Comparative evaluation of 18F-labeled glutamic acid and glutamine as tumor metabolic imaging agents

Abstract

18F-labeled (2S, 4R)-4-fluoro-L-glutamine (4F-GLN) has demonstrated high uptake in tumor cells that undergo high growth and proliferation. Similar tumor targeting properties have also been observed for 18F-labeled (2S,4R)-4-fluoro-L-glutamate (4F-GLU), suggesting that both are useful imaging agents. A new labeling procedure facilitates the preparation of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU with confirmed radiochemical and enantiomeric purity. Here, we report the preparation and comparative evaluation of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU as tumor metabolic imaging agents. Methods: Uptake of enantiomerically pure 18F-(2S,4R)4F-GLN and 18F-(2S,4R) 4F-GLU was determined in 3 tumor cell lines (9L, SF188, and PC-3) at selected time points. The in vitro cell uptake mechanism was evaluated by inhibition studies in 9L cells. In vivo biodistribution and PET studies were performed on male F344 rats bearing 9L tumor xenografts. Results: In vitro cell uptake studies showed that 18F-(2S,4R)4F-GLN displayed higher uptake than 18F-(2S,4R) 4F-GLU. Amino acid transport system ASC (alanine-serine-cysteine-preferring; in particular, its subtype ASCT2 [SLC1A5 2 (SLC7A11 gene) played an important role gene]) and system X c- in transporting 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU, respectively, across the membrane. After being transported into cells, a large percentage of 18F-(2S,4R)4F-GLN was incorporated into protein, whereas 18F-(2S,4R)4F-GLU mainly remained as the free amino acid in its original form. In vivo studies of 18F-(2S,4R) 4F-GLN in the 9L tumor model showed a higher tumor uptake than 18F-(2S,4R)4F-GLU, whereas 18F-(2S,4R)4F-GLU had a slightly higher tumor-to-background ratio than 18F-(2S,4R)4F-GLN. Imaging studies showed that both tracers had fast accumulation in 9L tumors. Compared with 18F-(2S,4R)4F-GLU, 18F-(2S,4R)4F-GLN exhibited prolonged tumor retention reflecting its incorporation into intracellular macromolecules. Conclusion: Differences in uptake and metabolism in tumor cells were found between 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU. Both agents are potentially useful as metabolic tracers for tumor imaging. Copyright © 2012 by the Society of Nuclear Medicine and Molecular Imaging, Inc.