Use of Acute Hyperphenylalaninemia in Rhesus Monkeys to Examine Sensitivity and Stability of the l-[1-11C]Leucine Method for Measurement of Regional Rates of Cerebral Protein Synthesis with Pet

We have previously shown by direct comparison with autoradiographic and biochemical measurements that the l-[1-11C]leucine positron emission tomography method provides accurate determinations of regional rates of cerebral protein synthesis (rCPS) and the fraction (Λ) of unlabeled leucine in the precursor pool for protein synthesis derived from arterial plasma. In this study, we examine sensitivity of the method to detect changes in Λ and stability of the method to measure rCPS in the face of these changes. We studied four isoflurane-anesthetized monkeys dynamically scanned with the high resolution research tomograph under control and mild hyperphenylalaninemic conditions. Hyperphenylalaninemia was produced by an infusion of phenylalanine that increased plasma phenylalanine concentrations three- to five-fold. In phenylalanine-infused monkeys, plasma leucine concentrations remained relatively constant, but values of Λ were statistically significantly decreased by 11% to 15%; rCPS was unaffected. Effects on Λ are consistent with competitive inhibition of leucine transport by increased plasma phenylalanine. The effect on Λ shows that competition for the transporter results in a reduction in the fraction of leucine in the precursor pool for protein synthesis coming from plasma. Even under these hyperphenylalaninemic conditions, rCPS remains unchanged due to the compensating increased contribution of leucine from protein degradation to the precursor pool.