Exploration of Bicyclic Peptide Ligands for Immune-Specific PET Imaging: Targeting Tumor PD-L1 with [18F]AlF-BCY10959

作者：Xiaobo Wang, Jianyang Fang, Fei Kang, Jia Wang, Jia Wang, Meng Niu, Hengan Ou, Jiajun Ye, Mingru Zhang, Jie Dong, Guiyu Li, Zhiguo Liu, Wenbin Zeng, Jing Wang, Jing Wang · 发表于：Molecular Pharmaceutics · 年份：2025 · DOI：10.1021/acs.molpharmaceut.5c00442 · 被引用次数：5 · 研究领域：Radiopharmaceutical Chemistry and Applications、Peptidase Inhibition and Analysis、Cancer Immunotherapy and Biomarkers

As a new modality of ligands, bicyclic peptides hold great promise in the discovery of novel programmed death ligand 1 (PD-L1) targeted radiotracers, which have not yet been reported. In this study, first-in-class bicyclic peptide-based radiotracers [ 18 F]AlF-BCY509 and [ 18 F]AlF-BCY10959 were developed and evaluated for PET imaging of tumor PD-L1 expression. The automatic radiosynthesis was achieved with robust radiochemical yields (55.1–90.2%) and high molar activity (42.5–90.8 GBq/μmol). Cell-based assays demonstrated high specificity and affinity of [ 18 F]AlF-BCY509 and [ 18 F]AlF-BCY10959 with IC 50 values of 9.36 ± 1.35 and 7.12 ± 1.24 nM and K D values of 11.41 ± 1.04 and 8.09 ± 0.85 nM. In PET imaging, the accumulation of [ 18 F]AlF-BCY10959 in PD-L1-positive tumors with moderate retention over 120 min was discovered, with the tumor uptake of 14.74 ± 1.67%ID/cc and tumor-to-muscle ratio of 12.41 ± 1.07 at 30 min. The in vivo specificity was strictly verified by PD-L1-knockout and PD-L1-positive tumors with blocking. The biodistribution manifested a rapid distribution and fast clearance from the body, supporting the favorable pharmacokinetics of [ 18 F]AlF-BCY10959. [ 18 F]AlF-BCY10959 was excreted through the urinary and hepatobiliary systems, indicating the doomed radiation exposure organs. The effective doses of [ 18 F]AlF-BCY10959 and [ 18 F]-FDG were comparable, highlighting its safety for human use. In conclusion, [ 18 F]AlF-BCY10959 provides an attractive opt...