PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ 18F]fluoro-6-deoxy-D-fructose

Abstract Introduction: Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) was developed for PET imaging of fructose metabolism in breast cancer via the fructose-preferred facilitative hexose transporter, GLUT5. In the brain, GLUT5 is predominantly expressed on microglial cells that are activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. Methods: 6-[18F]FDF was evaluated in a neuroinflammation model induced by unilateral injection of lipopolysaccharide (LPS) into the right striatum (50 µg/animal) in male and female rats. Comparison of 6-[18F]FDF and the glucose derivative [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG), was performed by longitudinal dynamic PET imaging in vivo. Immunohistochemistry was conducted to examine the presence of activated microglia (Iba-1) and astrocytes (GFAP) in fixed brain tissues. Results: In LPS-injected rats, increased accumulation of radioactivity from 6-[18F]FDF was observed in the ipsilateral striatum compared to the contralateral side at 24-48 hr post-LPS injection, with plateaued uptake at 60-120 min significantly higher in the right (0.985 ± 0.047 SUV) vs. left (0.819 ± 0.033 SUV) striatum at 48 h (P = 0.002; n = 4M/3F). The ipsilateral-contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential peaked at 48 h (male: 0.25 ± 0.03; female: 0.11 ± 0.03) and was significantly decreased at later time points of one, two and four weeks; and was higher in male rats (P = 0.017). In contrast, increased [18F]FDG uptake was observed in the ipsilateral striatum compared to the contralateral striatum and was highest at one week post-LPS injection. Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes in the ipsilateral striatum. Conclusions: This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in the brain with applications in neuroinflammatory and neurodegenerative diseases.