Imaging of Actively Proliferating Bacterial Infections by Targeting the Bacterial Metabolic Footprint with d-[5-¹¹C]-Glutamine

Abstract

Since most d-amino acids (DAAs) are utilized by bacterial cells but not by mammalian eukaryotic hosts, recently DAA-based molecular imaging strategies have been extensively explored for noninvasively differentiating bacterial infections from the host’s inflammatory responses. Given glutamine’s pivotal role in bacterial survival, cell growth, biofilm formation, and even virulence, here we report a new positron emission tomography (PET) imaging approach using d-5-[11C]­glutamine (d-[5-11C]-Gln) for potential clinical assessment of bacterial infection through a comparative study with its l-isomer counterpart, l-[5-11C]-Gln. In both control and infected mice, l-[5-11C]-Gln had substantially higher uptake levels than d-[5-11C]-Gln in most organs except the kidneys, showing the expected higher use of l-[5-11C]-Gln by mammalian tissues and more efficient renal excretion of d-[5-11C]-Gln. Importantly, our work demonstrates that PET imaging with d-[5-11C]-Gln is capable of detecting infections induced by both Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) in a dual-infection murine myositis model with significantly higher infection-to-background contrast than with l-[5-11C]-Gln (in E. coli, 1.64; in MRSA, 2.62, p = 0.0004). This can be attributed to the fact that d-[5-11C]-Gln is utilized by bacteria while being more efficiently cleared from the host tissues. We confirmed the bacterial infection imaging specificity of d-[5-11C]-Gln by comparing its uptake in active bacterial infections versus sterile inflammation and with 2-deoxy-2-[18F]­fluoroglucose ([18F]­FDG). These results together demonstrate the translational potential of PET imaging with d-[5-11C]-Gln for the noninvasive detection of bacterial infectious diseases in humans.

Synthesis and Evaluation of Novel Norfloxacin Isonitrile 99mTc Complexes as Potential Bacterial Infection Imaging Agents

“…At present, the distinction between infection and sterile inflammation is of great significance. A variety of radiopharmaceuticals have been developed to detect inflammation [9][10][11][12][13][14][15][16][17][18][19]. For example, 18 F-2-Fluoro-2-deoxy-D-glucose ([ 18 F]FDG) have already been used for infection imaging in clinics.…”

11C-Para-aminobenzoic acid PET imaging of S. aureus and MRSA infection in preclinical models and humans

“…Over the last decade, multiple bacteria-specific PET imaging agents have been developed to target distinct metabolic pathways (13). These efforts have led to the characterization of radiolabeled sugars, such as 18 F-FDS (7,14), ᴅ-amino acids that get incorporated in the bacterial cell wall (15,16), and other promising compounds (1,2,17).…”

Pathophysiology and Molecular Imaging of Diabetic Foot Infections

“…Uptake of L-5-[ 11 C]glutamine was higher in the heat-killed control site when compared to D-5-[ 11 C]glutamine, indicating that the D-stereoisomer had better pathogen specificity. When D-5-[ 11 C]glutamine was compared to 18 F-FDG in a sterile inflammation model, 18 F-FDG uptake was significantly higher, further demonstrating the specificity of D-5-[ 11 C]glutamine for bacterial metabolism [148]. Although 11 C-labeled amino acid-based imaging shows specificity, widespread adoption for clinical use may be limited because of the 20-min half-life of 11 C. Microorganisms may also be targeted based on their vitamin uptake.…”