PT  - JOURNAL ARTICLE
AU  - Kirby, Alexia
AU  - Graf, Dominic
AU  - Suchý, Mojmír
AU  - Calvert, Nicholas D.
AU  - Charlton, Thomas A.
AU  - Ben, Robert N.
AU  - Addison, Christina L.
AU  - Shuhendler, Adam
TI  - It’s a Trap! Aldolase-Prescribed C<sub>4</sub> Deoxyradiofluorination Affords Intracellular Trapping and the Tracing of Fructose Metabolism by PET
AID  - 10.2967/jnumed.123.266905
DP  - 2024 Mar 01
TA  - Journal of Nuclear Medicine
PG  - 475--480
VI  - 65
IP  - 3
4099  - http://jnm.snmjournals.org/content/65/3/475.short
4100  - http://jnm.snmjournals.org/content/65/3/475.full
SO  - J Nucl Med2024 Mar 01; 65
AB  - 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, [18F]4-fluoro-4-deoxyfructose ([18F]4-FDF), in high molar activity. Results: Through heavy isotope tracing by mass spectrometry, we demonstrated that C4-deoxyfluorination of fructose led to effective trapping as fluorodeoxysorbitol and fluorodeoxyfructose-1-phosphate in vitro, unlike C1- and C6-fluorinated analogs that resulted in fluorolactate accumulation. This observation was consistent in vivo, where [18F]6-fluoro-6-deoxyfructose displayed substantial bone uptake due to metabolic processing whereas [18F]4-FDF did not. Importantly, [18F]4-FDF exhibited low uptake in healthy brain and heart tissues, known for their high glycolytic activity and background levels of [18F]FDG uptake. [18F]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 C4 radiodeoxyfluorination of fructose in enabling effective radiotracer trapping, overcoming limitations of C1 and C6 radioanalogs toward a clinically viable tool for imaging fructolysis in highly glycolytic tissues.