Near-infrared molecular imaging for monitoring therapy in AD mouse models

用于监测 AD 小鼠模型治疗的近红外分子成像

• 批准号: 9130088
• 负责人: Chongzhao Ran
• 金额: $ 8.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130088
• 关键词: APP-PS1; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloidosis; Animals; Antibodies; Antibody Therapy; Biological Assay; Boston; Brain; Categories; Clinical; Clinical Trials; Collaborations; Communities; Curcumin; Cyclohexanes; Data; Detection; Development; Enzyme-Linked Immunosorbent Assay; FDA approved; Fluorescence; Future; Goals; Grant; Health; Image; In Vitro; Methods; Molecular; Monitor; Mus; Near-Infrared Fluorescence Imaging Probe; Near-infrared optical imaging; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Positron-Emission Tomography; Protocols documentation; Radioactive; Research; Services; Signal Transduction; Speed; Staging; Technology; Testing; Therapeutic Studies; Tracer; Validation; analog; base; beta-site APP cleaving enzyme 1; cost; cost effectiveness; cost efficient; drug candidate; drug development; drug discovery; drug efficacy; efficacy evaluation; imaging modality; imaging platform; imaging probe; in vivo; inhibitor/antagonist; meetings; molecular imaging; mouse model; operation; pre-clinical; prevent; therapeutic effectiveness; tool; treatment duration; two-photon

 DESCRIPTION (provided by applicant): 1. The need of widely applicable imaging methods for AD drug development at the preclinical stage: PET imaging with Aß specific tracers has been widely applied in clinical trials and three Aß PET tracers have been approved by FDA for clinical use. PET imaging is an emerging tool for preclinical AD research as well. However, its application for monitoring drug treatment in small animals is limited, due to the following reasons: 1) the high cost of PET probe synthesis and PET scanning, 2) radioactive material practice, and 3) the insufficiency of current Aß PET tracers that are only sensitive for insoluble Aßs, but not for total Aßs. These factors prevent numerous labs from using PET imaging for preclinical AD therapeutic studies. Near infrared fluorescence (NIRF) molecular imaging is believed to have the capacity to meet this demand due to its cost-effectiveness, speed, wide availability, and easy-to-use operation. We believe this cost-efficient technology will enable significantly more drug candidates go through preclinical animal studies, and consequentially more candidates will enter into clinical trials. 2. The need of imaging probes for both soluble and insoluble Aß species: In the course of AD progression, the predominance of the subspecies changes gradually from soluble species to insoluble fibrils and plaques, however all Aß species are co-existing at most of the stages. This indicates the need for probes that are sensitive to both soluble and insoluble Aßs. Currently, the development of PET probes for insoluble species has been very successful. However, the availability of imaging probes for the detection of total Aßs is still elusive. Our preliminary data showed that curcumin analogues CRANAD-3 and -58 have the capability of detecting not only insoluble Aß species, but also soluble Aß species in vitro and in vivo. In this application, we propose to validate CRANAD-3 and -58 as reliable NIRF imaging probes to monitor the efficacy of several categories of AD drug candidates in mouse models. Our ultimate goal is to establish a reliable and affordable imaging platform that will be widely available for AD drug discovery community.

 描述（申请人提供）： 1. AD药物开发临床前阶段需要广泛适用的成像方法：Aß特异性示踪剂的PET成像已广泛应用于临床试验，三种Aß PET示踪剂已被FDA批准用于临床PET 成像也是临床前 AD 研究的新兴工具，但由于以下原因，其在监测小动物药物治疗方面的应用受到限制：1）PET 探针合成成本较高。和 PET 扫描，2) 放射性物质实践，以及 3) 目前仅对不溶物敏感的 Aß PET 示踪剂的不足 Aßs，但不是总 Aßs。这些因素阻止了许多实验室使用 PET 成像进行临床前 AD 治疗研究，近红外荧光 (NIRF) 分子成像因其成本效益、速度、我们相信，这种具有成本效益的技术将使更多的候选药物能够进行临床前动物研究，从而使更多的候选药物进入临床试验。可溶性和可溶性成像探针 不溶性 Aß 物种：在 AD 进展过程中，亚种的优势逐渐从可溶性物种转变为不溶性原纤维和斑块，但所有 Aß 物种在大多数阶段共存，这表明需要敏感的探针。目前，用于不溶性物质的 PET 探针的开发非常成功，但是用于检测总 Aßs 的成像探针仍然可用。我们的初步数据表明，姜黄素类似物 CRANAD-3 和 -58 不仅能够检测不溶性 Aß 物种，而且能够在体外和体内检测可溶性 Aß 物种。在本应用中，我们建议验证 CRANAD-3 和 - 58 作为可靠的 NIRF 成像探针，用于监测几类 AD 候选药物在小鼠模型中的功效。我们的最终目标是建立一个可靠且负担得起的成像平台，该平台将广泛用于 AD 药物发现界。