作为潜在肿瘤成像剂的F-18标记的2,4-二氨基嘧啶型FAK靶向抑制剂的设计、合成及生物学评价
Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential tumour imaging agents.
作者信息
Qi Yueheng, Li Ye, Fang Yu, Qiang Bingchao, Gao Hang, Wang Shuxia, Zhang Huabei
机构信息
Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, China.
College of Chemistry and Chemical Engineering, Anyang Normal University, No. 436 Xian'ge Road, Anyang 455000, Henan Province, China.
出版信息
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127452. doi: 10.1016/j.bmcl.2020.127452. Epub 2020 Jul 28.
As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by H NMR, C HNMR, and HRMS spectra. These compounds, with an IC range of 5.0-205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [F]Q-2 and [F]Q-4, with respective IC values of 5.0 nM and 21.6 nM, were labelled by F, accompanied by evaluation of their biodistributions. For [F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [F]Q-2 is a potential PET tracer for tumour diagnosis.
作为一种细胞内非受体酪氨酸激酶，粘着斑激酶（FAK）在大多数肿瘤类型中都能高度表达，因此被视为一个有前景的抗肿瘤靶点。在本研究中，设计、合成了一系列新型的靶向FAK的2,4-二氨基嘧啶抑制剂，并通过氢核磁共振（¹H NMR）、碳氢核磁共振（¹³C¹H NMR）和高分辨质谱（HRMS）光谱对其进行了表征。这些化合物的半数抑制浓度（IC）范围为5.0 - 205.1 nM，对FAK显示出优异的抑制活性。两种化合物，[¹⁸F]Q-2和[¹⁸F]Q-4，其IC值分别为5.0 nM和21.6 nM，用¹⁸F进行了标记，并对它们的生物分布进行了评估。对于[¹⁸F]Q-2，在注射后30分钟，观察到了良好的靶标与非靶标比值，肿瘤/血液、肿瘤/肌肉和肿瘤/骨骼的比值分别为1.17、2.99和2.19。结果表明，[¹⁸F]Q-2是一种潜在的用于肿瘤诊断的正电子发射断层显像（PET）示踪剂。
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