Aβ和tau蛋白分子探针在阿尔茨海默病早期诊断的联合研究

Alzheimer's disease (AD) is characterized by early neuropathological pathways-extracellular Senile Plaque （SP）deposits and intracellular neurofibrillary tangles (NFTs) in the brain.β-amyloid (Aβ) and tau protein imagings can be used to observe changes of SP and NFTs in brain in a direct, delicate and specific way. This study was designed to produce Aβ protein tracer ([11C]-PIB) and Tau protein tracer ([18F]-THK523) , conduct preclinic researchs, including chemical synthesis, isotope labelling, quality control, pharmacology and toxicology, and to explore the potential value and applied prospects for [11C]-PIB and [18F]-THK523 as Aβ and tau protein molecular probes in AD. The preliminary studies demonstrated that the diagnostic sensitivity for [11C]-PIB in AD is 100%, however, there are Aβ deposits in some neural diseases and normal olderly. In order to make up the relatively inadequate specificity for Aβ imaging, we designed to study the diagnosis of AD in a combined way with [11C]-PIB and [18F]-THK523 imagings. With complementary advantages of high sensitivity for Aβ protein and high specificity for tau protein, Aβand tau imaging tracers may serve as in vivo markers for early diagnosis of AD, especially providing a new method of the detection of preclinical AD (with clinical dementia rating of 0), playing an important role in the quantitative analysis,early diagnosis and efficacy monitoring of AD. The combined imagings of Aβand tau protein may be profoundly significant in dectecting and diagnosing of preclinical AD.

老年斑（SP）和神经纤维缠（NFTs）是阿尔茨海默病（AD）早期病理标志，Aβ蛋白和tau蛋白活体显像能直观、灵敏、特异地分别反应SP和NFTs的变化情况。本课题研制性能优良的Aβ蛋白显像剂[11C]-PIB和tau蛋白显像剂[18F]-THK523，进行临床前相关研究，同时探讨其作为Aβ蛋白和tau蛋白显像剂在AD的潜在价值和应用前景。前期研究提示[11C]-PIB在AD的诊断灵敏度为100%，但一些神经系统疾病和正常老年中亦可见Aβ蛋白沉积，针对Aβ蛋白特异性相对不足，本课题利用特异性tau蛋白显像剂联合显像，高灵敏性Aβ蛋白与高特异性tau蛋白优势互补，为AD早期诊断，特别是临床前期AD的检诊提供新方法。本课题将为临床上以SP和NFTs为主要病理特征的AD的定量分析、早期诊断和疗效监测提供合适的正电子显像药物，Aβ蛋白和tau蛋白联合显像对AD的早期诊断且提高诊断符合率具有深远意义。

根据课题研究计划，自主设计两种tau蛋白分子探针[18F]-THK523和[11C]-TKF、以及tau蛋白和Aβ蛋白分子耦合探针[18F]-TKP，并建立自动化合成工艺及临床前相关研究，与Aβ蛋白显像（[11C]- PIB、[18F]-flutemetamol）联合应用与比较，为临床显像奠定基础。.1. [18F]-THK52前体经自主改进后，标记率、放化纯、比活度有明显改善，分别为（70±5%；>90%；2.5 ± 0.5 GBq/µmol），细菌性和内毒素检测均为阴性。.2. [18F]-THK523在正常C57小鼠的Micro PET显像符合预期；[18F]-THK523急性毒性研究显示安全；放射自显影结果Micro PET相匹配。[18F]-THK523稳定性好、脂溶性好、不带电荷及血浆蛋白结合率较低且不具有质量浓度依赖性，同时[18F]-THK523为小分子。综上而言,[18F]-THK523满足脑显像剂的基本要求。药代动力学实验显示 [18F]-THK523给药后2 min具有较高进脑量，特别是海马区域，随后快速清除。.3.Tau蛋白显像剂[11C]-TKF在正常动物体内主要通过胆道代谢，总体进脑量较[18F]-THK523更为理想，并且快速洗脱，急性毒性实验阴性。 [11C]-TKF标记率约>40%（无衰减较正），放化纯>95%。.4.自主设计了新型Tau蛋白和Aβ双靶点分子探针[18F]-TKP（前体THKP和标准品TKPF国内外均没有报道）。临床前研究显示[18F]-TKP是一种靶向研究Aβ蛋白和Tau蛋白的潜在PET显像剂。进脑量最高在注射[18F]-TKP后2min，其他大多数脑区的分布相似。.5.通过 [11C]- PIB显像结合脑葡萄糖（FDG）的PET显像，提取脑认知功能调节的关键区域后扣带回、楔叶、嗅皮层、额叶皮质、内侧颞叶及外侧颞叶，并分析临床认知量表MMSE的相关性，比较出MCI人群转化为AD与MCI未转化人群脑部FDG代谢的不同，后扣带回的葡萄糖代谢减低及Aβ蛋白沉积增多的异同在MCI转化中发挥了关键作用，为以后MCI所致AD的早期诊断及治疗提供理论依据，减轻AD治疗的经济负担和社会发挥潜在的价值。.6.临床前分子影像分析显示Tau蛋白和Aβ双靶点联合显像优势互补，在AD早期诊断中提供有效定量分析手段。