Development of RI probe for the measurement of glial metabolism.

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Evaluation of [^<14>C]-acetate as a selective RI probe for the measurement of glial metabolism in rodent brain was performed. A significant and dose-dependent decrease in [^<14>C]-acetate uptake in the striatum infused with fluorocitrate, a selective glial toxin, was seen, which indicated that [^<14>C]-acetate might reflect glial TCA cycle. Microinjection of ibotenic acid into rat striatum caused a significant enhancement of glucose utilization, whereas a significant reduction of [^<14>C]-acetate uptake and these changes in energy metabolism induced by excitatory amino acid were completely blocked by pretreatment with MK-801. [^<14>C]-Acetate uptake was sensitive against to a very short-term occlusion of middle cerebral artery (3-10 minutes) and reperfusion, more than 50% of reduction of [^<14>C]-acetate uptake in ischemic core was observed. In contrast, significant increases in [^<14>C]-acetate uptake in the brain of rats in other animal models such as Mn toxicity or Li-pilocarpine ep … More ilepsy were observed. These results indicated that [^<14>C]-acetate seemed to be a useful tool for the measurement of dysfunction of glial metabolism.In order to improve the brain uptake, a new type of pro-radiotracer, which easily pass through the blood-brain-barrier, and rapidly converted to labeled acetate in the brain by carboxyl esterase. These kinds of [^<14>C]-phenylacetate and [^<14>C]-benzylacetate were synthesized, and evaluated their potential as a RI probe. Among them, [^<14>C]-benzylacetate showed the highest brain uptake (about two times higher than [^<14>C]-deoxyglucose). It was rapidly hydrolyzed in intact rat brain, and less than 5% of total radioactivity was remained as [^<14>C]-benzylacetate itself at 1 minute post injection of the tracer. Radiochemical analysis using TLC revealed that about 90% of [^<14>C]-benzylacetate was converted to [^<14>C]-glutamate and [^<14>C]-glutamine within 10 minutes after the tracer injection. These results strongly indicated that [^<14>C] ([^<11>C])-labeled benzylacetate seemed to have a high potential radio tracer for the measurement of glial metabolism in intact brain. Less