Scientific Publications Database
Article Title: It's a Trap! Aldolase-Prescribed C4 Deoxyradiofluorination Affords Intracellular Trapping and the Tracing of Fructose Metabolism by PETAuthors: Kirby, Alexia; Graf, Dominic; Suchy, Mojmir; Calvert, Nicholas D.; Charlton, Thomas A.; Ben, Robert N.; Addison, Christina L.; Shuhendler, Adam
Journal: JOURNAL OF NUCLEAR MEDICINE Volume 65 Issue 3
Date of Publication:2024
Abstract:
Fructose metabolism has been implicated in various diseases, including metabolic disorders, neurodegenerative disorders, cardiac disorders, and cancer. However, the limited availability of a quantitative imaging radiotracer has hindered its exploration in pathology and diagnostic imaging. Methods: We adopted a molecular design strategy based on the catalytic mechanism of aldolase, a key enzyme in fructolysis. We successfully synthesized a radiodeoxyfluorinated fructose analog, [F-18]4-fluoro-4-deoxyfructose ([F-18]4-FDF), in high molar activity. Results: Through heavy isotope tracing by mass spectrometry, we demonstrated that C-4-deoxyfluorination of fructose led to effective trapping as fluorodeoxysorbitol and fluorodeoxyfructose-1-phosphate in vitro, unlike C-1- and C-6-fluorinated analogs that resulted in fluorolactate accumulation. This observation was consistent in vivo, where [F-18]6-fluoro-6-deoxyfructose displayed substantial bone uptake due to metabolic processing whereas [F-18]4-FDF did not. Importantly, [F-18]4-FDF exhibited low uptake in healthy brain and heart tissues, known for their high glycolytic activity and background levels of [F-18]FDG uptake. [F-18]4-FDF PET/CT allowed for sensitive mapping of neuro- and cardioinflammatory responses to systemic lipopolysaccharide administration. Conclusion: Our study highlights the significance of aldolase-guided C-4 radiodeoxyfluorination of fructose in enabling effective radiotracer trapping, overcoming limitations of C-1 and C-6 radioanalogs toward a clinically viable tool for imaging fructolysis in highly glycolytic tissues.