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（通过应用程序提供）：1。在临床前阶段，需要广泛适用的成像方法：具有Aß特定示踪剂的PET成像已广泛应用于临床试验中，FDA已批准了三个AßPET示踪剂供临床使用。 PET成像也是临床前广告研究的新兴工具。但是，由于以下原因，其在小动物中监测药物治疗的应用受到限制：1）PET探针合成和PET扫描的高成本，2）放射性材料实践，以及3）当前AßPET示踪剂的不足，仅对不溶性敏感 Aßs，但不是总aßs。这些因素阻止了许多实验室使用PET成像进行临床前广告疗法研究。据信，由于其成本效益，速度，广泛的可用性和易于使用的操作，近乎感染的荧光（NIRF）分子成像具有满足需求的能力。我们认为，这种具有成本效益的技术将使更多的候选药物进行临床前动物研究，因此，更多的候选者将参加临床试验。 2。固体和固体的成像问题的需求 不溶性Aß物种：在AD进展过程中，亚种的优势从可溶性的原纤维和斑块逐渐变化，但是所有Aß物种在大多数阶段都存在。这表明需要对可溶性和不溶性aßs敏感的问题。目前，不溶性物种的宠物问题的发展非常成功。但是，对于检测总aßs检测的成像问题仍然难以捉摸。我们的初步数据表明，姜黄素类似物Cranad -3和-58具有不仅检测不溶性Aß的能力，而且还可以在体外和体内溶于aß物种。在此应用中，我们建议将Cranad -3和-58验证为可靠的NIRF成像问题，以监视小鼠模型中几类AD药物候选物的效率。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药物发现社区。