肿瘤的高发病率和死亡率已经成为危害人类健康的主要疾病之一，而肿瘤的早诊 断、早治疗是目前防治癌主要策略。粘着斑激酶是一种可高度磷酸化的非受体蛋白（Focal Adhesion Kinase，FAK），在肿瘤的各个阶段均起到重要作用，并在肺癌、乳 腺癌、肝癌和脑胶质瘤等多种类型肿瘤细胞中均过量表达，而抑制 FAK 的表达则会导 致肿瘤细胞的凋亡，因此 FAK 可能是潜在的肿瘤诊疗靶点。本文设计合成一系列靶向 FAK 的抑制剂并用 ¹⁸F 标记研究其生物学性质及作为 PET 肿瘤显像剂的潜力。

本文通过药物设计软件 SYBYL 及 AMBER 指导设计并合成出了一系列 FAK 小分 子抑制剂，化学结构通过核磁及质谱确认。通过 HTRF^®方法测定化合物的体外 FAK 激 酶抑制活性。用 ¹⁸F 放射性标记方法制备 FAK 肿瘤显像剂，通过肿瘤模型鼠的体内生 物分布、阻断实验及 PET 显像实验初步研究其生物学特性。

本文制备了 5 类新型靶向 FAK 的肿瘤显像剂分子，对第 1 类中结构相似的 5 个含 氟化合物进行了分子动力学模拟研究；共测试了 29 个化合物的体外 FAK 激酶抑制活性； 对其中 8 个化合物进行了 ¹⁸F 放射性标记并研究其理化性质及 S180 荷瘤小鼠的体内生 物分布；对其中 1 个 ¹⁸F 标记物进行了 S180 荷瘤小鼠动物 PET 影像学研究。29 个化合 物的体外 FAK 激酶抑制活性均较好，其中 22、23、Q-1、Q-3 和 Q-10 比目前临床研究 中的 PF-562271（6.9 nM）及 GSK-2256098（18.0 nM）的 FAK 激酶抑制活性更好，其 IC50 分别为 3.0 nM、0.6 nM、3.2 nM、5.0 nM 和 3.73 nM。5 个结构相似的含氟化合物 的分子动力学模拟研究结果显示此类 FAK 抑制剂的嘧啶环上 5 位的取代基为 Br 时显示 出与 FAK 蛋白更稳定的结合，这也与其 FAK- IC50 结果相匹配。在 S180 荷瘤小鼠的体 内生物分布研究方面，[¹⁸F]Q-1 和[¹⁸F]Q-10 的肿瘤最大摄取值分别为 3.35±0.32％ID/g 和 3.66 ± 0.02％ID/g，其瘤/血比值分别为 1.61 和 3.69，瘤/肌比值分别为 2.08 和 3.15， 瘤/骨比值分别为 2.48 和 1.81，均显示出较高的肿瘤摄取值和较高的靶与非靶比，其 FAK- IC₅₀ 分别为 3.2 nM 和 3.73 nM。[¹⁸F]Q-1 的 PET 显像分析显示¹⁸F]Q-1 能够在肿瘤中特异性摄取。结果显示[¹⁸F]Q-1 和[¹⁸F]Q-10 是有希望的靶向 FAK 的肿瘤显像剂。

The high morbidity and mortality of tumors has become one of the main diseases endangering human health, and early diagnosis and early treatment of tumors are the current main strategies for tumors. Focal adhesion kinase is a highly phosphorylated non-receptor protein (Focal Adhesion Kinase, FAK). It plays an important role in all stages of tumors. It also plays an important role in cancer, cancer, liver cancer and glioma. Tumor cells are overexpressed, and the inhibition of FAK expression transformation leads to the design and synthesis of tandem FAK inhibitors and the use of ¹⁸F labeling to study its biological properties and potential as a PET tumor imaging agent.

In this paper, a series of FAK small molecule inhibitors were designed and synthesized through the guidance of the drug design software SYBYL and AMBER, and the chemical structure was confirmed by NMR and mass spectrometry. The in vitro FAK kinase inhibitory activity of the compound was determined by the HTRF^®method. The FAK tumor imaging agent was prepared by the ¹⁸Fradioactive labeling method, and its biological characteristics were preliminarily studied through the biological distribution of tumor model mice, blocking experiments and PET imaging experiments.

In this paper, five new types of FAK-targeted tumor imaging agent molecules were prepared, and molecular dynamics simulation studies were performed on five fluorine-containing compounds with similar structures in the first category; a total of 29 compounds were tested for their in vitro FAK kinase inhibitory activities; Eight compounds were radiolabeled with 18F and their physicochemical properties and biodistribution in S180 tumor-bearing mice were studied. One of the 18F markers was subjected to PET imaging studies  in  S180  tumor-bearing  mice.   In  vitro  FAK   kinase  inhibitory  activities  of  29 compounds are all better, of which 22, 23, Q-1, Q-3 and Q-10are better than PF-562271 (6.9 nM) and GSK-2256098 (18.0 nM) in current clinical studies The FAK kinase inhibitory activity is better, with IC50 of 3.0 nM, 0.6 nM, 3.2 nM, 5.0 nM and 3.73 nM, respectively. The molecular dynamics simulation results of five fluorine-containing compounds with similar structures showed that when the 5-position substituent on the pyrimidine ring of this type of FAK inhibitor is Br, it shows more stable binding to the FAK protein, which is also  the result of FAK-IC50 Match. In the study of the in vivo biodistribution of S180 tumor-bearing mice, the maximum tumor uptake values of [¹⁸F]Q-1 and [¹⁸F]Q-10 were 3.35±0.32%ID/g and 3.66±0.02%ID/g, respectively. The tumor/blood ratios were 1.61 and 3.69, the tumor/muscle ratios were 2.08 and 3.15, and the tumor/bone ratios were 2.48 and 1.81, respectively. They all showed higher tumor uptake and higher target to non-target ratio. FAK-IC50 is 3.2 nM and 3.73 nM, respectively. [¹⁸F]Q-1 PET imaging analysis showed that [¹⁸F]Q-1 can be specifically taken up in tumors. The results show that [¹⁸F]Q-1 and  [¹⁸F]Q-10 are promising tumor imaging agents targeting FAK.