UNLABELLED: l-3-(18)F-α-methyl tyrosine ((18)F-FAMT) has been developed as a PET radiotracer for tumor imaging. Clinical studies have demonstrated the usefulness of (18)F-FAMT PET for the prediction of prognosis and the differentiation of malignant tumors and benign lesions. (18)F-FAMT exhibits higher cancer specificity in peripheral organs than other amino acid PET tracers and (18)F-FDG. The accumulation of (18)F-FAMT is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L highly upregulated in cancers. In this study, we examined the interaction of 3-fluoro-l-α-methyl-tyrosine (FAMT) with amino acid transporters to assess the mechanisms of (18)F-FAMT uptake in PET. METHODS: We applied in vitro assays using established mammalian cell lines stably expressing LAT1 or a non-cancer-type system L isoform LAT2. The inhibitory effect on l-(14)C-leucine uptake and the induction effect on efflux of preloaded l-(14)C-leucine were examined for FAMT and other amino acid tracers. FAMT transport was compared among cell lines with varied LAT1 expression level. RESULTS: FAMT prominently inhibited LAT1-mediated l-(14)C-leucine uptake in a competitive manner but had less of an effect on LAT2. In the efflux experiments, FAMT induced the efflux of preloaded l-(14)C-leucine through LAT1, indicating that FAMT is transported by LAT1 and not by LAT2. Among amino acid-related compounds examined in this study, including those used for PET tracers, the compounds with an α-methyl group such as FAMT, 2-fluoro-l-α-methyl-tyrosine, 3-iodo-l-α-methyl-tyrosine, and l-α-methyl-tyrosine were well transported by LAT1 but not by LAT2. However, l-methionine, l-tyrosine, 3-fluoro-l-tyrosine, 2-fluoro-l-tyrosine, and O-(2-fluoroethyl)-l-tyrosine were transported by both LAT1 and LAT2, suggesting that the α-methyl moiety is responsible for the LAT1 selectivity of FAMT. FAMT transport rate and LAT1 protein level were well correlated, supporting the importance of LAT1 for the cellular uptake of FAMT. CONCLUSION: Distinct from other amino acid PET tracers, because of its α-methyl moiety, FAMT is selective to LAT1 and not transported by LAT2. This property of FAMT is proposed to contribute to highly tumor-specific accumulation of (18)F-FAMT in PET.
UNLABELLED: l-3-(18)F-α-methyl tyrosine ((18)F-FAMT) has been developed as a PET radiotracer for tumor imaging. Clinical studies have demonstrated the usefulness of (18)F-FAMT PET for the prediction of prognosis and the differentiation of malignant tumors and benign lesions. (18)F-FAMT exhibits higher cancer specificity in peripheral organs than other amino acid PET tracers and (18)F-FDG. The accumulation of (18)F-FAMT is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L highly upregulated in cancers. In this study, we examined the interaction of 3-fluoro-l-α-methyl-tyrosine (FAMT) with amino acid transporters to assess the mechanisms of (18)F-FAMT uptake in PET. METHODS: We applied in vitro assays using established mammalian cell lines stably expressing LAT1 or a non-cancer-type system L isoform LAT2. The inhibitory effect on l-(14)C-leucine uptake and the induction effect on efflux of preloaded l-(14)C-leucine were examined for FAMT and other amino acid tracers. FAMT transport was compared among cell lines with varied LAT1 expression level. RESULTS:FAMT prominently inhibited LAT1-mediated l-(14)C-leucine uptake in a competitive manner but had less of an effect on LAT2. In the efflux experiments, FAMT induced the efflux of preloaded l-(14)C-leucine through LAT1, indicating that FAMT is transported by LAT1 and not by LAT2. Among amino acid-related compounds examined in this study, including those used for PET tracers, the compounds with an α-methyl group such as FAMT, 2-fluoro-l-α-methyl-tyrosine, 3-iodo-l-α-methyl-tyrosine, and l-α-methyl-tyrosine were well transported by LAT1 but not by LAT2. However, l-methionine, l-tyrosine, 3-fluoro-l-tyrosine, 2-fluoro-l-tyrosine, and O-(2-fluoroethyl)-l-tyrosine were transported by both LAT1 and LAT2, suggesting that the α-methyl moiety is responsible for the LAT1 selectivity of FAMT. FAMT transport rate and LAT1 protein level were well correlated, supporting the importance of LAT1 for the cellular uptake of FAMT. CONCLUSION: Distinct from other amino acid PET tracers, because of its α-methyl moiety, FAMT is selective to LAT1 and not transported by LAT2. This property of FAMT is proposed to contribute to highly tumor-specific accumulation of (18)F-FAMT in PET.
Authors: David M Schuster; Cristina Nanni; Stefano Fanti; Shuntaro Oka; Hiroyuki Okudaira; Yusuke Inoue; Jens Sörensen; Rikard Owenius; Peter Choyke; Baris Turkbey; Trond V Bogsrud; Tore Bach-Gansmo; Raghuveer K Halkar; Jonathon A Nye; Oluwaseun A Odewole; Bital Savir-Baruch; Mark M Goodman Journal: J Nucl Med Date: 2014-11-13 Impact factor: 10.057
Authors: Norbert Galldiks; Karl-Josef Langen; Nathalie L Albert; Marc Chamberlain; Riccardo Soffietti; Michelle M Kim; Ian Law; Emilie Le Rhun; Susan Chang; Julian Schwarting; Stephanie E Combs; Matthias Preusser; Peter Forsyth; Whitney Pope; Michael Weller; Jörg C Tonn Journal: Neuro Oncol Date: 2019-05-06 Impact factor: 12.300
Authors: Matthew B Nodwell; Hua Yang; Helen Merkens; Noeen Malik; Milena Čolović; Rainer E Martin; François Bénard; Paul Schaffer; Robert Britton Journal: J Nucl Med Date: 2019-01-25 Impact factor: 10.057