Investigations into the synthesis,radiofluorination and conjugation of a new [18F]fluorocyclobutyl prosthetic group and its in vitro stability using a tyrosine model system

The ¹⁸F]fluorocyclobutyl group has the potential to be a metabolically stable prosthetic group for PET tracers. The synthesis of the radiolabeling precursor cis-cyclobutane-1,3-diyl bis(toluene-4-sulfonate) 8 was obtained from epibromohydrin in 7 steps (2% overall yield). The radiolabeling of this precursor 8 and its conjugation to l-tyrosine as a model system was successfully achieved to give the new non-natural amino acid 3-¹⁸F]fluorocyclobutyl-l-tyrosine (L-3-¹⁸F]FCBT) ¹⁸F]17 in 8% decay-corrected yield from the non-carrier-added ¹⁸F]fluoride. L-3-¹⁸F]FCBT was investigated in vitro in different cancer cell lines to determine the uptake and stability. The tracer ¹⁸F]17 showed a time dependent uptake into different tumor cell lines (A549, NCI-H460, DU145) with the best uptake of 5.8% injected dose per 5 × 10⁵ cells after 30 min in human lung carcinoma cells A549. The stability of L-3-¹⁸F]FCBT in human and rat plasma and the stability of the non-radioactive L-3-FCBT in rat hepatocytes were both found to be excellent. These results show that the non-natural amino acid L-3-¹⁸F]FCBT is a promising metabolically stable radiotracer for positron emission tomography.