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: 8470112
• 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/8470112
• 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; 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; screening; 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.

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 物种成像功能的成像方式。这些方式中的每一种都有其自身的优点和缺点；多模态成像是一种结合了多种模态信息的新兴方法，它为以下方面提供了根本性改进：1）准确检测，以实现早期诊断和空间定位； 2）有关目标分子活动的明确信息； 3）从动物研究到临床试验的轻松转化。迄今为止，多模态成像工作主要集中在两个目标：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）通过开发多模态成像探针来获得更准确的目标分子水平信息。此类探针特别适合检测和监测 AD 和其他神经退行性疾病。 姜黄素是印度咖喱的主要类姜黄素，已用于淀粉样沉积物的离体检测。然而，其快速代谢和穿过血脑屏障（BBB）的有限渗透不允许其用作体内成像剂。在此应用中，我们建议创建一个具有 NIR 特性的姜黄素衍生物小型库，用于体外和体内初步筛选，并使用 PET 和 19F MR 成像记者对选定的候选物进行修饰，以进行 NIR/MRI/PET 成像。我们将进一步对转基因动物体内AD病理进行NIR/PET/19F MRI多模态成像。最后，我们将尝试使用合成的探针来监测治疗结果，对 AD 疗法进行有限的治疗诊断研究。 此外，几种非常有前途的 PET 探针，例如 PiB（匹兹堡化合物 B）和 AV-45，已显示出主要对不溶性 A2 斑块进行成像的功效；然而，我们仍然缺乏对可溶性 A2 物质进行成像的探针，这种物质是早期 AD 病理阶段可能的有毒物质。由于我们的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，因此我们将在本应用中进一步研究这种现象。如果成功的话，通过一系列用于检测不溶性斑块和可溶性 A2 物质的探针，我们相信最终我们将能够监测阿尔茨海默病淀粉样变性病理学的整个过程。