Noninvasive Demonstration of In Vivo 3‐Fluoro‐3‐Deoxy‐D‐Glucose Metabolism in Rat Brain by ¹⁹F Nuclear Magnetic Resonance Spectroscopy: Suitable Probe for Monitoring Cerebral Aldose Reductase Activities

Abstract

The metabolism of 3-fluoro-3-deoxy-D-glucose (3-FDG) in rat brain in vivo was investigated noninvasively using 19F nuclear magnetic resonance (NMR) spectroscopy. Following an intravenous infusion of 3-FDG, 400 mg/kg, four resonances assigned to the alpha and beta anomers of 3-FDG, 3-fluoro-3-deoxy-D-sorbitol, and 3-fluoro-3-deoxy-D-fructose were clearly resolved in brain, a result indicating that 3-FDG is metabolized primarily into the aldose reductase sorbitol (ARS) pathway. An orally administered aldose reductase inhibitor, sorbinil, caused reduction of the flux of 3-FDG into the ARS, an observation suggesting that the method can be applied in quantitative studies of ARS pathway activities. Studies of 24-h urine specimens showed that in addition to the two metabolites observed in brain, F- was excreted into the urine. 3-FDG appears to be a suitable metabolic probe for assessing glucose metabolism in the ARS pathway by in vivo 19F NMR spectroscopy.

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“…Kwee et al [306] introduced 3-fluoro-3-deoxy-D-glucose (3-FDG) as a probe of aldose reductase activity in brain and demonstrated metabolism. The elimination of 3-FDG from brain is slow relative to 2-FDG [310] and it has been used to probe metabolic pathways [306,[311][312][313].…”

Fluorine‐19 NMR imaging of glucose metabolism

“…Inappropriately high activities of aldose reductase, however, have been postulated to be an underlying mechanism in the development of certain diabetes-associated complications such as cataracts or neuropathy and efforts in the treatment of these diabetic complications have been directed at the inhibition of aldose reductase activity (1 7). The 3-FDG has been found to be a suitable tracer for measuring aldose reductase activities in vivo (2). The present study demonstrated that the spatial distribution of aldose reductase activities can be quantitatively imaged in live animals noninvasively using 3-FDG and I9F NMR imaging.…”

“…Although both 2-FDG and 2-FDG-6-phosphate contribute to resonance 6-124 following 2-FDG infusion, 2-FDG-6-phosphate is considered to be the main substrate responsible for resonance 6-124 (12, 13). The 3-FDSL is the sole contributor of resonance 6-137 following 3-FDG infusion (2). In the present study, the 2-FDG-6-phosphate or 3-FDSL resonance was imaged to reflect glucose utilization or aldose reductase activities, respectively.…”

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“…Phosphorylation to the main phosphorylated metabolite was slower than the conversion of 2-FDG to 2-FDG-6-P, and hydrolysis of this phosphate metabolite appeared to be more rapid than 2-FDG-6-P [52]. NMR-based studies of 3-FDG metabolism indicate that unlike 2-FDG, 3-FDG is metabolized via the polyol pathway [53], first to 3-fluoro-3-deoxy-D-sorbitol by aldose reductase, and then sequentially to 3-fluoro-3-deoxy-D-fructose and 3-fluoro-3-deoxy-D-gluconic acid [54,55]. 3-Deoxy-3-fluoro-D-gluconate-6-phosphate appears to be formed directly from 3-deoxy-3-fluoro-Dgluconic acid [56] (Fig.…”