<scp>d</scp>-[5-¹¹C]-Glutamine Positron Emission Tomography Imaging for Diagnosis and Therapeutic Monitoring of Orthopedic Implant Infections

Orthopedic implant infections (OIIs) present diagnostic and therapeutic challenges, owing to the lack of methods to distinguish between active infection and sterile inflammation. To address this unmet need, d-amino-acid-based radiotracers with unique metabolic profiles in microorganisms have emerged as a novel class of infection-specific imaging agents. Given the pivotal role of d-glutamine in bacterial biofilm formation and virulence, herein, we explored the potential of positron emission tomography (PET) imaging with d-[5-¹¹C]-Glutamine (d-[5-¹¹C]-Gln) for early detection and treatment monitoring of OIIs. <i>In vitro</i> studies confirmed an active uptake of d-[5-¹¹C]-Gln by <i>Staphylococcus aureus</i> (<i>S. aureus</i>) biofilm commonly associated with OIIs. <i>In vivo</i> evaluations included PET imaging comparisons with d-[5-¹¹C]-Gln <i>vs</i> l-[5-¹¹C]-Gln or 2-deoxy-2-[¹⁸F]-fluoroglucose ([¹⁸F]-FDG) in a rat OII model with tibial implantation of sterile or <i>S. aureus</i><i>-</i>colonized stainless-steel screws before and after treatment. These studies demonstrated that the uptake of d-[5-¹¹C]-Gln was significantly higher in the infected screws than that in sterile screws (∼3.4-fold, <i>p</i> = 0.008), which displayed significantly higher infection-to-background muscle uptake ratios (∼2-fold, <i>p</i> = 0.011) with d-[5-¹¹C]-Gln as compared to l-[5-¹¹C]-Gln. Following a 3 week vancomycin treatment, imaging with d-[5-¹¹C]-Gln showed a significant reduction in uptake at the infected sites (∼3-fold, <i>p</i> = 0.0008). Further regression analyses revealed a superior correlation of residual infection-associated radiotracer uptake with the postimaging <i>ex vivo</i> bacterial counts for d-[5-¹¹C]-Gln (<i>k</i> = 0.473, <i>R</i>² = 0.796) <i>vs</i> [¹⁸F]-FDG (<i>k</i> = 0.212, <i>R</i>² = 0.434), suggesting that d-[5-¹¹C]-Gln PET had higher sensitivity for detecting residual bacterial burden than [¹⁸F]-FDG PET. Our results demonstrate the translational potential of d-[5-¹¹C]-Gln PET imaging for noninvasive detection and treatment monitoring of OIIs.