Peng Simin, Li Baoyuan, Sun Mingming, Yang Jiaqi, Cai Zhikai, Liu Yang, Tang Peipei, Feng Dan, Cao Qianyong, Ran Pengcheng, Hu Kongzhen
Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
J Med Chem. 2025 Jul 10;68(13):14019-14027. doi: 10.1021/acs.jmedchem.5c01163. Epub 2025 Jun 18.
Fibroblast activation protein (FAP)-targeting radioligands hold promise for cancer theranostics. Cyclic peptide-based DOTA-FAP-2286 radioligands have demonstrated high kidney uptake and retention, raising concerns regarding potential nephrotoxicity. Hence, we aimed to design three cysteic acid-modified FAP-targeting cyclic peptide ligands (DOTA-C1/C2/C3-FAP-2286) for reducing renal retention and optimizing pharmacokinetic properties. Competitive binding assays revealed maintained potent affinity for FAP (IC < 150 nM). Following systematic preclinical evaluation, [Ga]Ga-C1-FAP-2286 exhibited optimal biodistribution characteristics, reducing renal uptake by 50% (2.12 ± 0.19% ID/g, < 0.05), while maintaining tumor accumulation (7.08 ± 0.35 vs 6.26 ± 0.82% ID/g for [Ga]Ga-FAP-2286), yielding a significantly improved tumor-to-kidney ratio (3.34 ± 0.15 vs 1.59 ± 0.53% ID/g). First-in-human PET/CT imaging in a metastatic gastric cancer patient demonstrated superior diagnostic performance compared to [F]FDG, with intense uptake in primary lesions (SUV = 3.0), including [F]FDG-negative and metastatic lesions. Thus, [Ga]Ga-C1-FAP-2286 is a clinically translatable tracer for imaging FAP-expressing malignancies.
靶向成纤维细胞活化蛋白（FAP）的放射性配体在癌症诊疗方面具有应用前景。基于环肽的DOTA-FAP-2286放射性配体已显示出较高的肾脏摄取和滞留，引发了对潜在肾毒性的担忧。因此，我们旨在设计三种半胱氨酸修饰的靶向FAP的环肽配体（DOTA-C1/C2/C3-FAP-2286），以减少肾脏滞留并优化药代动力学性质。竞争性结合试验表明对FAP保持了强效亲和力（IC<150 nM）。经过系统的临床前评估，[镓]Ga-C1-FAP-2286表现出最佳的生物分布特征，肾脏摄取减少了50%（2.12±0.19% ID/g，<0.05），同时保持肿瘤蓄积（[镓]Ga-FAP-2286为7.08±0.35 vs 6.26±0.82% ID/g），肿瘤与肾脏的比值显著提高（3.34±0.15 vs 1.59±0.53% ID/g）。一名转移性胃癌患者的首次人体PET/CT成像显示，与[氟]FDG相比，其诊断性能更优，在原发性病变（SUV = 3.0）中有强烈摄取，包括[氟]FDG阴性和转移性病变。因此，[镓]Ga-C1-FAP-2286是一种可临床转化的用于成像FAP表达恶性肿瘤的示踪剂。
