1. Peptidoglycan-Targeted [18F]3,3,3-Trifluoro‑d‑alanine Tracer for Imaging Bacterial Infection
- Author
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Sorlin, Alexandre M, López-Álvarez, Marina, Biboy, Jacob, Gray, Joe, Rabbitt, Sarah J, Rahim, Junaid Ur, Lee, Sang Hee, Bobba, Kondapa Naidu, Blecha, Joseph, Parker, Mathew FL, Flavell, Robert R, Engel, Joanne, Ohliger, Michael, Vollmer, Waldemar, and Wilson, David M
- Subjects
Chemical Sciences ,Lung ,Biomedical Imaging ,Infectious Diseases ,Rare Diseases ,2.2 Factors relating to the physical environment ,4.1 Discovery and preclinical testing of markers and technologies ,Infection ,infection imaging ,positron emission tomography ,peptidoglycan ,d-amino acids ,radiotracer ,metabolism ,Chemical sciences - Abstract
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.
- Published
- 2024