用于阿尔茨海默病诊断和治疗效果评价的sigma-2受体分子探针

Alzheimer’s disease (AD) seriously affects human health and quality of life. Many drug candidates targeting amyloid-beta plaque clearance have failed recently. It is well known that oligomers are the most toxic form of the amyloid-beta protein. Sigma-2 receptor antagonist CT1812 is a novel drug candidate for treatment of AD. It can prevent the binding of oligomers to receptors on neurons, displace oligomers from synaptic receptor and clear oligomers from the brain into the cerebrospinal fluid and thus improve cognitive decline in AD patients. Therefore, sigma-2 receptor is the novel therapeutic target of early stage of AD. However, there is no molecular probe used in clinical trial for neuroimaging of sigma-2 receptors in the brain currently. The main contents of the project are as follows. (1) Design, synthesis and evaluation of 18F-labeled molecular probes and fluorescent probes targeting sigma-2 receptors. (2) Investigation of sublocation of sigma-2 receptors and therapeutic mechanism of drug candidates for treatment of AD using fluorescent probes and 18F-labeled probes. (3) Neuroimaging of sigma-2 receptors in the brain of different AD model and control animals using 18F-labeled probes together with noninvasive technique positron emission tomography (PET). (4) Comparison of the expression difference of sigma-2 receptors in the brain during the progress of AD. The investigation in this project may provide us suitable PET molecular probes for neuroimaging of sigma-2 receptors in the brain used for diagnosis of AD and highly sensitive tool for efficacy monitoring of emerging AD therapeutic strategies.

阿尔茨海默病（AD）严重影响人类健康和生活质量，而AD治疗新药研发屡遭失败。sigma-2 (σ2)受体拮抗剂CT1812作用于Abeta毒性最大的寡聚体，能抑制Abeta寡聚体与神经元受体结合，将Abeta寡聚体清除至脑脊液中，从而促进AD患者认知功能恢复。因此，σ2受体是AD早期治疗的新靶点。但尚没有靶向σ2受体、监测AD患者脑中σ2受体变化情况的可视化分子探针。本课题拟设计合成靶向σ2受体、用于AD脑活体显像的18F标记的分子探针和研究σ2受体亚细胞定位的荧光探针，并进行相关的生物评价实验，在分子水平上深入探索新型AD治疗药物的独特作用机理，并配合PET显像在活体水平上无创、高灵敏地显示σ2受体在正常脑和不同AD模型脑中的变化情况。该项目有望研制出性能优异的用于AD早期诊断的σ2受体PET分子探针，将为评价AD治疗效果提供高灵敏的工具，加速实现AD病人的个性化诊断和治疗。

Sigma-2（σ2）受体不仅是阿尔茨海默病（AD）早期治疗的新靶点，而且是肿瘤增殖的生物标志物。本课题设计合成了含有6,7-二甲氧基-1,2,3,4-四氢异喹啉、5,6-二甲氧基异吲哚啉或甲磺酰基异吲哚啉等药效团的系列σ2受体配体，制备了靶向σ2受体的18F标记的分子探针和荧光探针以及靶向σ1受体的18F标记的哌嗪类分子探针，并进行了相应的体内外生物评价。取得的创新性结果如下：（1）获得了分子探针1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole，该探针对σ2受体具有高亲和性和高选择性，是迄今为止报道的啮齿动物和猴脑中具有最高进脑量、最高脑/血比、最高体内特异结合率以及合适的脑内药代动力学的σ2受体显像剂。（2）获得了新颖的18F标记的分子探针1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-(2-[18F]fluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one，该探针对σ2受体具有纳摩尔数量级亲和性和高选择性，可以清晰地显示U87MG肿瘤，且与σ2受体结合特异性高，有望用于脑瘤增殖状态的显像。（3）获得了综合性质优异的σ1受体激动型分子探针(S)-[18F]FBFP和拮抗型分子探针(R)-[18F]FBFP，它们在非人灵长类动物恒河猴PET显像结果均优于处于临床试验阶段的σ1受体脑显像剂(S)-(-)-[18F]Fluspidine。因此，该课题不仅为AD的早期诊断和治疗效果评价提供了性质优异的σ1受体和σ2受体分子探针，而且为脑瘤增殖状态的显像提供了高特异性的σ2受体分子探针。利用上述探针进行PET显像，将为有效评估AD和癌症病人的治疗策略提供依据，加速实现AD和癌症病人的个性化治疗。