Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein

  • J Med Chem. 2022 Jun 23;65(12):8245-8257. doi: 10.1021/acs.jmedchem.1c02162.
Lingxin Meng  1 ,  Jianyang Fang  1 ,  Liang Zhao  2  3 ,  Tingting Wang  1 ,  Pu Yuan  1 ,  Zuoquan Zhao  4 ,  Rongqiang Zhuang  1 ,  Qin Lin  3 ,  Haojun Chen  2 ,  Xiaoyuan Chen  5  6  7 ,  Xianzhong Zhang  1 ,  Zhide Guo  1
Affiliations
  • 1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
  • 2. Department of Nuclear Medicine & Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
  • 3. Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
  • 4. Department of Nuclear Medicine, Cardiovascular Institute and FuWai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, China.
  • 5. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 119074, Singapore.
  • 6. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
  • 7. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
PMID: 35658448 DOI: 10.1021/acs.jmedchem.1c02162
Abstract

The fibroblast activation protein (FAP), overexpressed on cancer-associated fibroblasts (CAFs), has become a valuable target for tumor diagnosis and therapy. However, most FAP-based radioligands show insufficient tumor uptake and retention. In this study, three novel albumin-binding FAP ligands (denoted as FSDD0I, FSDD1I, and FSDD3I) were labeled with 68Ga and 177Lu to overcome these limitations. Cell-based studies and molecular docking assays were performed to identify the specificity and protein-binding properties for FAP. Positron emission tomography (PET) scans in human hepatocellular carcinoma patient-derived xenografts (HCC-PDXs) animal models revealed longer blood retention of 68Ga-FSDD0I than 68Ga-FAPI-04, 68Ga-FSDD1I, and 68Ga-FSDD3I. Remarkably, 68Ga-FSDD3I had prominent tumor-to-nontarget (T/NT) ratios. The prominent tumor retention properties of 177Lu-FSDD0I in single photon emission computed tomography (SPECT) imaging and biodistribution studies were demonstrated. In summary, this study reports a proof-of-concept study of albumin-binding radioligands for FAP-targeted imaging and targeted radionuclide therapy (TRT).

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