Kinetic Modeling of 18F-(2S,4R)4-Fluoroglutamine in Mouse Models of Breast Cancer to Estimate Glutamine Pool Size as an Indicator of Tumor Glutamine Metabolism.

Abstract

The PET radiotracer 18F-(2S,4R)4-fluoroglutamine (18F-Gln) reflects glutamine transport and can be used to infer glutamine metabolism. Mouse xenograft studies have demonstrated that 18F-Gln uptake correlates directly with glutamine pool size and is inversely related to glutamine metabolism through the glutaminase enzyme. To provide a framework for the analysis of 18F-Gln-PET, we have examined 18F-Gln uptake kinetics in mouse models of breast cancer at baseline and after inhibition of glutaminase. We describe results of the preclinical analysis and computer simulations with the goal of model validation and performance assessment in anticipation of human breast cancer patient studies. Methods: Triple-negative breast cancer and receptor-positive xenografts were implanted in athymic mice. PET mouse imaging was performed at baseline and after treatment with a glutaminase inhibitor or a vehicle solution for 4 mouse groups. Dynamic PET images were obtained for 1 h beginning at the time of intravenous injection of 18F-Gln. Kinetic analysis and computer simulations were performed on representative time-activity curves, testing 1- and 2-compartment models to describe kinetics. Results: Dynamic imaging for 1 h captured blood and tumor time-activity curves indicative of largely reversible uptake of 18F-Gln in tumors. Consistent with this observation, a 2-compartment model indicated a relatively low estimate of the rate constant of tracer trapping, suggesting that the 1-compartment model is preferable. Logan plot graphical analysis demonstrated late linearity, supporting reversible kinetics and modeling with a single compartment. Analysis of the mouse data and simulations suggests that estimates of glutamine pool size, specifically the distribution volume (VD) for 18F-Gln, were more reliable using the 1-compartment reversible model than the 2-compartment irreversible model. Tumor-to-blood ratios, a more practical potential proxy of VD, correlated well with volume of distribution from single-compartment models and Logan analyses. Conclusion: Kinetic analysis of dynamic 18F-Gln-PET images demonstrated the ability to measure VD to estimate glutamine pool size, a key indicator of cellular glutamine metabolism, by both a 1-compartment model and Logan analysis. Changes in VD with glutaminase inhibition support the ability to assess response to glutamine metabolism-targeted therapy. Concordance of kinetic measures with tumor-to-blood ratios provides a clinically feasible approach to human imaging.