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Glia account for 90% of human brain cells and have a significant role in brain homeostasis. Thus, specific in vivo imaging markers of glial metabolism are potentially valuable. In the brain, 2-fluoroacetate is selectively taken up by glial cells and becomes metabolically trapped in the tricarboxylic acid cycle. Recent work in rodent brain injury models demonstrated elevated lesion uptake of 2-[18F]fluoroacetate ([18F]FACE), suggesting possible use for specifically imaging glial metabolism. To assess this hypothesis, we evaluated [18F]FACE kinetics in rodent models of cerebral hypoxia-ischemia at 3 and 24 hours post insult. Lesion uptake was significantly higher at 30 minutes post injection (P<0.05). An image-based method for input function estimation using cardiac blood was validated. Analysis of whole blood showed no significant metabolites and plasma activity concentrations of ∼50% that of whole blood. Kinetic models describing [18F]FACE uptake were developed and quantitatively compared. Elevated [18F]FACE uptake was found to be driven primarily by K1/k2 rather than k3, but changes in the latter were detectable. The two-tissue irreversible uptake model (2T3k) was found to be necessary and sufficient for modeling [18F]FACE uptake. We conclude that kinetic modeling of [18F]FACE uptake represents a potentially useful tool for interrogation of glial metabolism. [ABSTRACT FROM AUTHOR]