The Influx of Neutral Amino Acids into the Porcine Brain During Development: A Positron Emission Tomography Study

Pigs of three different age groups (newborns, 1 week old, 6 weeks old) were used to study the transport of the large neutral amino acids 6-[F-18]fluoro-L-DOPA ([F-18]FDOPA) and 3-O-methyl-6-[F-18]fluoro-L-DOPA ([F-18]OMFD) across the blood-brain barrier (BBB) with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the blood-brain clearance (K-1) and the rate constant for the brain-blood transfer (k(2)) of [F-18]FDOPA and [F-18]OMFD after i.v. injection. A 40-70% decrease of K-1(OMFD), K-1(FDOPA) and k(2)(OMFD) from newborns to juvenile pigs was found whereas k(2)(FDOPA) did not change. Generally, K-1(OMFD) and k(2)(OMFD) are lower than K-1(FDOPA) and k(2)(FDOPA) in all regions and age groups. The changes cannot be explained by differences in brain perfusion because the measured regional cerebral blood flow did not show major changes during the first 6 weeks after birth. In addition, alterations in plasma amino acids cannot account for the described transport changes. In newborn and juvenile pigs, HPLC measurements were performed. Despite significant changes of single amino acids (decrease: Met, Val, Leu; increase: Tyr), the sum of large neutral amino acids transported by LAT1 remained unchanged. Furthermore, treatment with a selective inhibitor of the LAT1 transporter (BCH) reduced the blood-brain transport of [F-18]FDOPA and [F-18]OMFD by 35% and 32%, respectively. Additional in-vitro studies using human LAT1 reveal a much lower affinity of FDOPA compared to OMFD or L-DOPA. The data indicate that the transport system(s) for neutral amino acids underlie(s) developmental changes after birth causing a decrease of the blood-brain barrier permeability for those amino acids during brain development. It is suggested that there is no tight coupling between brain amino acid supply and the demands of protein synthesis in the brain tissue. (C) 2004 Elsevier B.V. All rights reserved.