Detection of tumor hypoxia with the PET-labeled specific tracer, [18F]-EF3 : pre-clinical validation on murine tumor models and early clinical study

(eng) The main aim of this thesis was to assess the non-invasive detection of tumor hypoxia using a [18F]-labeled trifluorine derivative of etanidazole. The first part was to elaborate murine tumor models in which modification of hypoxia could be studied to confirm the detection of hypoxia with EF5 immunofluorescence (IF). Using EF5 IF measurements, we were able to differentiate between tumor strains and to induce hypoxia modification, according to % O2 breathed. EF5 flow cytometry (FC) was less reliable, being poorly correlated to EF5 IF. Any of the two EF5 methods was found to be correlated with Eppendorf measurements of pO2 performed within the same models but not within the same individual tumors. Therefore, we compared EF5 binding as assessed by IF to pO2 measured by Electron Paramagnetic Resonance oximetry. This was performed not only in the same individual tumor but also in a specially designed in vivo tumor model where the two methods were colocalized. Our data demonstrated a highly significant relationship with most of EF5 binding occurring under pO2 of less than 10 mmHg in an original manner. The second part was the preclinical validation of [18F]-EF3. EF5 IF was used as a standard to which [18F]-EF3 could be compared. We first comprehensively studied the pharmacokinetics, biodistribution and metabolism of [18F]-EF3 in mice. We thereafter studied tumor binding of [18F]-EF3 at the microscopic level using autoradiography and in individual tumors using gamma counting, in animals under normoxic, hypoxic and hyperoxic conditions and in several murine tumor models and compared it to FMISO. As the third part of this thesis, the first phase I study with [18F]-EF3 in humans was performed in 10 patients with head and neck squamous cell carcinoma.