A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy

PURPOSE: A series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68–labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics. METHODS: The precursor LuFL (20) and [(nat)Lu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [(177)Lu]Lu-LuFL ([(177)Lu]21) and [(177)Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy. RESULTS: LuFL (20) and [(nat)Lu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC(50): 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC(50): 6.69 ± 0.88 nM). In vitro cellular studies showed that (18)F-/(177)Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [(18)F]/[(177)Lu]21 revealed higher tumor uptake and longer tumor retention than those of [(68) Ga]/[(177)Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [(177)Lu]21 group, than for the control group and the [(177)Lu]Lu-FAPI-04 group. CONCLUSION: The novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with (18)F- and (177)Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06169-5.