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.
The aim of this study was to investigate whether D-amino acid isomers of O-(11)C-methyl tyrosine ((11)C-CMT) and O-(18)F-fluoromethyl tyrosine ((18)F-FMT) were better than the corresponding L-isomers as tumor- detecting agents with PET in comparison with the difference between L- and D-methyl-(11)C-methionine ((11)C-MET).


METHODS
L- and D-(11)C-MET, (11)C-CMT, and (18)F-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 (11)C-MET, (11)C-CMT, and (18)F-FMT in turpentine-induced inflammatory tissue was assayed in comparison with (18)F-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 (11)C-MET, (11)C-CMT, and (18)F-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-(11)C-MET, the uptake of L-isomers of (11)C-CMT and (18)F-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 (11)C-CMT and (18)F-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-(11)C-MET uptake and a slight reduction of D-(11)C-MET uptake into protein fractions, whereas no significant changes were detected with L- and D-(11)C-CMT and (18)F-FMT. D-Isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT did not accumulate in turpentine-induced inflammatory tissue, where (18)F-FDG revealed a high uptake. Whole-body imaging with a PPIS provided consistent distribution data obtained from the tissue dissection analysis.


CONCLUSIONS
These results suggest that D-isomers of (11)C-CMT and (18)F-FMT could be potentially better tracers than L- and D-(11)C-MET for tumor imaging with PET.
Tsukada
Hideo
H
PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka 434-8601, Japan. tsukada@crl.hpk.co.jp
Sato
Kengo
K
Fukumoto
Dai
D
Nishiyama
Shingo
S
Harada
Norihiro
N
Kakiuchi
Takeharu
T
D000818:Animals; D002250:Carbon Radioisotopes; D005260:Female; D005462:Fluorine Radioisotopes; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008715:Methionine / Q000737:chemistry / Q000493:pharmacokinetics; D008781:Methyltyrosines / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D009928:Organ Specificity; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014425:Turpentine; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051598:Whole Body Imaging
D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008781:Methyltyrosines; C493093:O-(18F)fluoromethyl-L-tyrosine; D019275:Radiopharmaceuticals; D014443:Tyrosine; D008715:Methionine; D014425:Turpentine