Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia.
Fluorinated derivatives of etanidazole are being explored as probes for tumor hypoxia. Our research group has synthesized [18F]fluoroetanidazole (FETA) and now reports the oxygen dependency of binding to cells in vitro, the biodistribution of the tracer in tumor-bearing mice and the analysis of metabolites in their plasma and urine.


METHODS
Four cultured rodent cell lines (V79, 36B10, EMT6 and RIF1) were incubated with [18F]FETA for various times under graded O2 concentrations. We also compared the biodistributions of [18F]FETA and [18F]fluoromisonidazole (FMISO) at 2 and 4 h postinjection in C3H mice bearing KHTn tumors (130-430 mg). Reverse-phase high-performance liquid chromatography was used to distinguish metabolites from parent drugs in urine and plasma of mice injected with [18F]FETA or [18F]FMISO.


RESULTS
In cells labeled in vitro, O2 levels of 600-1300 ppm inhibited binding by 50% relative to uptake under anoxic conditions (<10 ppm). These inhibitory values are not statistically different from those reported for [18F]FMISO in the same cell lines (700-1500 ppm). In the biodistribution studies, uptake in heart, intestine, kidney and tumor was similar for both tracers 4 h after injection, whereas retention of [18F]FETA in liver and lung was significantly lower. Less uptake of [18F]FETA in liver suggests that this nitroimidazole is metabolized less than [18F]FMISO. The brain-to-blood ratios indicate that [18F]FETA readily crosses the blood-brain barrier. High-performance liquid chromatography of urine demonstrated that 10% of [18F]FETA-derived activity was in metabolites at 2 h postinjection, with 15% in metabolites by 4 h; comparable values for [18F]FMISO were 36% and 57%, respectively.


CONCLUSIONS
We conclude from these data that [18F]FETA holds promise as a new hypoxia tracer in patients, having oxygen dependency of binding similar to [18F]FMISO in vitro and displaying less retention in liver and fewer metabolites in vivo.
Rasey
J S
JS
Department of Radiation Oncology, University of Washington School of Medicine, Seattle 98195, USA.
Hofstrand
P D
PD
Chin
L K
LK
Tewson
T J
TJ
D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media; D006224:Cricetinae; D003412:Cricetulus; D017341:Etanidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005910:Glioma / Q000000981:diagnostic imaging / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D012513:Sarcoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D003287:Contrast Media; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C110581:fluoroetanidazole; C031843:fluoromisonidazole; D017341:Etanidazole; D008920:Misonidazole; D010100:Oxygen