Zhou Hui, Zhong Jiawei, Liu Yang, Peng Simin, Yan Qingsong, Wang Lijuan, Zhong Yuhua, Hu Kongzhen
GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Nuclear Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Eur J Med Chem. 2025 Feb 5;283:117115. doi: 10.1016/j.ejmech.2024.117115. Epub 2024 Nov 29.
FAP-targeting radioligands are used in cancer diagnosis and therapy, but their effectiveness is limited by poor tumor uptake and retention. This study aimed to develop new radioligands using an optimized amino acid linker and ibuprofen for better pharmacokinetics. Three novel quinoline-based FAP ligands with an ibuprofen moiety were synthesized and radiolabeled with gallium-68 and lutetium-177. The synthesized FAP ligands FAPI-Ibu1, 2, 3 showed high binding affinity for FAP, with IC values of 1.17 ± 0.09, 0.29 ± 0.06, and 0.78 ± 0.12 nM, respectively. Lu-labeled FAP ligands showed stability in vitro and demonstrated significant binding to human plasma proteins as well as FAP specificity. PET imaging and biodistribution studies of Ga- or Lu-labeled FAPI-Ibu1, 2, 3 revealed improved tumor accumulation and retention. Dosimetry calculation showed that [Lu]Lu-FAPI-Ibu3 delivered a 9.9-fold higher absorbed dose to tumor than [Lu]Lu-FAPI-04, but only 2.6-fold higher absorbed dose to kidneys leading to 3.8-fold improvement in the tumor-to-kidney absorbed dose ratios. In the endoradiotherapy study, 18.5 MBq of [Lu]Lu-FAPI-Ibu3 resulted in longer median survival than the equivalent dose of [Lu]Lu-FAPI-04 (22 vs 16 days). Three ibuprofen-modified FAP radioligands significantly improved tumor uptake, retention, and growth suppression compared to [Lu]Lu-FAPI-04, with [Lu]Lu-FAPI-Ibu3 emerging as the most promising candidate for further clinical translational studies.
靶向FAP的放射性配体用于癌症诊断和治疗，但其有效性受到肿瘤摄取和滞留不佳的限制。本研究旨在使用优化的氨基酸连接体和布洛芬开发新的放射性配体，以获得更好的药代动力学。合成了三种带有布洛芬部分的新型喹啉基FAP配体，并用镓-68和镥-177进行放射性标记。合成的FAP配体FAPI-Ibu1、2、3对FAP显示出高结合亲和力，IC值分别为1.17±0.09、0.29±0.06和0.78±0.12 nM。镥标记的FAP配体在体外显示出稳定性，并证明与人血浆蛋白有显著结合以及FAP特异性。对镓或镥标记的FAPI-Ibu1、2、3进行的PET成像和生物分布研究显示肿瘤蓄积和滞留有所改善。剂量学计算表明，[镥]镥-FAPI-Ibu3对肿瘤的吸收剂量比[镥]镥-FAPI-04高9.9倍，但对肾脏的吸收剂量仅高2.6倍，导致肿瘤与肾脏吸收剂量比提高3.8倍。在体内放射治疗研究中，18.5 MBq的[镥]镥-FAPI-Ibu3导致的中位生存期比等效剂量的[镥]镥-FAPI-04更长（22天对16天）。与[镥]镥-FAPI-04相比，三种布洛芬修饰的FAP放射性配体显著改善了肿瘤摄取、滞留和生长抑制，[镥]镥-FAPI-Ibu3成为进一步临床转化研究最有前景的候选者。
