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Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging

Hongmei YuanAffiliated Hospital of Southwest Medical UniversityHaiyang LiDepartment of Nuclear MedicineTongtong WuNuclear Medicine and Molecular Imaging Key Laboratory of Sichuan ProvinceSufan TangDepartment of Nuclear MedicineYinwen WangDepartment of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province and Frontiers Science Center for Disease Related Molecular Network, West China HospitalZhicong YangDepartment of Pharmaceutics, School of PharmacyYang LiuDepartment of Nuclear MedicineWenlu ZhengDepartment of Nuclear MedicineNan LiuDepartment of Nuclear Medicine, Sichuan Provincial People’s HospitalYue ChenDepartment of Nuclear MedicineZhijun ZhouNuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province

Molecular Pharmaceuticsjournal2025en

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Annotatsiya

Fibroblast activation protein (FAP), highly overexpressed in cancer-associated fibroblasts (CAFs), is crucial in tumor pathogenesis and progression, making it an important target for diagnosis and therapy. This study presents the design of a series of FAP inhibitors (FAPIs) derived from UAMC-1110 derivative, modified with zwitterions and polyethylene glycol (PEG). The novel 68Ga-labeled tracers show improved pharmacokinetics compared to 68Ga-FAPI-04. Small animal positron emission tomography/computed tomography (micro-PET/CT) on U87MG tumor-bearing nude mice revealed that 68Ga-FAPI-BN-1, incorporating boron trifluoride zwitterion, and 68Ga-FAPI-P8PN, with phosphate zwitterion and PEG8 modifications, demonstrated high tumor uptake and minimal normal tissue uptake. Biodistribution studies confirmed their excellent tumor accumulation and tumor-to-normal tissue ratios (T/NT). Specifically, 68Ga-FAPI-BN-1 exhibited a tumor uptake of 49.31 ± 2.76%ID/g at 1 h, with a tumor/muscle ratio of 24, while 68Ga-FAPI-P8PN showed a tumor uptake of 42.19 ± 3.21% ID/g at 0.5 h, with a tumor/muscle ratio of 23. These results indicate that these tracers hold promise as effective molecular imaging agents targeting FAP.

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Peptidase Inhibition and Analysis Cardiac Structural Anomalies and Repair Protease and Inhibitor Mechanisms

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DOI: 10.1021/acs.molpharmaceut.5c00464

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