@article {Viswanathjnumed.120.250977, author = {Varsha Viswanath and Rong Zhou and Hsiaoju Lee and Shihong Li and Abigail Cragin and Robert K. Doot and David A. Mankoff and Austin R Pantel}, title = {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}, elocation-id = {jnumed.120.250977}, year = {2020}, doi = {10.2967/jnumed.120.250977}, publisher = {Society of Nuclear Medicine}, abstract = {The PET radiotracer [18F]-(2S,4R)4{\textlnot}-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 pre-clinical analysis and computer simulations with the goal of model validation and performance assessment in anticipation of human breast cancer patient studies. Methods: TNBC and receptor-positive xenografts were implanted in athymic mice. PET mouse imaging was performed at baseline and after treatment with a glutaminase inhibitor (CB-839, Calithera, Inc.) or a vehicle solution for a total of four mouse groups. Dynamic PET images were obtained for one hour beginning at the time of intravenous injection of 18F-FGln. Kinetic analysis and computer simulations were performed on a representative time-activity curves (TAC), testing 1- and 2-compartment models to describe kinetics. Results: Dynamic imaging for one hour captured blood and tumor TACs indicative of largely reversible uptake of 18F-FGln in tumors. Consistent with this observation, a two-compartment model indicated a relatively low estimate of trapping (k3), suggesting that the one-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 pools size, specifically the VD for 18F-FGln, were more reliably estimated using the one-compartment reversible model compared to the two-compartment irreversible model. Tumor-to-blood ratios, a more practical potential proxy of VD, demonstrated good correlation 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 one-compartment model and Logan analysis. Changes in VD with glutaminase inhibition supports the ability to assess response to glutamine metabolism-targeted therapy. Concordance of kinetic measures with tumor-to-blood ratios provides a clinically feasible approach for human imaging.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/early/2020/12/04/jnumed.120.250977}, eprint = {https://jnm.snmjournals.org/content/early/2020/12/04/jnumed.120.250977.full.pdf}, journal = {Journal of Nuclear Medicine} }