TY - JOUR
T1 - Chemoenzymatic Syntheses of Fluorine-18-Labeled Disaccharides from [18F] FDG Yield Potent Sensors of Living Bacteria In Vivo
AU - Sorlin, Alexandre M.
AU - López-Álvarez, Marina
AU - Rabbitt, Sarah J.
AU - Alanizi, Aryn A.
AU - Shuere, Rebecca
AU - Bobba, Kondapa Naidu
AU - Blecha, Joseph
AU - Sakhamuri, Sasank
AU - Evans, Michael J.
AU - Bayles, Kenneth W.
AU - Flavell, Robert R.
AU - Rosenberg, Oren S.
AU - Sriram, Renuka
AU - Desmet, Tom
AU - Nidetzky, Bernd
AU - Engel, Joanne
AU - Ohliger, Michael A.
AU - Fraser, James S.
AU - Wilson, David M.
N1 - Funding Information:
The authors thank Drs. Gayatri Gowrishankar, Niren Murthy, Bin Shen, Dima Hammoud, and Sanjay Jain for helpful discussions. We also thank the UCSF Clinical Laboratories (Drs. Charles Chiu and Helen Reyes) for providing clinical strains and Shari Dhaene for enzyme expression. Grant sponsors NIH R01EB024014, NIH R01EB025985, NIH R01EB030897, and NIH R21AI164684; DOD A132172; and UCSF Bold and Basic.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/8/16
Y1 - 2023/8/16
N2 - Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[18F]-fluoro-d-glucose ([18F]FDG), the most common tracer used in clinical imaging, to form [18F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [18F]FDG was reacted with β-d-glucose-1-phosphate in the presence of maltose phosphorylase, the α-1,4- and α-1,3-linked products 2-deoxy-[18F]-fluoro-maltose ([18F]FDM) and 2-deoxy-2-[18F]-fluoro-sakebiose ([18F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (β-1,3), and cellobiose (β-1,4) phosphorylases to synthesize 2-deoxy-2-[18F]fluoro-trehalose ([18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose ([18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose ([18F]FDC). We subsequently tested [18F]FDM and [18F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [18F]FDM and [18F]FSK were stable in human serum with high accumulation in preclinical infection models. The synthetic ease and high sensitivity of [18F]FDM and [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of these tracers to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [18F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.
AB - Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[18F]-fluoro-d-glucose ([18F]FDG), the most common tracer used in clinical imaging, to form [18F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [18F]FDG was reacted with β-d-glucose-1-phosphate in the presence of maltose phosphorylase, the α-1,4- and α-1,3-linked products 2-deoxy-[18F]-fluoro-maltose ([18F]FDM) and 2-deoxy-2-[18F]-fluoro-sakebiose ([18F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (β-1,3), and cellobiose (β-1,4) phosphorylases to synthesize 2-deoxy-2-[18F]fluoro-trehalose ([18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose ([18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose ([18F]FDC). We subsequently tested [18F]FDM and [18F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [18F]FDM and [18F]FSK were stable in human serum with high accumulation in preclinical infection models. The synthetic ease and high sensitivity of [18F]FDM and [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of these tracers to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [18F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.
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U2 - 10.1021/jacs.3c03338
DO - 10.1021/jacs.3c03338
M3 - Article
C2 - 37535945
AN - SCOPUS:85168222188
SN - 0002-7863
VL - 145
SP - 17632
EP - 17642
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 32
ER -