二嗪类Aβ分子探针的合理设计及其AD多模态成像应用

Molecular imaging plays key roles in biological research, drug R&D, diagnostics. Molecular imaging probes is a key cornerstone of this technology. Alzheimer’s disease (AD) is the major cause of cases of dementia and rising seriously social problem. The hypothesis that the pathogeny of this disease is owing to Aβ plaques from β-Amyloid (Aβ) deposition is most prevailing. Consequently, Aβ plaque is a marker for AD detection, and it is vital to early diagnosis for effective therapy of AD. However, it was not satisfactory for reported molecular probes to detect Aβ plaques in vivo. Our project aims to develop a series of fluorogenic diazine-based far red/NIR probes used for Aβ detection, analyze structure-activity relationship to obtain excellent Aβ probes. Base on this, combined with different molecular imaging technology, we will design 18F-PET/FI dual-modality probes for more precise detection of Aβ plaques in vivo. Finally, it will report pretargeting PET/FI dual-modality probes based on tetrazine-conjugates and D3 peptide with its mimics in the third part. This system is more reliable and accurate detection efficiency in vivo owing to the orthogonality of tetrazine and the targeting ability of D3 peptide to Aβ proteins. The implementation of this project will promote the development of molecular imaging of Aβ plaques in vivo and provide a solid foundation for early diagnosis and treatment of AD.

分子影像技术在生物学研究、药物开发、疾病诊断等方面扮演着重要作用，其中分子探针是分子成像的关键基础。阿尔兹海默疾病（AD）是老年痴呆病最常见的形式，正逐步引发严重的社会问题。脑部Aβ蛋白沉积形成Aβ斑块是人们普遍接受的AD致病机理。Aβ可作为AD检查的标志物，并且AD的早期诊断对其有效治疗至关重要。然而，目前的分子探针对Aβ斑块的活体检测仍然不是很理想。因此，本项目拟开发一系列二嗪类远红/近红外荧光探针，并进行系统的构效关系研究，以获得性能优异的Aβ斑块探针。在此基础上，结合不同分子成像技术，开发活体Aβ检测更加准确的18F-PET/FI双模态Aβ斑块探针。最后，结合四嗪Aβ探针生物正交性和D3肽的Aβ靶向性，首次开发预定位双靶向Aβ多模态体系，实现对活体Aβ斑块更高的检测灵敏度和可靠性。本项目的开展能够提升现有对Aβ斑块的分子成像检测技术，为临床AD的早期诊断和治疗奠定坚实的基础。

阿尔兹海默疾病（AD）是老年痴呆病最常见的形式，正逐步引发严重的社会问题。脑部Aβ蛋白沉积形成Aβ斑块是人们普遍接受的AD致病机理。Aβ可作为AD检查的标志物，并且AD的早期诊断对其有效治疗至关重要。然而，目前的分子探针对Aβ斑块的活体检测仍然不是很理想。因此，本项目开发了一系列二嗪类远红/近红外荧光探针，并进行系统的构效关系研究，获得数个性能优异的Aβ斑块探针。在所有探针中，部分探针的荧光发射波长达到了红光区域（约640 nm）,并且在二氯甲烷中拥有较高的量子产率(约0.3)。另外，部分染料还拥有较大的斯托克斯位移（大于100 nm）。并对探针在检测Aβ斑块聚集体的选择性、灵敏性和脂水分配系数方面进行了详细的评估。初步实现了探针对AD老鼠切片Aβ斑块和活体检测。在此基础上，功能衍生化后，初步实现了Aβ双模态18F-PET/FI探针的构建。本项目的开展能够提升现有对Aβ斑块的分子成像检测技术，为临床AD的早期诊断和治疗奠定坚实的基础。