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: 7868912
• 负责人: Chongzhao Ran
• 金额: $ 15.36万
• 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/7868912
• 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

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）：特异于A2种类（包括可溶性A2寡聚体、不溶性原纤维和斑块）的新型分子成像探针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物质成像能力的成像模式。这些模式中的每一种都有其自身的优点和缺点;多模式成像是一种新兴的方法，它结合了来自一种以上模式的信息，为以下方面提供了根本性的改进：1）准确检测，以允许早期诊断和空间定位; 2）关于靶分子活性的明确信息; 3）易于从动物研究转化为临床试验。迄今为止，多模态成像工作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配准以精确的空间定位; 2）通过开发多模态成像探针来实现目标的更精确的分子水平信息。这样的探针将特别适合于检测和监测AD和其他神经退行性疾病。 姜黄素是印度咖喱中主要的类姜黄素，已被用于淀粉样蛋白沉积物的离体检测。然而，其快速代谢和有限的穿过血脑屏障（BBB）的渗透不允许其用作体内成像剂。在本申请中，我们提出创建具有NIR特性的姜黄素衍生物的小型文库用于体外和体内初步筛选，并使所选候选物适于用PET和19 F MR成像报告物进行修饰以用于NIR/MRI/PET成像。我们将进一步在体内转基因动物中进行AD病理的NIR/PET/19 F MRI多模态成像。最后，我们将尝试使用合成的探针进行有限的AD治疗的治疗诊断学研究，以监测治疗结果。 此外，几种非常有前途的PET探针，如Pi B（Bibrburg化合物B）和AV-45，已显示出主要用于成像不溶性A2斑块的功效;然而，我们仍然缺乏用于成像可溶性A2物质的探针，可溶性A2物质是早期AD病理阶段的可能毒性物质。由于在我们的初步研究中合成的姜黄素衍生物显示出明显的结合单体物种，我们将在本申请中进一步研究这种现象。如果成功的话，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学的整个过程。 公共卫生关系：该研究将为阿尔茨海默病的临床前动物研究和药物开发提供有益的帮助，并将为阿尔茨海默病的早期和准确的临床诊断提供潜在的能力。