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

作者：Lingxin Meng, Jianyang Fang, Liang Zhao, Tingting Wang, Pu Yuan, Zuoquan Zhao, Rongqiang Zhuang, Qin Lin, Haojun Chen, Xiaoyuan Chen, Xianzhong Zhang, Zhide Guo · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.1c02162 · 被引用次数：62 · 研究领域：Peptidase Inhibition and Analysis、Cardiac Structural Anomalies and Repair、Neuropeptides and Animal Physiology

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 FSDD 0 I, FSDD 1 I, and FSDD 3 I) were labeled with 68 Ga and 177 Lu 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 68 Ga-FSDD 0 I than 68 Ga-FAPI-04, 68 Ga-FSDD 1 I, and 68 Ga-FSDD 3 I. Remarkably, 68 Ga-FSDD 3 I had prominent tumor-to-nontarget (T/NT) ratios. The prominent tumor retention properties of 177 Lu-FSDD 0 I 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).