In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography.
Development of hypoxia-targeted therapies has stimulated the search for clinically applicable noninvasive markers of tumour hypoxia. Here, we describe the validation of [(18)F]fluoroetanidazole ([(18)F]FETA) as a tumour hypoxia marker by positron emission tomography (PET). Cellular transport and retention of [(18)F]FETA were determined in vitro under air vs nitrogen. Biodistribution and metabolism of the radiotracer were determined in mice bearing MCF-7, RIF-1, EMT6, HT1080/26.6, and HT1080/1-3C xenografts. Dynamic PET imaging was performed on a dedicated small animal scanner. [(18)F]FETA, with an octanol-water partition coefficient of 0.16+/-0.01, was selectively retained by RIF-1 cells under hypoxia compared to air (3.4- to 4.3-fold at 60-120 min). The radiotracer was stable in the plasma and distributed well to all the tissues studied. The 60-min tumour/muscle ratios positively correlated with the percentage of pO(2) values <5 mmHg (r=0.805, P=0.027) and carbogen breathing decreased [(18)F]FETA-derived radioactivity levels (P=0.028). In contrast, nitroreductase activity did not influence accumulation. Tumours were sufficiently visualised by PET imaging within 30-60 min. Higher fractional retention of [(18)F]FETA in HT1080/1-3C vs HT1080/26.6 tumours determined by dynamic PET imaging (P=0.05) reflected higher percentage of pO(2) values <1 mmHg (P=0.023), lower vessel density (P=0.026), and higher radiobiological hypoxic fraction (P=0.008) of the HT1080/1-3C tumours. In conclusion, [(18)F]FETA shows hypoxia-dependent tumour retention and is, thus, a promising PET marker that warrants clinical evaluation.
Barthel
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H
Cancer Research UK PET Oncology Group, Department of Cancer Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Wilson
H
H
Collingridge
D R
DR
Brown
G
G
Osman
S
S
Luthra
S K
SK
Brady
F
F
Workman
P
P
Price
P M
PM
Aboagye
E O
EO
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging; D015687:Cell Hypoxia; D017341:Etanidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005354:Fibrosarcoma / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous
D005462:Fluorine Radioisotopes; C110581:fluoroetanidazole; D017341:Etanidazole