Luo Yang, Jin Wenbin, Zang Jie, Wang Guochang, Zhu Lin, Kung Hank F
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
J Med Chem. 2025 Jan 9;68(1):348-360. doi: 10.1021/acs.jmedchem.4c02015. Epub 2024 Dec 22.
Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound exhibited a strong FAP binding affinity with an IC of 7.44 nM. Radiolabeled [Ga]Ga- and [Lu]Lu- demonstrated enhanced cell uptake. positron emission tomography/computed tomography (PET/CT) imaging showed that [Ga]Ga- displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [Ga]Ga-FAPI-04 (SUV: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [Ga]Ga- (48.15 vs 5.72% ID/g at 120 min). Similarly, [Lu]Lu- exhibited higher tumor uptake than [Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [Ga]Ga/[Lu]Lu-, is a promising candidate for tumor theranostics.
成纤维细胞活化蛋白（FAP）在癌症相关成纤维细胞（CAF）中过表达，是癌症诊断和治疗的一个有前景的靶点。缺氧是实体瘤的一个常见特征。通过将缺氧敏感的硝基咪唑（NI）掺入FAP靶向剂FAPI-04中，开发了一种二价试剂DOTA-NI-FAPI-04（）。化合物表现出很强的FAP结合亲和力，IC为7.44 nM。放射性标记的[Ga]Ga-和[Lu]Lu-显示细胞摄取增强。正电子发射断层扫描/计算机断层扫描（PET/CT）成像显示，与[Ga]Ga-FAPI-04相比，[Ga]Ga-在U87MG荷瘤小鼠中显示出显著更高的特异性摄取和滞留（SUV：120分钟时为7.87 vs 1.99% ID/mL）。生物分布研究证实[Ga]Ga-具有更好的肿瘤摄取（120分钟时为48.15 vs 5.72% ID/g）。同样，[Lu]Lu-比[Lu]Lu-FAPI-04表现出更高的肿瘤摄取（120分钟时为50.75 vs 20.48% ID/g）。这些初步结果表明，含硝基咪唑的二价靶向剂[Ga]Ga/[Lu]Lu-是肿瘤诊疗的一个有前景的候选物。
