Comparative evaluation of transport mechanisms of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid and l-[methyl-11C]methionine in human glioma cell lines

Abstract

Positron emission tomography (PET) with amino acid tracers is useful for the visualization and assessment of therapeutic effects on gliomas. Our purpose is to elucidate the transport mechanisms of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid (anti-[18F]FACBC) and l-[methyl-11C]methionine ([11C]Met) in normal human astrocytes (NHA), low-grade (Hs683, SW1088), and high-grade (U87MG, T98G) human glioma cell lines. Because the short half-lives of fluorine-18 and carbon-11 are inconvenient for in vitro experiments, trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid (anti-[14C]FACBC) and l-[methyl-14C]methionine ([14C]Met) were used instead of the PET tracers. Time-course uptake experiments showed that uptake of anti-[14C]FACBC was 1.4–2.6 times higher than that of [14C]Met in NHA and low-grade glioma cells, and was almost equal to that of [14C]Met in high-grade glioma cells. To identify the amino acid transporters (AATs) involved in the transport of anti-[14C]FACBC and [14C]Met, we carried out competitive inhibition experiments using synthetic/naturally-occurring amino acids as inhibitors. We found that anti-[14C]FACBC uptake in the presence of Na+ was strongly inhibited by l-glutamine and l-serine (the substrates for ASC system AATs), whereas l-phenylalanine and 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH, the substrates for L system AATs) robustly inhibited Na+-independent anti-[14C]FACBC uptake. Regardless of Na+, [14C]Met uptake was inhibited strongly by l-phenylalanine and BCH. Moreover, the exchange transport activity of l-glutamine for anti-[14C]FACBC was stronger than that of BCH in the presence of Na+, whereas that for [14C]Met was almost equal to BCH. These results demonstrate that ASC and L are important transport systems for anti-[18F]FACBC uptake, while system L is predominantly involved in [11C]Met transport in human astrocytes and glioma cells.