Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals. In rats on the KD for 10 days, (11)C-AcAc uptake by the brain increased 7- to 8-fold, an increase similar to that induced by 48 h fasting. In rats and humans, paired PET scans ((11)C-AcAc followed immediately by(18)fluorodeoxyglucose) will be conducted to assess the uptake of AcAc and glucose by the brain while on the KD and in neurological disorders associated with aging.