5-(2-18F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Journal of Nuclear Medicine

Linjing Mu¹  Stefanie D. Krämer¹  Tobias L. Ross¹  Adrienne Müller¹  Simon M. Ametamey¹  Claudia Keller¹  Olga F. Kuznetsova¹  Dominic Franck¹  Christian Schweinsberg¹  Roger Schibli¹  Cristina Müller¹ 

关键词: PET;    tumor imaging;    LAT;    SLC7A;    tryptophan;   

DOI  :  10.2967/jnumed.111.096289

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Large neutral l-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic l-amino acids may also be substrates of aromatic l-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. 18F- and 11C-labeled neutral aromatic amino acids, such as l-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-FDOPA) and 5-hydroxy-l-[β-11C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-l-[β-11C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the 18F-labeled tryptophan analog 5-(2-18F-fluoroethoxy)-l-tryptophan (18F-l-FEHTP) as a PET probe for tumor imaging. Methods: 18F-l-FEHTP was synthesized by no-carrier-added 18F fluorination of 5-hydroxy-l-tryptophan. In vitro cell uptake and efflux of 18F-l-FEHTP and 18F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites. Results: 18F-l-FEHTP specific activity and radiochemical purity were 50–150 GBq/μmol and greater than 95%, respectively. In vitro cell uptake of 18F-l-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37°C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. 18F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for 18F-l-FEHTP and 18F-FDOPA at 30–45 min after injection. In contrast to the 18F-FDOPA PET results, pretreatment with the AADC inhibitor S-carbidopa did not affect the 18F-l-FEHTP PET results. No decarboxylation products of 18F-l-FEHTP were detected in the xenograft homogenates. Conclusion: 18F-l-FEHTP accumulates in endocrine and nonendocrine tumor models via LAT1 transport but is not decarboxylated by AADC. 18F-l-FEHTP may thus serve as a PET probe for tumor imaging and quantification of tumor LAT1 activity. These findings are of interest in view of the ongoing evaluation of LAT1 substrates and inhibitors for cancer therapy.

【 授权许可】

Unknown