Modelling and simulation of the influence of acute and chronic hypoxia on [18F]fluoromisonidazole PET imaging.

Tumour hypoxia can be assessed by positron emission tomography (PET) using radiotracers like [(18)F]fluoromisonidazole (Fmiso). The purpose of this work was to independently investigate the influence of chronic and acute hypoxia on the retention of Fmiso on the microscale. This was approached by modelling and simulating tissue oxygenation and Fmiso dynamics on the microscale based on tumour histology. Diffusion of oxygen and Fmiso molecules in tissue- and oxygen-dependent Fmiso binding were included in the model. Moreover, a model of fluctuating vascular oxygen tension was incorporated to theoretically predict the effects of acute hypoxia. Simulated tissue oxygen tensions (PO(2)) are strongly influenced by the modelled periodical fluctuations (period 40 min, total amplitude 10 mmHg and mean 35 mmHg). Fluctuations led to variations in mean PO(2) of up to 41% and in the hypoxic fraction (PO(2)  < 5 mmHg) from 56% up to 65%. Significant Fmiso retention is caused by chronic (87%) as well as acute hypoxia (13%). By simulating Fmiso injection during different phases of the vascular PO(2) fluctuation cycle, it was found that acute hypoxia of an empirically valid magnitude does not influence the reproducibility of PET imaging. Thus, it may be impossible to separate acute and chronic hypoxia from serial PET images.