Synthesis of [18F]-labelled Maltose Derivatives as PET Tracers for Imaging Bacterial Infection

Abstract

Purpose To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections. Procedures It is known that maltose and maltodextrins are energy sources for bacteria. Hence, 18F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(α-D-glucopyranosyl)-6-deoxy-6-[18F]fluoro-D-glucopyranoside (6-[18F]fluoromaltose) and 4-O-(α-D-glucopyranosyl)-1-deoxy-1-[18F]fluoro-D-glucopyranoside (1-[18F]fluoromaltose) as bacterial infection PET imaging agents. 6-[18F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2′,3′,-di-O-acetyl-4′,6′-benzylidene-α-D-glucopyranosyl)-6-deoxy-6-nosyl-D-glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[18F]fluoromaltose. In an analogous procedure, 1-[18F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O-(2′,3′,4′,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D-glucopranoside (9). Stability of 6-[18F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 °C was determined. Escherichia coli uptake of 6-[18F]fluoromaltose was examined. Results A reliable synthesis of 1- and 6-[18F]fluoromaltose has been accomplished with 4–6 and 5–8 % radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[18F]fluoromaltose was sufficiently stable over the time span needed for PET studies (~96 % intact compound after 1-h and ~65 % after 2-h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[18F]fluoromaltose. Competition assays showed that the uptake of 6-[18F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose. Conclusion We have successfully synthesized 1- and 6-[18F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake experiments in E. coli and stability studies suggest a possible application of 6-[18F]fluoromaltose as a new PET imaging agent for visualization and monitoring of bacterial infections.

A novel synthesis of 6′′‐[18F]‐fluoromaltotriose as a PET tracer for imaging bacterial infection

“…It has been known that enterobacteriacease express the enzyme sorbitol‐6‐phosphate dehydrogenase which is responsible for sorbitol metabolism. We showed the use of 6‐[ 18 F]fluoromaltose, and Ning et al reported the application of 18 F‐ labeled fluoromaltohexose as PET probes targeting the bacterial maltodextrin transporter, to image all bacterial infections caused by both Gram positive and Gram negative bacteria. Both of these tracers demonstrated great specificity for distinguishing bacterial infection from inflammation but had poor signal to noise ratios due to possible metabolism in the hepatobiliary system.…”

Specific Imaging of Bacterial Infection Using 6″-18F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria

“…We have previously demonstrated the development of 6-18 F-fluoromaltose (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org), a probe from a novel class of tracers targeting the maltodextrin transporter in bacteria (14,15). The concept of this class of tracers stems from an earlier study by Murthy et al, who showed that the maltodextrin transporter is unique to bacteria and that a fluorescently labeled maltohexose probe was able to image E. coli-induced myositis in rats (16).…”

Visualisierung molekularer Zielstrukturen bei Entzündungen und Infektionen

“…7) kann mittels nukleophieler Substitution von entsprechenden Precursoren synthetisiert werden. Die derzeit erzielbaren Ausbeuten sind bislang gering [102]. 6-[ 18 F]Fluormaltose reichert sich in unterschiedlichen Bakterienkulturen an.…”