FAP Inhibitors as Novel Small Molecules for Cancer Imaging using Radionuclide

Abstract

Tumors are encircled by various non-cancerous cell types in the extracellular matrix, including fibroblasts, endothelial cells, immune cells, and cytokines. Fibroblasts are the most critical cells in the tumor stroma and play an important role in tumor development, which has been highlighted in some epithelial cancers. Many studies have shown a tight connection between cancerous cells and fibroblasts in the last decade. Regulatory factors secreted into the tumor environment by special fibroblast cells, cancer-associated fibroblasts (CAFs), play an important role in tumor and vessel development, metastasis, and therapy resistance. This review addresses the development of FAP inhibitors, emphasizing the first, second, and latest generations. First-generation inhibitors exhibit low selectivity and chemical stability, encouraging researchers to develop new scaffolds based on preclinical and clinical data. Second-generation enzymes such as UAMC-1110 demonstrated enhanced FAP binding and better selectivity. Targeted treatment and diagnostic imaging have become possible by further developing radionuclide-labeled fibroblast activation protein inhibitors (FAPIs). Although all three FAPIs (01, 02, and 04) showed excellent preclinical and clinical findings. The final optimization of these FAPI scaffolds resulted in FAPI-46 with the highest tumor-to-background ratio and better binding affinity.