Preparation and Bioevaluation of <sup>18</sup>F-Labeled Small-Molecular Radiotracers <i>via</i> Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors
Xin Hu, Gao‐Chao Lv, Di Hua, Nan Zhang, Qingzhu Liu, Shuai Qin, Lixia Zhang, Hongjie Xi, Ling Qiu, Jianguo Lin
Abstract
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 (IC 50 ): 15.53 nM) and the low-affinity compound LGSu - 2 (IC 50: 189.70 nM) as a control were selected for 18 F-radiolabeling by sulfur(VI) fluoride exchange chemistry (SuFEx) to use for PET imaging. [ 18 F] LGSu - 1 and [ 18 F] 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, [ 18 F] LGSu - 1 ( 5.00 ± 0.06%AD) showed higher cellular uptake than [ 18 F] 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 [ 18 F] 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.