| Summary: | Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[<sup>18</sup>F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[<sup>18</sup>F]FDF will specifically image microglia following neuroinflammatory insult. 6-[<sup>18</sup>F]FDF and, for comparison, [<sup>18</sup>F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[<sup>18</sup>F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; <i>p</i> = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[<sup>18</sup>F]FDF uptake expressed as binding potential (<i>BP</i><sub>SRTM</sub>) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [<sup>18</sup>F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (<i>BP</i><sub>SRTM</sub> = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[<sup>18</sup>F]FDF to neuroinflammatory stimuli in rat brain. 6-[<sup>18</sup>F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.
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