Fibroblast activation protein targeted therapy using [(177)Lu]FAPI-46 compared with [(225)Ac]FAPI-46 in a pancreatic cancer model

PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used (64)Cu and (225)Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter ((177)Lu)-labelled FAPI-46 and alpha-emitter ((225)Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [(18)F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [(177)Lu]FAPI-46 and [(225)Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [(177)Lu]FAPI-46 and [(225)Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [(177)Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [(225)Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [(18)F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [(177)Lu]FAPI-46 and [(225)Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [(177)Lu]FAPI-46 and [(225)Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [(177)Lu]FAPI-46 were relatively slow but lasted longer than those of [(225)Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05554-2.