Dataset Information

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose.

ABSTRACT: Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]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-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]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-[18F]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; p = 0.002, n = 4M/3F). The ipsilateral-contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 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-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.

SUBMITTER: Boyle AJ

PROVIDER: S-EPMC9736258 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose.

Boyle Amanda J AJ Murrell Emily E Tong Junchao J Schifani Christin C Narvaez Andrea A Wuest Melinda M West Frederick F Wuest Frank F Vasdev Neil N

Molecules (Basel, Switzerland) 20221203 23

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]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-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected ma ...[more]

PMID: 36500626

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Project description:Glutathione is the predominant endogenous cellular antioxidant, playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen species. With cysteine as the rate-limiting substrate in glutathione biosynthesis, the cystine/glutamate transporter (system xc(-)) represents a potentially attractive PET biomarker to enable in vivo quantification of xc(-) activity in response to oxidative stress associated with disease. We have developed a system xc(-) substrate that incorporates characteristics of both natural substrates, L-cystine and L-glutamate (L-Glu). L-aminosuberic acid (L-ASu) has been identified as a more efficient system xc(-) substrate than L-Glu, leading to an assessment of a series of anionic amino acids as prospective PET tracers. Herein, we report the synthesis and in vitro and in vivo validation of a lead candidate, (18)F-5-fluoro-aminosuberic acid ((18)F-FASu), as a PET tracer for functional imaging of a cellular response to oxidative stress with remarkable tumor uptake and retention.(18)F-FASu was identified as a potential PET tracer based on an in vitro screening of compounds similar to L-cystine and L-Glu. Affinity toward system xc(-) was determined via in vitro uptake and inhibition studies using oxidative stress-induced EL4 and SKOV-3 cells. In vivo biodistribution and PET imaging studies were performed in mice bearing xenograft tumors (EL4 and SKOV-3).In vitro assay results determined that L-ASu inhibited system xc(-) as well as or better than L-Glu. The direct comparison of uptake of tritiated compounds demonstrated more efficient system xc(-) uptake of L-ASu than L-Glu. Radiosynthesis of (18)F-FASu allowed the validation of uptake for the fluorine-bearing derivative in vitro. Evaluation in vivo demonstrated primarily renal clearance and uptake of approximately 8 percentage injected dose per gram in SKOV-3 tumors, with tumor-to-blood and tumor-to-muscle ratios of approximately 12 and approximately 28, respectively. (18)F-FASu uptake was approximately 5 times greater than (18)F-FDG uptake in SKOV-3 tumors. Dynamic PET imaging demonstrated uptake in EL4 tumor xenografts of approximately 6 percentage injected dose per gram and good tumor retention for at least 2 h after injection.(18)F-FASu is a potentially useful metabolic tracer for PET imaging of a functional cellular response to oxidative stress. (18)F-FASu may provide more sensitive detection than (18)F-FDG in certain tumors.

Dataset Information

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose.

Publications

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[<sup>18</sup>F]fluoro-6-deoxy-D-fructose.

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