Fang Yu, Wang Dawei, Xu Xingyu, Dava Gila, Liu Jianping, Li Xiang, Xue Qianqian, Wang Huan, Zhang Jiangshan, Zhang Huabei
Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University No. 19 Xinjiekouwai Street, Haidian District Beijing 100875 People's Republic of China
College of Chemistry and Chemical Engineering, Anyang Normal University No. 436 Xian'ge Avenue Anyang 455000 People's Republic of China.
RSC Adv. 2018 Mar 14;8(19):10333-10345. doi: 10.1039/c8ra00652k. eCollection 2018 Mar 13.
Focal adhesion kinase (FAK) has been identified as a promising target in the early diagnosis and therapy of tumor. In this work, we obtained and evaluated another two novel pyrimidine-based F-18 labeled tumor imaging agents targeting FAK. Among them, the corresponding F-19 standards [F]2, displayed inhibition of FAK with IC values of 57.1 nM (better than the results in our published work) and showed an good selectivity profile against some other kinds of cancer-related kinases. [F]2 also had relatively good results in the biodistribution in S180-tumor-bearing mice, with tumor uptake of 5.40 ± 0.12 and 5.96 ± 0.09 % ID per g at 15 and 30 min post-injection, respectively. What's more, [F]2 could be accumulated in tumor at 30 min post-injection, which could be observed from the coronal micro-PET images of mice bearing S180 tumor. In addition, the blocking study for the [F]2 with PF-562271 (one of the well-known best selective FAK inhibitor), displayed distinct reduction in the uptake of the radiotracer in tumor at 30 min post-injection in mice, suggesting that the uptake of [F]2 in tumor was due to FAK over-expression or high expression in tumor. And the results of the molecular dynamics (MD) simulations and the docking studies were in consistent with the changing trends of the interaction between the F-19 standards and the FAK. Finally, in order to further increase the uptake of the F-18 labeled tracer in tumor, the following points should arouse attention, which could also be considered as the new findings and contributions of this study to the field of the tumor imaging agents: (1) the F-18 labeled tumor radiotracers which have closer interaction with the FAK, should be further designed, building of models such as 3D-QSAR model to make reasonable guidance to our drug design and consideration of some functional groups which have hydrogen-bonding or salt-bridge interactions with key residues in the kinase domain of FAK; (2) the F-18 radiotracers with better pharmacokinetic properties should be designed, building of dynamic drug absorption and distribution model in different tissues, to predict whether the molecules have ideal absorption in tumor and low uptake in non-target tissues. The relevant study is being undertaken.
粘着斑激酶（FAK）已被确定为肿瘤早期诊断和治疗中有前景的靶点。在本研究中，我们获得并评估了另外两种基于嘧啶的新型F-18标记的靶向FAK的肿瘤显像剂。其中，相应的F-19标准品[F]2对FAK的抑制作用的IC值为57.1 nM（优于我们已发表工作中的结果），并且对其他几种癌症相关激酶显示出良好的选择性。[F]2在荷S180肿瘤小鼠中的生物分布也有相对较好的结果，在注射后15分钟和30分钟时，肿瘤摄取分别为每克5.40±0.12和5.96±0.09%ID。此外，注射后30分钟时[F]2可在肿瘤中蓄积，这可从小鼠荷S180肿瘤的冠状位微型PET图像中观察到。另外，用PF-562271（一种著名的最佳选择性FAK抑制剂）对[F]2进行阻断研究，结果显示在注射后30分钟时小鼠肿瘤中放射性示踪剂的摄取明显降低，这表明[F]2在肿瘤中的摄取是由于肿瘤中FAK的过表达或高表达。分子动力学（MD）模拟和对接研究的结果与F-19标准品和FAK之间相互作用的变化趋势一致。最后，为了进一步提高F-18标记示踪剂在肿瘤中的摄取，应注意以下几点，这也可视为本研究对肿瘤显像剂领域的新发现和贡献：（1）应进一步设计与FAK相互作用更紧密的F-18标记肿瘤放射性示踪剂，构建3D-QSAR模型等模型，为我们的药物设计提供合理指导，并考虑一些与FAK激酶结构域中的关键残基具有氢键或盐桥相互作用的官能团；（2）应设计具有更好药代动力学性质的F-18放射性示踪剂，构建不同组织中的动态药物吸收和分布模型，以预测分子在肿瘤中是否具有理想的吸收以及在非靶组织中的低摄取。相关研究正在进行中。
