F18标记的喹唑啉类EGFR表达肿瘤显像剂研究

Cancer has become the first killer of human beings. The PET imaging technique has developed fast because it possesses accurate diagnosis, high specificity and effective evaluation. The earlier tumor is detected, the more effective therapy can be achieved. The search for satisfactory tumor imaging agents from 18F labeled drugs meets the development of drugs used as tumor diagnosis. There was exponential growth of the PET application in hospitals in our country, while the 18F labeled drugs explored in our country is lack. 18F labeled imaging agents suffered from lots of false positive diagnosis, consequently, the research on novel 18F labeled tumor imaging agents is the focus of modern nuclear medicine. It has been reported that quinazoline core has capability of localizing tumor and high tumor uptake with the peak value between 30 to 120 min which were scarcely found in other drugs. The objective of our project is to design novel 18F labeled quinazoline derivatives as imaging agents for EGFR tumor detection by introducing alkyl, halogen sugar, polyhydric alcohol and polyethylene glycol ether groups to quinazoline derivatives synthesized previously by us. Our aim is to fill in the blanks of our country in exploring independent intellectual property rights of novel 18F labeled drugs for diagnosis which possess high tumor selection, low toxicity, high specificity and accurate diagnosis. The success of this project is of great significance to national development of novel drugs, promotion of PET and economic development. So we earnestly request great support.

肿瘤已成为人类第一杀手，因PET显像相对诊断率高、特异性强、评价疗效好的特点，发展非常迅速。而肿瘤的治疗关键在于早发现，从18F标记药物的研究中寻找性能好的肿瘤显像剂更符合肿瘤诊断药物的发展要求。我国医院PET的使用率成指数倍增长，而自研的18F标记药物却是空白。氟-18标记的显像剂仍存在许多假阳性诊断，因此新型18F标记肿瘤显像剂研究是新世纪核药学界的焦点课题。现已证实喹唑啉结构具有亲肿瘤性质，在肿瘤中吸收很高，最大峰值出现在30～120min,是难得的药物结构体系。本项目希望在我们现有基础上通过引入糖、多羟基醇、聚乙二醇醚等修等饰喹唑啉l结构设计新型18F标记的喹唑啉类EGFR肿瘤诊断剂，研发出对肿瘤选择性强、毒性低、特异性高、评价疗效好的具有自主知识产权的新型18F标记诊断药物，填补我国在该领域的空白。该项目如果取得成功，将对我国的新药研发、PET的推广和经济发展具有重大意义。

一、抗肿瘤和诊断的喹唑啉衍生物.以喹唑啉作为优势结构骨架，以Vandetanib、Canertinib、Lapatinib、Icotinib为参考，改变喹唑啉环6，7-位上的侧链结构，同时对喹唑啉4位的 4-位苯胺基进行侧链修饰改造，通过系列合成得到了八个系列共700多个新型喹唑啉类衍生物；以在保持喹唑啉母环及 6- 位的取代基保持不变，7-位的取代基改变的前提下，合成得到了16个F-19喹唑啉类衍生物，进而得到了6个F-18标记的喹唑啉类衍生物，对其进行了1H NMR、13C NMR、MS、HPLC等结构表征。对合成的全部八个系列、700个新型喹唑啉类衍生物进行体外抗肿瘤活性评价。用MTT法以PC3、HepG2、A549、MCF-7、DU145、SH-SY5Y六种肿前景的瘤细胞对700个目标化合物进行抗肿瘤活性初步筛选；筛选出来29个具有开发前景的喹唑啉类衍生物，进而对筛选出来29个具有开发前景的喹唑啉类衍生物中的12个目标位进行了体内筛选研究，其中六个化合物在抗肝癌、肺癌、前列腺癌和SY5Y等有很好的研发前景。该课题申请国际专利1个，国内专利2个，批准国内专利1个，在European Journal of Medicinal Chemistry、BMC等期刊上发表文章6篇。.二、单分子检测技术在基因诊断的前沿性研究.单分子检测对众多疾病的超前诊断具有快速、高效、样板数小等优点，具有很大的优化前景。我们利用超精细的微纳加工技术和巧妙的界面化学修饰方法成功地构建了基于硅纳米线器件的单分子生物传感器以及高增益硅纳米线场效应晶体管电路实时监测无标签F 1的ATP水解的方法，通过一系列的温度、梯度、电学测试获得了单个DNA或蛋白质分子的杂交动力学信息，进而，从实验上直接观察到单个碱基分辨率的杂交动力学过程，实现了在超低浓度下区分单个DNA分子、F1蛋白逐个吸附于硅线表面的高灵敏高效率检测，这个平台可以自然地扩展到检测到许多其他带电的化学物质，许多重要的生物大分子的单分子检测对众多疾病的超前诊断具有重要作用。该课题为未来疾病诊断开创了新思路，具有速度快、检测方便、样板数少等优点。相关文章发表在Angew Chem Int Edit、ACS NANO、Advanced Scince、Nanoscale等期刊上，文章内容引发了许多同行的关注。