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Lookup NU author(s): Dr Jacob BiboyORCiD, Dr Joseph Gray, Professor Waldemar Vollmer
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Authors. Published by American Chemical Society. Imaging is increasingly used to detect and monitor bacterial infection. Both anatomic (X-rays, computed tomography, ultrasound, and MRI) and nuclear medicine ([111In]-WBC SPECT, [18F]FDG PET) techniques are used in clinical practice but lack specificity for the causative microorganisms themselves. To meet this challenge, many groups have developed imaging methods that target pathogen-specific metabolism, including PET tracers integrated into the bacterial cell wall. We have previously reported the d-amino acid derived PET radiotracers d-methyl-[11C]-methionine, d-[3-11C]-alanine, and d-[3-11C]-alanine-d-alanine, which showed robust bacterial accumulation in vitro and in vivo. Given the clinical importance of radionuclide half-life, in the current study, we developed [18F]3,3,3-trifluoro-d-alanine (d-[18F]-CF3-ala), a fluorine-18 labeled tracer. We tested the hypothesis that d-[18F]-CF3-ala would be incorporated into bacterial peptidoglycan given its structural similarity to d-alanine itself. NMR analysis showed that the fluorine-19 parent amino acid d-[19F]-CF3-ala was stable in human and mouse serum. d-[19F]-CF3-ala was also a poor substrate for d-amino acid oxidase, the enzyme largely responsible for mammalian d-amino acid metabolism and a likely contributor to background signals using d-amino acid derived PET tracers. In addition, d-[19F]-CF3-ala showed robust incorporation into Escherichia coli peptidoglycan, as detected by HPLC/mass spectrometry. Based on these promising results, we developed a radiosynthesis of d-[18F]-CF3-ala via displacement of a bromo-precursor with [18F]fluoride followed by chiral stationary phase HPLC. Unexpectedly, the accumulation of d-[18F]-CF3-ala by bacteria in vitro was highest for Gram-negative pathogens in particular E. coli. In a murine model of acute bacterial infection, d-[18F]-CF3-ala could distinguish live from heat-killed E. coli, with low background signals. These results indicate the viability of [18F]-modified d-amino acids for infection imaging and indicate that improved specificity for bacterial metabolism can improve tracer performance.
Author(s): Sorlin AM, Lopez-Alvarez M, Biboy J, Gray J, Rabbitt SJ, Rahim JU, Lee SH, Bobba KN, Blecha J, Parker MF, Flavell RR, Engel J, Ohliger M, Vollmer W, Wilson DM
Publication type: Article
Publication status: Published
Journal: JACS Au
Year: 2024
Volume: 4
Issue: 3
Pages: 1039-1047
Print publication date: 25/03/2024
Online publication date: 26/02/2024
Acceptance date: 06/02/2024
Date deposited: 03/04/2024
ISSN (electronic): 2691-3704
Publisher: American Chemical Society
URL: https://doi.org/10.1021/jacsau.3c00776
DOI: 10.1021/jacsau.3c00776
Data Access Statement: The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.3c00776.
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