Criteria for the tracer kinetic measurement of cerebral protein synthesis in humans with positron emission tomography

Abstract

The principles and initial results of the use of PET to measure the local cerebral metabolic rate for protein synthesis ( lCRPS ) in humans are described. The labeling of leucine, phenylalanine, and methionine in the carboxyl position provides a strategy (selective position labeling) for discriminating between the incorporation of these amino acids into proteins and metabolic oxidation. In metabolic oxidation the label is removed from tissue through decarboxylation. The resulting labeled carbon dioxide is diluted by the tissue carbon dioxide pool, cleared from cerebral tissue by blood flow, and subsequently ventilated by the lungs. This approach also provides a plasma input function that is free of other labeled amino acids produced through systemic reactions, such as those that occur for methionine labeled in the methyl group. The measured lCRPS is in good agreement with values determined by Smith and Sokoloff by autoradiographic and biochemical assay techniques, as are the measured kinetic rate constants of bidirectional transport, incorporation into proteins, and metabolism, as determined in monkeys and humans using L-leucine labeled with carbon-11 in position 1 (L-[1-11C]leucine) with PET. The tissue leucine precursor pool exhibits a rapid turnover rate (1.5 to 2 minutes), while the metabolic pathway has a half-time (about 18 minutes) that is close to the radioactive half-life of carbon-11. The dietary state was found to affect the branching ratio of lCRPS /metabolism, with a fasted value of 0.4 and carbohydrate feed values ranging up to 1.7. The principle of the method appears sound, and a first-order model provides good fits to data, but much more work is required to determine and validate the model structure and to optimize the study conditions and estimation criteria.

Positron emission tomography methods with potential for increased understanding of mental retardation and developmental disabilities

“…11 C]L-leucine in humans 20 years ago [Phelps et al, 1984;Hawkins et al, 1989], but has not been widely applied due to difficulties with the chemical synthesis of the radiotracer and the lack of a method to estimate the fraction of amino acid pool derived from protein breakdown in the tissue [Smith et al, 1988], leading to an underestimation of the rate of protein synthesis. The estimate of the tissue-derived amino acid pool was particularly a problem for the study of developmental disorders, since the amount of brain amino acid recycling was reported to change as a function of age [Sun et al, 1995].…”

Estimation of Local Cerebral Protein Synthesis Rates with L-[1-11C]Leucine and PET: Methods, Model, and Results in Animals and Humans

“…As discussed by Phelps et al (1984), a rapid turn- over time of the precursor pool, relative to the half time of the label, is desirable to insure reasonable uptake into the protein compartment within the study period. The half-times of turnover of the pre cursor compartment in this study, in the range of 1 to 3 min (Table 1), satisfies this requirement.…”

PET in clinical oncology

“…In order to evaluate this possibility and to develop a method for quantiting protein synthesis in other states, several in vivo protein synthesis estimation methods have been developed. The most completely validated of the available techniques validated used 11C-leucine [91][92][93].…”

“…Kennedy et al [97] later applied this technique to studies of the visual system of monkeys. Phelps et al [91] used the L isomer of leucine labeled with 1~C to estimate protein synthesis in vivo with PET, using a model based on that of Smith et al. The essential L-amino acids leucine, methionine, and phenylalanine are highly extracted through the blood brain barrier via facilitated transport. Following transport into the brain, the amino acids may either be esterified to their corresponding tRNAs for incorporation into protein, or may become substrates for various metabolic pathways.…”