Synthesis and radiolabelling strategies of fibroblast activation protein ligands: a review

Fibroblast activation protein (FAP) has been the subject of several studies as a promising molecular target for cancer diagnostics and therapy. Fibroblast activation protein (FAP) is overexpressed on the surface of cancer-associated fibroblasts (CAFs). The latter represent a key element of the tumour microenvironment (TME) thanks to their ability to remodel the extracellular matrix, promote angiogenesis and suppress antitumor immune responses. Based on this rationale, many FAP inhibitors have been developed, used as radiolabelled molecular imaging probes in nuclear medicine. Some of these investigational radiopharmaceuticals have already been extensively studied in clinical settings for cancer imaging, whereas other molecular imaging techniques, such as PET with [¹⁸F]FDG, have limitations, especially in tumours with low metabolic activity. In addition, FAPI derivatives have potential for theragnostic in delivering targeted cancer therapies. This systematic review provides an overview of the latest updates reported in literature on the synthesis and radiolabelling methods of FAP ligands, specifically on FAPI-04, FAPI-46, FAPI-74 and Onco-Fap. The main aim is to summarize the current methodologies, highlighting the key advancements and challenges in the development of these radiopharmaceuticals.