Selective PET imaging of bacterial infection using a glycosylated ¹⁸F-fluorodeoxyglucose-derived tracer

Distinguishing bacterial infection from non-infectious inflammation remains challenging because most clinical imaging detects the host inflammatory response rather than the bacteria themselves. The widely used glucose analogue ¹⁸F-fluorodeoxyglucose accumulates in metabolically active tissues, including immune cells, resulting in high background signals and limited specificity. Here we report a positron emission tomography tracer that directly targets bacterial metabolism by exploiting the phosphotransferase system, a carbohydrate transport pathway absent in mammalian cells. O-glycosylation of ¹⁸F-fluorodeoxyglucose generated a library of alkyl glucosides in a single step (33-92% yield), enabling rapid screening for bacterial uptake. In vitro studies identified a methanol-derived tracer in which the β-anomer showed selective incorporation into Staphylococcus species via the glucose-specific phosphotransferase transporter. This positron emission tomography tracer was stable in human serum and showed minimal uptake in mammalian cells and uninfected tissues. In murine models, it detected sites of live gram-positive infection with more than sixfold higher signal than non-infected tissue, without accumulation in aseptic inflammation, and enabled monitoring of response to antibiotic therapy.