Invasive fungal infections (IFIs), specifically in immunocompromised patients, have become a grave healthcare concern worldwide. Fungi are capable of utilizing external D-amino acids (DAAs) including D-glutamine for their metabolism and growth by rapidly upregulating D-amino acid oxidases. Here we expand the use of positron emission tomography (PET) imaging with D-[5-11C]-Glutamine (D-[5-11C]-Gln) for noninvasive detection of IFIs in mouse models infected with Candida albicans (C. albicans). METHODS: Comparative in vitro studies of D-[5-11C]-Gln vs. L-[5-11C]-Gln were conducted in fungal (C. albicans and C. tropicalis) and bacterial strains (E. coli and S. aureus), where heat-killed cultures were used as negative controls. Dynamic In vivo PET imaging was performed from 0 – 60 min post injection of radiotracer in immunocompetent CD-1 mice infected with C. albicans subcutaneously (SC) or intramuscularly (IM) in individual hind-limbs, and heat-killed fungi in the shoulder muscle, followed by ex vivo histological staining and microbiological culture assessments. RESULTS: The dynamic cellular uptake showed significantly higher uptake rates for D-[5-11C]-Gln (~415%) than L-[5-11C]-Gln (~150%) from 30-min to 90-min. No substantial uptake was observed in heat-killed controls. Further, D-[5-11C]-Gln showed significantly (p &lt; 0.05) higher uptake in fungi vs. bacterial species. As expected, comparative PET imaging studies demonstrated significantly higher infection-to-background ratios for D-[5-11C]-Gln vs. L-[5-11C]-Gln in both SC (ratio = 1.7, p = 0.016) and IM (ratio = 1.8, p = 0.004) infections with no significant difference observed between localized inflammation sites and untreated muscle background (heat-killed site/muscle: ~1.25). CONCLUSION: Our results demonstrated the translational potential of PET imaging with D-[5-11C]-Gln for noninvasive detection of IFIs.

Positron emission tomography imaging of invasive fungal infections with D-[5-11C]-glutamine

ACS Spring 2022

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