粘着斑激酶(Focal Adhesion Kinase, FAK)是一种非受体型酪氨酸激酶，在肿瘤的发生、发展和转移等各个环节起着至关重要的作用。FAK在绝大多数种类的肿瘤细胞中都是高度或过度表达的，因此，FAK是一个潜在的肿瘤诊疗靶点。 据我们所知，直到目前为止，在靶向FAK的小分子药物研究方面，人们只是在普药层面上进行了作为肿瘤治疗药物的FAK小分子抑制剂的研究，先前并没有在放射性药物层面上进行靶向FAK的用于肿瘤早期诊断的药物的研究报道。因此，在本项研究中，我们首次尝试进行了新型F-18标记的靶向FAK的肿瘤显像剂的研究。 我们目前已经共制备了五类新型F-18标记的靶向FAK的肿瘤显像剂分子，及其相对应的F-19标准品和部分药物中间体分子，共26个化合物。对其中24个化合物进行了体外FAK酶活性抑制研究；两个化合物进行了体外不同种类的酶活性选择性抑制研究；12个F-18标记化合物进行了体外稳定性等理化性质测试、荷S180肿瘤小鼠的体内生物分布研究；2个F-18标记化合物进行了荷S180肿瘤小鼠的小动物PET/CT影像学研究（包括阻断实验研究）；对其中10个F-19标准品分子或药物中间体分子同FAK的相互作用，进行了分子动力学模拟方面的计算化学研究。 在体外FAK酶活性抑制研究方面，有两个5-氯-1,3-嘧啶类的F-19标准品以及药物中间体（[19F]TAE-2、IM3-1、[19F]TAE-1和IM3-2）的结果非常理想，分别为0.4 nM、2.2 nM、3.7 nM和4.7 nM，其中前三个化合物在此方面，均优于目前文献报道的药效最好的FAK抑制剂PF-562,271（美国辉瑞公司研制，目前正在进行临床II期研究），IM3-2也在此方面与之处于同一数量级（对这几个分子同样值得在普药层面上进行抗肿瘤活性的深入研究）；在荷S180肿瘤小鼠的体内生物分布研究方面，有四个F-18标记物（5-溴-1,3-嘧啶类的[18F]2a和[18F]2b，5-氯-1,3-嘧啶类的[18F]TAE-2，1,3,5-三嗪类的[18F]TAE-4）的结果较好，分别于尾静脉注射后30 min、30 min、60 min和30 min在肿瘤组织中的吸收达到吸收峰值，分别为5.80±0.06、5.96±0.09、6.29±0.49和7.66±0.85 %ID/g，瘤/肉值分别为3.14、2.49、2.56和1.75，瘤/骨值分别为2.76、1.55、1.44和2.09，瘤/血值分别为4.43、1.94、11.03和1.13；在荷S180肿瘤小鼠的小动物PET/CT影像学研究方面，影像学研究结果表示，5-溴-1,3-嘧啶类的[18F]2a和[18F]2b能够在肿瘤组织中明显地浓聚；药物阻断实验的结果，连同之前的体外不同激酶选择性抑制实验结果表明，[18F]2a和[18F]2b可能是具有选择性的靶向FAK的肿瘤显像剂；在分子动力学模拟研究方面，分子动力学模拟的结果同10个F-19标准品或药物中间体分子和FAK作用的变化趋势相一致。

FAK (Focal Adhesion Kinase), a non-receptor tyrosine kinase, plays an essential role in tumor development, progression and metastasis. FAK is over-expressed or highly expressed in a wide variety of types of tumor cells. Therefore, FAK has been suggested as a promising target in the diagnosis and therapy of tumor. To the best of our knowledge, however, people only concentrated on the research of FAK small molecule inhibitors for the tumor therapy at the level of the generic pharmaceuticals. Therefore, in this study, the first attempt was made to develop a series of F-18 labeled FAK targeted radiotracers for the early diagnosis of tumor at the level of the radiopharmaceuticals. To date, we have prepared five types of novel F-18 labeled FAK targeted tumor imaging agents, and their F-19 standards and pharmaceutical intermediates (twenty-six compounds in sum). Among which, the in vitro FAK inhibitory study of twenty-four compounds, in vitro stability study and in vivo biodistribution study in mice bearing S180 tumor of twelve F-18 labeled compounds, micro-PET/CT imaging study of two F-18 labeled compounds, and the molecular dymamics (MD) study of ten small molecules, have been performed. In the in vitro FAK inhibitory study, results of [19F]TAE-2, IM3-1, [19F]TAE-1 and IM3-2 were excellent, of which FAK IC50 values are 0.4 nM, 2.2 nM, 3.7 nM and 4.7 nM, respectively. The results of the three former compounds are better than that of the positive control drug PF-562,271, and IM3-2 is basically in the same magnitude with PF-562,271. What’s more, in the in vivo biodistribution study in mice bearing S180 tumor, results of [18F]2a, [18F]2b, [18F]TAE-2 and [18F]TAE-4 were relatively good, their uptake in tumor reached to the peak value of 5.80±0.06, 5.96±0.09, 6.29±0.49 and 7.66±0.85 %ID/g at 30 min, 30 min, 60 min and 30 min, respectively. In addition, the micro-PET/CT imaging study showed that the [18F]2a and [18F]2b could be obviously accumulated in tumor, especially at 30 min post-injection. Furthermore, the results of the MD (molecular dynamics) simulation were in agreement with the changing trends of the interaction between the ten different small molecules and the FAK.