型多模态 NIR/PET/19F MRI 探头对 AD 淀粉样变性病理进行成像

• 批准号: 8264190
• 负责人: Chongzhao Ran
• 金额: $ 15.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264190
• 关键词: APP-PS1; Algorithms; Alzheimer' s Disease; Amyloid; Amyloidosis; Animals; Antibodies; Binding; Blood - brain barrier anatomy; Brain; CH3OCF2CH(CF3)OCH2F; Clinical Trials; Curcumin; Deposition; Detection; Early Diagnosis; Human; Hybrids; Image; In Vitro; Libraries; Location; Magnetic Resonance Imaging; Measures; Metabolism; Modality; Modification; Molecular; Monitor; Neurodegenerative Disorders; Outcome; Pathological Staging; Pathology; Penetration; Positron-Emission Tomography; Property; Reporter; Research; Screening procedure; Slice; System; Testing; Therapeutic; Therapeutic Uses; Time; Toxicity Tests; Transgenic Animals; Translations; base; clinical Diagnosis; design; drug development; falls; imaging modality; imaging probe; in vitro testing; in vivo; inhibitor/antagonist; molecular imaging; mouse model; novel; pre-clinical; public health relevance; secretase; theranostics

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.

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寡聚体、不溶性纤维和斑块，对于准确和早期检测AD病理以及药物开发和治疗监测是不可或缺的。近红外成像(NIR)、磁共振成像(MRI)和正电子发射断层成像(PET)是目前为A2物种提供成像能力的成像方式。每一种模式都有自己的优缺点；多模式成像是一种新兴的方法，它结合了来自多个模式的信息，为以下方面提供了根本改进：1)准确的检测，以便进行早期诊断和空间定位；2)关于靶点分子活动的明确信息；3)易于从动物研究转换到临床试验。到目前为止，多模式成像的努力主要集中在两个目标上：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联合配准，以实现精确的空间定位；2)通过开发多模式成像探针来获得更准确的目标分子水平信息。这种探针特别适用于AD和其他神经退行性疾病的检测和监测。姜黄素是印度咖喱中的主要姜黄素类化合物，已被用于体外检测淀粉样蛋白沉积。然而，它的快速新陈代谢和有限的血脑屏障(BBB)渗透能力不允许它作为体内显像剂使用。在这项应用中，我们建议创建一个小型的具有近红外特性的姜黄素衍生物文库，用于体外和体内的初步筛选，并使用PET和19F磁共振成像报告对选定的候选进行修饰，以进行近红外/核磁共振/PET成像。我们将进一步在体内进行转基因动物AD病理的NIR/PET/19F MRI多模式成像。最后，我们将尝试使用合成的探针对AD治疗进行有限的诊断研究，以监测治疗结果。此外，几种非常有前景的PET探针，如PIB(匹兹堡化合物B)和AV-45，已经显示出主要用于成像不溶性A2斑块的有效性；然而，我们仍然缺乏用于成像可溶性A2物种的探针，而可溶性A2物种可能是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显著的结合，我们将在这一应用中进一步研究这一现象。如果成功，随着检测不溶性斑块和可溶性A2物种的探针库的建立，我们相信最终我们将能够监测阿尔茨海默病淀粉样变性病理的全程。 公共卫生意义：拟议的研究将有利于阿尔茨海默病的临床前动物研究和药物开发，并将具有潜在的能力，以早期和准确的临床诊断阿尔茨海默病。