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Evaluation of D-Isomers of O-¹¹C-Methyl Tyrosine and O-¹⁸F-Fluoromethyl Tyrosine as Tumor-Imaging Agents in Tumor-Bearing Mice: Comparison with L- and D-¹¹C-Methionine

PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan

Correspondence: For correspondence or reprints contact: Hideo Tsukada, PhD, PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamamatsu, Shizuoka 434-8601, Japan. E-mail: tsukada{at}crl.hpk.co.jp

The aim of this study was to investigate whether D-amino acid isomers of O-¹¹C-methyl tyrosine (¹¹C-CMT) and O-¹⁸F-fluoromethyl tyrosine (¹⁸F-FMT) were better than the corresponding L-isomers as tumor- detecting agents with PET in comparison with the difference between L- and D-methyl-¹¹C-methionine (¹¹C-MET). Methods: L- and D-¹¹C-MET, ¹¹C-CMT, and ¹⁸F-FMT were injected intravenously into BALB/cA Jcl-nu mice bearing HeLa tumor cells. At 5, 15, 30, and 60 min after injection, normal abdominal organs and xenotransplanted HeLa cells were sampled, and the uptake of each ligand was determined. Metabolic analyses of these compounds in the plasma were also performed. Accumulation of the D-isomers of ¹¹C-MET, ¹¹C-CMT, and ¹⁸F-FMT in turpentine-induced inflammatory tissue was assayed in comparison with ¹⁸F-FDG. The whole-body distribution of each tracer was imaged with a planar positron imaging system (PPIS). Results: Although the tumor uptake (standardized uptake value [SUV]) levels of the D-isomers of ¹¹C-MET, ¹¹C-CMT, and ¹⁸F-FMT were 261%, 72%, and 95% of each L-isomer 60 min after administration, the tumor-to-blood ratios of these D-isomers were 130%, 140%, and 182% of the corresponding L-isomers. In the blood, the D-isomers of these labeled compounds revealed a relatively faster elimination rate compared with their L-isomers, with a high peak uptake in the blood and kidney 5 min after administration. Compared with the natural amino acid ligand L-¹¹C-MET, the uptake of L-isomers of ¹¹C-CMT and ¹⁸F-FMT was relatively low and stable in the abdominal organs, whereas D-isomers revealed much lower levels and faster clearance rates compared with corresponding L-isomers. Among the abdominal organs, the pancreas showed a relatively high uptake of ¹¹C-CMT and ¹⁸F-FMT; the uptake of these D-isomers was much lower than that of L-isomers. Pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a marked reduction of L-¹¹C-MET uptake and a slight reduction of D-¹¹C-MET uptake into protein fractions, whereas no significant changes were detected with L- and D-¹¹C-CMT and ¹⁸F-FMT. D-Isomers of ¹¹C-MET, ¹¹C-CMT, and ¹⁸F-FMT did not accumulate in turpentine-induced inflammatory tissue, where ¹⁸F-FDG revealed a high uptake. Whole-body imaging with a PPIS provided consistent distribution data obtained from the tissue dissection analysis. Conclusion: These results suggest that D-isomers of ¹¹C-CMT and ¹⁸F-FMT could be potentially better tracers than L- and D-¹¹C-MET for tumor imaging with PET.

Key Words: D-amino acids • ¹¹C-methionine • O-¹¹C-methyl tyrosine • O-¹⁸F-fluoromethyl tyrosine • tumor imaging

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