Internal medicine

Fibroblast

Nuclear medicine

Cancer

Fibroblast activation protein, alpha

Chemistry

In vitro

Positron emission tomography

Biodistribution

Targeted therapy

Human serum albumin

Spect imaging

Cancer research

Biochemistry

Medicine

Journal of Medicinal Chemistry

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).

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