Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors.
Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors.
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DOI：
10.1021/acs.molpharmaceut.3c00355
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发表时间：
2023-07
影响因子：
4.9
通讯作者：
Xin Hu;Gaochao Lv;Di Hua;N. Zhang;Qingzhu Liu;Shuai Qin;Lixia Zhang;Hongjie Xi;L. Qiu;Jianguo Lin
中科院分区：
文献类型：
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作者：
Xin Hu;Gaochao Lv;Di Hua;N. Zhang;Qingzhu Liu;Shuai Qin;Lixia Zhang;Hongjie Xi;L. Qiu;Jianguo Lin
目前，肿瘤免疫治疗最有效的方法之一是阻断程序性细胞死亡蛋白1/程序性细胞死亡蛋白配体1（PD-1/PD-L1）免疫检查点。然而，在选择从免疫检查点疗法中受益的患者方面仍然存在重大挑战。正电子发射断层扫描（PET）是一种非侵入性分子成像技术，提供了一种准确检测PD-L1表达的新方法，并可以更好地预测对PD-1/PD-L1靶向免疫治疗的反应。在这里，我们设计并合成了一组新的含芳基氟硫酸酯的小分子化合物（LGSu-1，LGSu-2，LGSu-3和LGSu-4）的苯氧基甲基联苯支架的基础上。通过时间分辨荧光共振能量转移（TR-FRET）试验筛选后，选择最有效的化合物LGSu-1（半数最大抑制浓度（IC 50）：15.53 nM）和低亲和力化合物LGSu-2（IC 50：189.70 nM）作为对照，通过硫（VI）氟化物交换化学（SuFEx）进行18 F-放射性标记，用于PET成像。[18 F]LGSu-1和[18 F]LGSu-2通过一步放射性转化反应制备，放射转化率超过85%，放射化学产率接近30%。在B16-F10黑色素瘤细胞测定中，[18 F]LGSu-1（5.00 ± 0.06%AD）显示出比[18 F]LGSu-2（2.55 ± 0.04%AD）更高的细胞摄取，其中细胞摄取可被非放射性LGSu-1显著阻断。在体内实验中，B16-F10荷瘤小鼠的micro-PET成像和肿瘤切片的放射自显影显示，由于与PD-L1的结合亲和力更高，[18 F]LGSu-1在肿瘤中更有效地积累。上述实验结果证实了小分子探针LGSu-1作为肿瘤组织中靶向PD-L1成像示踪剂的潜力。
Nowadays, one of the most effective methods of tumor immunotherapy is blocking programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) immune checkpoints. However, there is still a significant challenge in selecting patients to benefit from immune checkpoint therapies. Positron emission tomography (PET), a noninvasive molecular imaging technique, offers a new approach to accurately detect PD-L1 expression and allows for a better prediction of response to PD-1/PD-L1 target immunotherapy. Here, we designed and synthesized a novel group of aryl fluorosulfate-containing small-molecule compounds (LGSu-1, LGSu-2, LGSu-3, and LGSu-4) based on the phenoxymethyl-biphenyl scaffold. After screening by the time-resolved fluorescence resonance energy transfer (TR-FRET) assay, the most potent compound LGSu-1 (half maximal inhibitory concentration (IC50): 15.53 nM) and the low-affinity compound LGSu-2 (IC50: 189.70 nM) as a control were selected for 18F-radiolabeling by sulfur(VI) fluoride exchange chemistry (SuFEx) to use for PET imaging. [18F]LGSu-1 and [18F]LGSu-2 were prepared by a one-step radiofluorination reaction in over 85% radioconversion and nearly 30% radiochemical yield. In B16-F10 melanoma cell assays, [18F]LGSu-1 (5.00 ± 0.06%AD) showed higher cellular uptake than [18F]LGSu-2 (2.55 ± 0.04%AD), in which cell uptake could be significantly blocked by the nonradioactivity LGSu-1. In vivo experiments, micro-PET imaging of B16-F10 tumor-bearing mice and radiographic autoradiography of tumor sections showed that [18F]LGSu-1 was more effectively accumulated in the tumor due to the higher binding affinity with PD-L1. The above experimental results confirmed the potential of the small-molecule probe LGSu-1 as a targeting PD-L1 imaging tracer in tumor tissues.