Abstract
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Introduction: (2S,4R)-4-18F-fluoro-L-glutamine (18F-FGln) has shown promise as a metabolic imaging marker in various types of cancer. A recent study in humans showed that 18F-FGln is a more specific marker for monitoring the metabolic activities of cancer cells compared to 18F-FDG. Although 18F-FGln PET has not yet been studied in inflammation, there has been ample evidence of the fact that the metabolism of major inflammatory cells relies heavily on glutamine. In this study, we aimed to explore the potential utility of the 18F-FGln as a novel metabolic imaging marker for inflammation in rat models of acute and chronic inflammatory conditions.
Methods: In this study, 18F-FGln was synthesized through a hybridized process (Figure 1A): 1) The 18F-labeled intermediate was prepared following an automated production protocol reported by X. Zhang et al. in 2016 using GE™ TRACERlab FXNPro module; 2) The acidic deprotection was conducted in a manual operation manner following the initial 18F-FGln synthesis report. For animal studies, two distinct rat models were used: the carrageenan-induced paw edema (CIPE) model for local and acute inflammation, and the collagen-induced arthritis (CIA) model for systemic and chronic inflammation. The CIPE model (n=4, Lewis female rats) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET scan. The CIA model (n=4, Lewis female rats) was generated by injecting 200 µg of collagen emulsion subcutaneously at the tail base 3-4 weeks before the PET scan. A qualitative scoring system from 0 to 4 (4 is the most severe) was used to assess the severity of paw inflammation. After a CT scan, 15.7±4.9 MBq of 18F-FGln was intravenously injected via the tail vein, followed by a dynamic micro-PET scan for 90 minutes under general anesthesia with isoflurane. The standard uptake value (SUV) of 18F-FGln was measured by placing a volume of interest in each paw, based on the anatomical CT image. The non-injected right hind paws of the CIPE model rats served as controls for both CIPE and CIA models. After obtaining micro-PET scans, the animals with CIA were sacrificed, and the paws were amputated and sent for tissue preparation. After decalcification, fixation, sectioning, and Hematoxylin & Eosin staining, the slides were digitalized for the visual assessment of inflammation.
Results: The total production time for 18F-FGln ranged from 86 to 110 min. Starting with 9.1-15.2 GBq fluorine-18 activity, 166-411 mBq amount of 18F-FGln was produced at the end of synthesis with the radiochemical purities of the final product range from 89% to 94%. All four rats with CIPE developed inflammation with score 4 in the injected hind paws (Table 1). Among four rats with CIA, two developed severe inflammation with score 4 in both hind paws while one developed asymmetric inflammation (score 4 and 2) and the other developed severe inflammation in only one hind paw (score 4 and 0) (Table 1). In the CIPE models, 18F-FGln uptake in the injected hind paws was higher compared to the non-injected hind paws by 51-93% (Figure 1B). In the CIA models, 18F-FGln uptake in the hind paws with severe inflammation (score 4) was higher compared to the averaged controls by 50-170% (Figure 1C). In contrast, 18F-FGln uptake in the paws with mild inflammation (score 2) and no inflammation (score 0) was slightly higher (29%) and lower (-9%), respectively, compared to the averaged controls. The pathological exam confirmed profound inflammation in the paws with CIA (Figure 1D).
Conclusions: 18F-FGln uptake was increased in both acute and chronic inflammation in rat models. The uptake level showed a trend towards correlation with the severity of induced inflammation in CIA models. Our findings present the first evidence of 18F-FGln as a potential inflammatory imaging marker.
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