Distributable, metabolic PET reporting of tuberculosis

R. M. Naseer Khan, Yong-Mo Ahn, Gwendolyn A. Marriner, Laura E. Via, Francois D’Hooge, Seung Seo Lee, Nan Yang, Falguni Basuli, Alexander G. White, Jaime A. Tomko, L. James Frye, Charles A. Scanga, Danielle M. Weiner, Michelle L. Sutphen, Daniel M. Schimel, Emmanuel Dayao, Michaela K. Piazza, Felipe Gomez, William Dieckmann, Peter Herscovitch, N. Scott Mason, Rolf Swenson, Dale O. Kiesewetter, Keriann M. Backus, Yiqun Geng, Ritu Raj, Daniel C. Anthony, JoAnne L. Flynn, Clifton E. Barry () and Benjamin G. Davis ()
Additional contact information
R. M. Naseer Khan: Chemistry Research Laboratory
Yong-Mo Ahn: National Institutes of Health (NIH)
Gwendolyn A. Marriner: National Institutes of Health (NIH)
Laura E. Via: National Institutes of Health (NIH)
Francois D’Hooge: Chemistry Research Laboratory
Seung Seo Lee: Chemistry Research Laboratory
Nan Yang: Chemistry Research Laboratory
Falguni Basuli: NIH
Alexander G. White: University of Pittsburgh
Jaime A. Tomko: University of Pittsburgh
L. James Frye: University of Pittsburgh
Charles A. Scanga: University of Pittsburgh
Danielle M. Weiner: National Institutes of Health (NIH)
Michelle L. Sutphen: National Institutes of Health (NIH)
Daniel M. Schimel: National Institutes of Health (NIH)
Emmanuel Dayao: National Institutes of Health (NIH)
Michaela K. Piazza: NIH
Felipe Gomez: NIH
William Dieckmann: NIH
Peter Herscovitch: NIH
N. Scott Mason: University of Pittsburgh
Rolf Swenson: NIH
Dale O. Kiesewetter: NIH
Keriann M. Backus: Chemistry Research Laboratory
Yiqun Geng: Chemistry Research Laboratory
Ritu Raj: Chemistry Research Laboratory
Daniel C. Anthony: University of Oxford
JoAnne L. Flynn: University of Pittsburgh
Clifton E. Barry: National Institutes of Health (NIH)
Benjamin G. Davis: Chemistry Research Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose – 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) – is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

Date: 2024
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DOI: 10.1038/s41467-024-48691-6

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