Modelling and simulation of [18F]fluoromisonidazole dynamics based on histology-derived microvessel maps

Abstract

Hypoxia can be assessed non-invasively by positron emission tomography (PET) using radiotracers such as [(18)F]fluoromisonidazole (Fmiso) accumulating in poorly oxygenated cells. Typical features of dynamic Fmiso PET data are high signal variability in the first hour after tracer administration and slow formation of a consistent contrast. The purpose of this study is to investigate whether these characteristics can be explained by the current conception of the underlying microscopic processes and to identify fundamental effects. This is achieved by modelling and simulating tissue oxygenation and tracer dynamics on the microscopic scale. In simulations, vessel structures on histology-derived maps act as sources and sinks for oxygen as well as tracer molecules. Molecular distributions in the extravascular space are determined by reaction-diffusion equations, which are solved numerically using a two-dimensional finite element method. Simulated Fmiso time activity curves (TACs), though not directly comparable to PET TACs, reproduce major characteristics of clinical curves, indicating that the microscopic model and the parameter values are adequate. Evidence for dependence of the early PET signal on the vascular fraction is found. Further, possible effects leading to late contrast formation and potential implications on the quantification of Fmiso PET data are discussed.