Comparative pharmacokinetics, biodistribution, metabolism and hypoxia-dependent uptake of [18F]-EF3 and [18F]-MISO in rodent tumor models.
OBJECTIVE
[18F]-EF3 allows non-invasive detection of hypoxia. In the framework of its validation, we aimed at comparing its pharmacokinetics, biodistribution, metabolism and specificity for hypoxia with the hypoxia tracer [18F]-FMISO.


METHODS
C3H mice were injected IV with 3.7-18.5 MBq of one of the two tracers. For pharmacokinetics experiments, blood, urines and feces were collected. For biodistribution experiments, 13 different organs were harvested. To assess the hypoxia-specificity of the tracers, intramuscular syngeneic FSA II tumor bearing mice breathing air or carbogen were used. Animals were sacrificed from 5 to 440 min after injection. Radioactivity was assessed ex-vivo in a gamma counter. Tracer metabolites were assessed with radio-HPLC of acetonitrile soluble fractions of tissues.


RESULTS
Elimination half-life in blood (mono-exponential fit) reached 81.8 and 99.7 min for [18F]-EF3 and [18F]-MISO, respectively (NS). After 440 min, 71+/-7% (mean+/-SD) of injected activity of [18F]-EF3 was collected in the urine while 9+/-2% was collected in the feces, compared to 71+/-15% and 23+/-15% for [18F]-MISO (NS). Biodistribution was similar with a homogeneous distribution in most organs as early as 5 min after injection. With time, an increased activity in organs involved in excretion (kidney, bladder, liver and GI tract) was measured for both tracers; however, an increased background activity in "oxic" normal tissues (brain, lung, and esophagus) was also observed for [18F]-MISO. The percentage of metabolites was higher for [18F]-MISO compared to [18F]-EF3 in nearly all samples. Tumor-to-muscle ratios (TMRs) ranging from 2 to 4 were obtained under air-breathing condition for both tracers.


CONCLUSIONS
Both tracers exhibited a similar pharmacokinetics and biodistribution in mice and accumulated in an hypoxia-dependent manner in tumors. However, more aspecific activity was observed with [18F]-MISO at late time points after tracer injection in normal tissues.
Mahy
Pierre
P
Centre for Molecular Imaging and Experimental Radiotherapy, Université catholique de Louvain, Brussels, Belgium.
De Bast
Marc
M
de Groot
Tjibbe
T
Cheguillaume
Arnaud
A
Gillart
Jacques
J
Haustermans
Karin
K
Labar
Daniel
D
Grégoire
Vincent
V
D000818:Animals; D005462:Fluorine Radioisotopes; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D009374:Neoplasms, Experimental / Q000378:metabolism; D009593:Nitroimidazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C438056:2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide; C115855:2-nitroimidazole acetamide; D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole