A fingerprint of 2-[(18)F]FDG radiometabolites – How tissue-specific metabolism beyond 2-[(18)F]FDG-6-P could affect tracer accumulation

Studies indicate that the radiotracer 2-[(18)F]fluoro-2-deoxy-D-glucose (2-[(18)F]FDG) can be metabolized beyond 2-[(18)F]FDG-6-phosphate (2-[(18)F]FDG-6-P), but its metabolism is incompletely understood. Most importantly, it remains unclear whether downstream metabolism affects tracer accumulation in vivo. Here we present a fingerprint of 2-[(18)F]FDG radiometabolites over time in cancer cells, corresponding tumor xenografts and murine organs. Strikingly, radiometabolites representing glycogen metabolism or the oxPPP correlated inversely with tracer accumulation across all examined tissues. Recent studies suggest that not only hexokinase, but also hexose-6-phosphate dehydrogenase (H6PD), an enzyme of the oxidative pentose phosphate pathway (oxPPP), determines 2-[(18)F]FDG accumulation. However, little is known about the corresponding enzyme glucose-6-phosphate dehydrogenase (G6PD). Our mechanistic in vitro experiments on the role of the oxPPP propose that 2-[(18)F]FDG can be metabolized via both G6PD and H6PD, but data from separate enzyme knockdown suggest diverging roles in downstream tracer metabolism. Overall, we propose that tissue-specific metabolism beyond 2-[(18)F]FDG-6-P could matter for imaging.