Kinetic Modeling of 3′-Deoxy-3′-¹⁸F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice

Abstract

39-Deoxy-39-18 F-fluorothymidine ( 18 F-FLT) is a thymidine analog that was developed for measuring tumor proliferation with PET. The aim of this study was to establish a kinetic modeling analysis method for quantitative 18 F-FLT PET studies in subcutaneous tumor models in mice. Methods: To explore the validity of an image-derived left ventricular input function, we measured equilibrium constants for plasma and whole blood and metabolite fractions in blood after 18 F-FLT injection. In parallel, dynamic 18 F-FLT PET scans were acquired in 24 mice with a small-animal dedicated PET scanner to compare arterial blood activities obtained by PET and blood sampling. We then investigated kinetic models for 18 F-FLT in human epithelial carcinoma (A431) and Lewis lung carcinoma tumor models in mice. Three-compartment models with reversible phosphorylation (k 4 6 ¼ 0, 3C5P) and irreversible phosphorylation (k 4 5 0, 3C4P) and a 2-compartment model (2C3P) were examined. The Akaike information criterion and F statistics were used to select the best model for the dataset. Gjedde-Patlak graphic analysis was performed, and standardized uptake values in the last frame were calculated for comparison purposes. In addition, quantitative PET parameters were compared with Ki-67 immunostaining results. Results: 18 F-FLT equilibrated rapidly (within 30 s) between plasma and whole blood, and metabolite fractions were negligible during PET scans. A high correlation between arterial blood sampling and PET data was observed. For 120-min dynamic PET data, the 3C5P model best described tissue time-activity curves for tumor regions. The net influx of 18 F-FLT (K FLT ) and k 3 obtained with this model showed reasonable intersubject variability and discrimination ability for tumor models with different proliferation properties. The K FLT obtained from the 60-or 90-min data correlated well with that obtained from the 120-min data as well as with the Ki-67 results. Conclusion: The image-derived arterial input function was found to be feasible for kinetic modeling studies of 18 F-FLT PET in mice, and kinetic modeling analysis with an adequate compartment model provided reliable kinetic parameters for measuring tumor proliferation.

Biodistribution and Uptake of 3′-Deoxy-3′-Fluorothymidine in ENT1-Knockout Mice and in an ENT1-Knockdown Tumor Model

“…ROIs for the blood input function were drawn over the heart. A threshold of 80% maximum over the heart was used to obtain ROIs between 5 and 15 mm 3 , and the previously described volume-correction factor was applied (14). The model is described by 4 kinetic parameters (K 1 , k 2 , k 3 , and k 4 ) and the fractional blood volume (fbv), which accounts for the nonzero vascular space within the tumor ROI.…”

Feasibility of Template-Guided Attenuation Correction in Cat Brain PET Imaging

“…The feasibility of this method for the whole body PET studies of rodents might provide an additional option for the accurate assessment of regional activity by both the semi-quantitative [35,45] and kinetic modeling methods [46][47][48] used in rodents.…”

Molecular Imaging Data Analysis

“…This type of quantitative analysis can be performed through careful dynamic image acquisition in combination with appropriate pharmacokinetic modeling and an arterial input function (AIF) that can be derived from dynamic images or blood samples during imaging sessions. Interested readers are encouraged to consult references (Muzic and Cornelius 2001;Phair and Misteli 2001;Bentourkia and Zaidi 2006;Ikoma, Watabe et al 2008;Kim, Lee et al 2008) for more detailed description on this type of quantification.…”