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

Abstract

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.