Comparative pharmacokinetics, biodistribution, metabolism and hypoxia-dependent uptake of [18F]-EF3 and [18F]-MISO in rodent tumor models.

BACKGROUND AND PURPOSE

[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.

MATERIALS AND 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.

CONCLUSION

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.