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Transport of 3-Fluoro-L-α-Methyl-Tyrosine by Tumor-Upregulated L-Type Amino Acid Transporter 1: A Cause of the Tumor Uptake in PET.
MedLine Citation:
PMID:  22743251     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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:
Pattama Wiriyasermkul; Shushi Nagamori; Hideyuki Tominaga; Noboru Oriuchi; Kyoichi Kaira; Hidekazu Nakao; Takeru Kitashoji; Ryuichi Ohgaki; Hidekazu Tanaka; Hitoshi Endou; Keigo Endo; Hiroyuki Sakurai; Yoshikatsu Kanai
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-28
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  -     ISSN:  1535-5667     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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