PET Imaging of Active Invasive Fungal Infections with d-[5-¹¹C]-Glutamine

Abstract

The increasing prevalence and severity of invasive fungal infections (IFIs), especially in immunocompromised populations, has amplified the need for rapid diagnosis of fungal pathogens. Radiotracers derived from D-amino acids (DAAs) show promise as bacterial-specific positron emission tomography (PET) imaging agents due to their preferential consumption by bacteria and largely nonutilization by hosts. Unlike mammals, fungi can utilize external DAAs including D-glutamine for their growth by rapidly upregulating DAA oxidases. Additionally, glutamine is essential for fungal nitrogen assimilation, survival, and virulence. We previously validated D-[5-11 C]-glutamine (D-[5-11 C]-Gln) as an efficient radiotracer targeting live bacterial soft-tissue infections.Here, we further expanded this investigation to evaluate its translational potential for PET imaging of IFIs in immunocompetent mouse models subcutaneously (SubQ) and intramuscularly (IM) infected with Candida albicans (C. albicans), using its L-isomer counterpart (L-[5-11 C]-Gln) as a control. Comparative studies between pathogens showed significantly (p < 0.05) higher uptake in fungi (C. albicans and C. tropicalis) versus tested bacterial species for D-[5-11 C]-Gln, suggesting that it could potentially serve as a more sensitive radiotracer for detection of fungal infections. Additionally, comparative PET imaging studies in immunocompetent infected mice demonstrated significantly higher infection-to-background ratios for D-versus L-[5-11 C]-Gln in both SubQ (ratio = 1.97, p = 0.043) and IM (ratio = 1.97, p = 0.028) infections. Fungal infection imaging specificity was confirmed with no significant difference observed between localized inflammation sites versus untreated muscle background (heat-killed injection site/untreated muscle: ∼1.1). Taken together, this work demonstrates the translational potential of D-[5-11 C]-Gln for noninvasive PET imaging of IFIs.

Development and Applications of D‐Amino Acid Derivatives‐based Metabolic Labeling of Bacterial Peptidoglycan

“…[54] The study found that in a dual infection mouse myositis model, PET imaging based on infections. [55] These data provide robust evidence for the clinical promise of D-amino acid-based PET tracers for imaging active infections in human. It's important to note that there may be a potential concern for high background uptake in some organs with rich microbiome, such as the gastrointestinal tract.…”

Development and Applications of D‐Amino Acid Derivatives‐based Metabolic Labeling of Bacterial Peptidoglycan

“…The study found that in a dual infection mouse myositis model, PET imaging based on [ 11 C]‐D‐Gln could detect infections induced by E. coli and MRSA with low uptake in sterile inflammation site and background tissue. The group also used [ 11 C]‐D‐Gln for imaging fungal infections [55] . These data provide robust evidence for the clinical promise of D‐amino acid‐based PET tracers for imaging active infections in human.…”

Bioorthogonal Radiolabeling of Azide-Modified Bacteria Using [18F]FB-sulfo-DBCO

“…Previous work has shown that numerous exogenous d -amino acids can be incorporated into peptidoglycan, including d -methionine, d -phenylalanine, d -tryptophan, and d -valine . In addition, another carbon-11 PET infection imaging strategy used d -[3- 11 C]­glutamine. , Derivatives of these d -amino acids, therefore, represent additional routes for bioorthogonal bacterial detection using PET.…”