Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging
机构：[1]Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[2]Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou, Sichuan 646000, China.[3]Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[4]Department 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 Hospital, Sichuan University, Chengdu 610065, China.四川大学华西医院[5]Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[6]Department of Nuclear Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.四川省人民医院
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.
基金：
National Natural Science
Foundation of China for funding this work (U20A20384); the
Doctoral Research Initiation Fund of Affiliated Hospital of
Southwest Medical University; Sichuan Science and Technology
Program (2022YFS0608-C3).
语种：
外文
被引次数：
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PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|2 区医学
小类|2 区药学3 区医学：研究与实验
最新[2025]版：
大类|2 区医学
小类|2 区药学3 区医学：研究与实验
JCR分区：
出版当年[2024]版：
Q1PHARMACOLOGY & PHARMACYQ2MEDICINE, RESEARCH & EXPERIMENTAL
最新[2024]版：
Q1PHARMACOLOGY & PHARMACYQ2MEDICINE, RESEARCH & EXPERIMENTAL
第一作者机构：[1]Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[2]Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou, Sichuan 646000, China.[3]Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[2]Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Jiangyang District, Luzhou, Sichuan 646000, China.[3]Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.[5]Institute of Nuclear Medicine, Southwest Medical University, Jiangyang District, Luzhou, Sichuan 646000, China.
推荐引用方式(GB/T 7714)：
Yuan Hongmei,Li Haiyang,Wu Tongtong,et al.Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging[J].Molecular Pharmaceutics.2025,22(8):4831-4843.doi:10.1021/acs.molpharmaceut.5c00464.
APA：
Yuan Hongmei,Li Haiyang,Wu Tongtong,Tang Sufan,Wang Yinwen...&Zhou Zhijun.(2025).Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging.Molecular Pharmaceutics,22,(8)
MLA：
Yuan Hongmei,et al."Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging".Molecular Pharmaceutics 22..8(2025):4831-4843
