Positron Emission Tomography Imaging of Bacterial Infections With an Enterobactin Analog to Monitor Treatment Efficacy With a Catechol Antibiotic

Positron emission tomography (PET) is an emerging tool under clinical investigation for the detection of bacterial infections. The ability to identify the site of infection and the pathogen's potential susceptibility to subsequent treatment approaches can streamline treatment and prevent misuse of antibiotics. Previous studies identified TREN-CAM as a promising scaffold for radiometal labeling using the positron-emitting radionuclide ⁶⁸Ga. Here, we investigate the suitability of ^67/68Ga-labeled TREN-CAM and enterobactin for the noninvasive imaging of an Escherichia coli infection. In vitro uptake experiments with [⁶⁷Ga]Ga^III-TREN-CAM demonstrate superior uptake in E. coli K12 and Pseudomonas aeruginosa PAO1 when compared with [⁶⁷Ga]Ga^III-DFO, a compound currently under clinical investigation for infection imaging. Selectivity experiments indicate that [⁶⁷Ga]Ga^III-TREN-CAM is recognized by the active transmembrane transport machinery for ^natFe^III-Ent. Using a soft tissue E. coli infection model, we demonstrate that [⁶⁸Ga]Ga^III-TREN-CAM selectively accumulates in infected tissue. Notably, [⁶⁸Ga]Ga^III-TREN-CAM provides better infection-to-inflammation contrast, accelerated blood clearance, and lower off-target accumulation compared to [⁶⁸Ga]Ga^III-Ent and [⁶⁸Ga]Ga^III-citrate. The potential of [⁶⁸Ga]Ga^III-TREN-CAM to serve as a tool to monitor the therapeutic efficacy of cefiderocol is also evaluated, offering insight into its utility in guiding antibiotic treatment.