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

 描述(由申请人提供)：1.临床前阶段AD药物开发需要广泛适用的成像方法：A？特异性示踪剂的PET成像已广泛应用于临床试验，3种A？PET示踪剂已被FDA批准用于临床。PET成像也是临床前AD研究的一种新兴工具。然而，由于以下原因，它在监测小动物药物治疗方面的应用是有限的：1)PET探针合成和PET扫描的高成本；2)放射性物质的使用；3)目前仅对不溶性药物敏感的示踪剂的不足 这些因素使许多实验室无法使用正电子发射计算机断层扫描技术进行临床前AD治疗研究。近红外荧光(NIRF)分子成像因其成本效益高、速度快、可获得性广、操作简单而被认为有能力满足这一需求。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试验，从而使更多的候选药物进入临床试验。2.对可溶性和可溶性的成像探针的需求 不溶性A？种：在AD的进展过程中，亚种的优势逐渐由可溶性种转变为不可溶的纤维和斑块，但在大多数阶段，所有A？种共存。这表明需要对可溶和不溶的S都敏感的探针。目前，针对不溶物种的聚酯探针的开发已经非常成功。然而，用于检测总A？S的成像探针的可用性仍然难以捉摸。我们的初步数据表明，姜黄素类似物CRANAD-3和-58不仅能够在体内外检测不溶的Aü物种，而且还能检测到可溶的Aü物种。在这个应用中，我们建议验证CRANAD-3和-58作为可靠的NIRF成像探针来监测几类AD候选药物在小鼠模型中的疗效。我们的最终目标是建立一个可靠和负担得起的成像平台，将广泛用于AD药物发现社区。

 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.