Radiolabeling and Preclinical Evaluation of [77Br]hGTS13, an xCT-Targeted Small Molecule

Abstract System xc– is an amino acid antiporter overexpressed in numerous cancers, including glioma, pancreatic, and lung cancers. Different glutamate derivative radiotracers allow for the imaging of system xc– by positron emission tomography (PET), such as [18F]hGTS13. Our goal was to radiolabel hGTS13 with the therapeutic Auger electron emitter bromine-77 (77Br) and determine if system xc– tolerates the substitution of fluorine-18 (18F) by 77Br. [77Br]hGTS13 was radiosynthesized by a nucleophilic aliphatic radiobromination. Its uptake in the nonsmall cell lung cancer cell lines H460 and A549 showed a high and sustained uptake. A competition assay with the natural substrates of system xc– and a synthetic inhibitor proved the specificity of [77Br]hGTS13. It remained 100% intact in human serum after a 1 h incubation at 37 °C. Ex vivo biodistribution studies in H460 tumor-bearing nude mice and rats showed similar tumor-associated radioactivity for [18F]hGTS13 and [77Br]hGTS13, but [77Br]hGTS13 was not stable, and the tumor uptake must therefore be interpreted with caution. The in vitro results prove that system xc– tolerates the substitution of the imaging radioisotope by a therapeutic one; however, in vivo stability requires careful consideration.