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

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).