2. Academic Validation
  3. Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging

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

  • Mol Pharm. 2025 Aug 4;22(8):4831-4843. doi: 10.1021/acs.molpharmaceut.5c00464.
Hongmei Yuan 1 2 3,  Haiyang Li 1 2 3,  Tongtong Wu 1 2 3,  Sufan Tang 1 2 3,  Yinwen Wang 4,  Zhicong Yang 1 2 3,  Yang Liu 1 2 5,  Wenlu Zheng 1 2 5,  Nan Liu 6,  Yue Chen 1 2 5,  Zhijun Zhou 1 2 5 3
Affiliations

Affiliations

  • 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.
  • 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.
PMID: 40670298 DOI: 10.1021/acs.molpharmaceut.5c00464
Abstract

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.

Keywords

68Ga; PET/CT imaging; fibroblast activation protein; fibroblast activation protein inhibitor; zwitterion.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-175322
    FAP抑制剂
    FAP
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