title: 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.
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan; Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-0942, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Oka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okudaira
authors.forename: David M
authors.initials: DM
authors.lastname: Schuster
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Shirakami
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D003503:Cyclobutanes / Q000493:pharmacokinetics*; D005910:Glioma / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D008715:Methionine / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D003503:Cyclobutanes; C117460:fluciclovine F-18; D008715:Methionine
keywords: 2-(methylamino)-isobutyric acid; 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid; AAT(s); ASCT2; Amino acid transporter; BCH; Glioma; LAT1; MeAIB; Methionine; N-ethylmaleimide; NEM; PET; [(11)C]Met; [(14)C]Met; amino acid transporter(s); anti-FACBC; anti-[(14)C]FACBC; anti-[(18)F]FACBC; l-[methyl-(11)C]methionine; l-[methyl-(14)C]methionine; positron emission tomography; trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid; trans-1-amino-3-fluoro[1-(14)C]cyclobutanecarboxylic acid