Abstract View
Facile O-glycosidation of [18F]FDG for the radiosynthesis of 18F-glucosides
Category: Fluorine-18 Chemistry
Authors:
Sang Hee Lee1, Jung Min Kim1, Marina López-Álvarez1, Anju Wadhwa1, Anil P. Bidkar1, Junaid Ur Rahim1, Joseph Blecha1, Robert R. Flavell1,2,3, Alvaro A. Ordoñez4, Youngho Seo1,2, Joanne Engel5, Michael A. Ohliger1,6, David M. Wilson1*
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, USA. 2UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. 3Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. 4Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. 5Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA, 6Department of Radiology, Zuckerberg San Francisco General Hospital, San Francisco, CA 94110, USA.
Introduction: [18F]FDG is the most widely available PET tracer in nuclear medicine for visualizing abnormal glucose metabolism. However, it has limited utility in infection imaging due to its lack of specificity in differentiating bacterial infection from host inflammation [1]. Beyond its diagnostic utility, [18F]FDG has been investigated as a practical 18F synthon for the preparation of 18F-glycosylated products [2]. In this study, we developed a facile O-glycosidation using widely available [18F]FDG to generate 18F-glucosides and explored their utility as infection imaging tracers.
Methods: [18F]FDG solutions were dried by azeotropic distillation with MeCN under a nitrogen stream at 100 °C. A solution of either 1M HCl·alcohol or 1M HCl in 25% dioxane/alcohol was added to vials containing dried [18F]FDG. The reaction mixtures were heated at 70-100 °C for 45 min. The resulting mixtures were concentrated under a nitrogen stream at 100 °C. The crude mixtures were dissolved in 85% MeCN /water and injected onto an HPLC system using YMC-Pack Polyamine II column (250 x 10.0 mm I.D. S-5μm, 85% MeCN/Water, flow rate: 4.0 mLmin-1). The identity of 18F-glucosides was confirmed by co-injection with the corresponding 19F standards using YMC-Pack Polyamine II column (250 x 4.6 mm I.D. S-5μm; 97.5% MeCN/water; 1 mLmin-1). Subsequent in vitro and in vivo evaluations of 18F-glucosides as infection imaging tracers were conducted according to our established protocols [3].
Results: Ficher glycosidation of [18F]FDG was initially performed using a commercially available HCl·methanol solution, resulting in the formation of an anomeric mixture of Me-2-[18F]FDG (75.1 ± 3.5%, decay-corrected). Other commercially available alcoholic·HCl solutions (EtOH, 2-PrOH, and 1-BuOH) were tested under similar conditions, providing the corresponding 18F-glucosides in high yields (83-92%, d.c.). For alcoholic·HCl combinations that were not commercially available, a 4 M HCl·dioxane solution diluted with the corresponding alcohol (1:3, v/v) and subsequently employed for the reaction to afford the corresponding 18F-glucosides in moderate to high yields (33-92%, d.c.). The resulting 18F-glucosides were screened in a bacterial panel to evaluate their bacterial specificity and selectivity. Me-2-[18F]FDG showed high uptake in Staphylococcus species, whereas [18F]2-5 exhibited moderate uptake in other gram-positive bacteria. No appreciable uptake was observed in gram negative bacteria. In vivo studies demonstrated that Me-2-[18F]FDG can detect S. aureus infection sites in murine myositis models.
Conclusions: We performed O-glycosidation to generate 18F-glucosides from [18F]FDG. Among the 18F-glucosides, Me-2-[18F]FDG was identified as a promising bacterial-specific PET radiotracer, particularly for detecting Staphylococcal infection with low background signals in non-target organs. Rapid transformation of the widely available [18F]FDG into 18F-glucosides may enable broader dissemination of pathogen-targeted imaging techniques. Although [18F]6-9 exhibited negligible bacterial specificity, these analogs could serve as [18F]FDG derived synthons for further applications without requiring full de novo production starting from the fluorine-18 anion.
References
[1] Pijl, J.P., et al. Limitations and pitfalls of FDG-PET/CT in infection and inflammation. Semin. Nucl. Med., 2021, 51, 633-645.
[2] Maschauer, S., et al. Sweetening pharmaceutical radiochemistry by 18F-fluoroglycosylation: a short review. Biomed Res. Int. 2014, 2014 (1), 214748.
[3] Lee, S.H., et al. Regioselective Glycosylation of Fluorine-18-Labeled Sorbitol for Enhanced Bacterial Detection In Vivo Using PET. JACS Au 2025, 5 (12), 6189-6199.
Figure. (A) Schematic illustration of O-glycosidation of [18F]FDG for the preparation of 18F-glucosides. (B) Structures of the synthesized 18F-glucosides via O-glycosidation of [18F]FDG. Radiochemical yield (%) was determined by HPLC purification (decay-corrected).