Chemoenzymatic Radiosynthesis of a Gluconate Transporter‐Targeted In Vivo Bacterial Sensor From Clinical [ ¹⁸ F]FDG

Abstract

ABSTRACT Many bacteria, but not mammalian cells, can directly import and metabolize extracellular gluconate via gluconate permease (GntP) and kinase (GntK). We hypothesized that fluorine‐18 labeled gluconic acid ([ 18 F]FGA) could leverage unique bacterial gluconate metabolism for pathogen‐specific PET imaging. Here, we report [ 18 F]FGA as a new PET tracer targeting bacterial gluconate metabolism. The chemoenzymatic radiosynthesis of [ 18 F]FGA was simple, only requiring readily available [ 18 F]FDG and glucose oxidase. [ 18 F]FGA showed broad detection sensitivity across multiple bacterial species, including multidrug‐resistant clinical isolates. Staphylococcus aureus transposon mutant studies showed substantial loss of [ 18 F]FGA uptake in GntP and GntK mutants, supporting high specificity for bacterial gluconate metabolism. [ 18 F]FGA PET selectively highlighted live bacterial infection, with high target‐to‐nontarget ratios in S. aureus (36‐fold) and Escherichia coli (30‐fold) in a murine model of myositis. Unlike [ 18 F]FDG, no appreciable uptake of [ 18 F]FGA was detected at sites of sterile inflammation. In a Klebsiella pneumoniae pneumonia model, [ 18 F]FGA showed significantly higher accumulation in the infected lung (5.2 ± 0.8%IA/cc) than in the uninfected lung (0.1 ± 0.0%IA/cc), further supporting its potential for imaging challenging clinical infections. Taken together, [ 18 F]FGA PET may be a useful tool for pathogen‐targeted imaging in clinical practice.