Chemoenzymatic Syntheses of Fluorine-18-Labeled Disaccharides from [¹⁸F] FDG Yield Potent Sensors of Living Bacteria In Vivo

Chemoenzymatic techniqueshave been applied extensively to pharmaceuticaldevelopment, most effectively when routine synthetic methods fail.The regioselective and stereoselective construction of structurallycomplex glycans is an elegant application of this approach that isseldom applied to positron emission tomography (PET) tracers. We soughta method to dimerize 2-deoxy-[F-18]-fluoro-d-glucose([F-18]FDG), the most common tracer used in clinical imaging,to form [F-18]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation.When [F-18]FDG was reacted with & beta;-d-glucose-1-phosphatein the presence of maltose phosphorylase, the & alpha;-1,4- and & alpha;-1,3-linkedproducts 2-deoxy-[F-18]-fluoro-maltose ([F-18]FDM)and 2-deoxy-2-[F-18]-fluoro-sakebiose ([F-18]FSK)were obtained. This method was further extended with the use of trehalose(& alpha;,& alpha;-1,1), laminaribiose (& beta;-1,3), and cellobiose(& beta;-1,4) phosphorylases to synthesize 2-deoxy-2-[F-18]fluoro-trehalose ([F-18]FDT), 2-deoxy-2-[F-18]fluoro-laminaribiose ([F-18]FDL), and 2-deoxy-2-[F-18]fluoro-cellobiose ([F-18]FDC). We subsequentlytested [F-18]FDM and [F-18]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [F-18]FDM and [F-18]FSK were stable inhuman serum with high accumulation in preclinical infection models.The synthetic ease and high sensitivity of [F-18]FDM and[F-18]FSK to S. aureus including methicillin-resistant(MRSA) strains strongly justify clinical translation of these tracersto infected patients. Furthermore, this work suggests that chemoenzymaticradiosyntheses of complex [F-18]FDG-derived oligomers willafford a wide array of PET radiotracers for infectious and oncologicapplications.