Determination of an Optimal Pharmacokinetic Model of ¹⁸F-FET for Quantitative Applications in Rat Brain Tumors

Abstract

O-(2-18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) is a radiolabeled artificial amino acid used in PET for tumor delineation and grading. The present study compares different kinetic models to determine which are more appropriate for 18 F-FET in rats. Methods: Rats were implanted with F98 glioblastoma cells in the right hemisphere and scanned 9-15 d later. PET data were acquired during 50 min after a 1-min bolus of 18 F-FET. Arterial blood samples were drawn for arterial input function determination. Two compartmental pharmacokinetic models were tested: the 2-tissue model and the 1-tissue model. Their performance at fitting concentration curves from regions of interest was evaluated using the Akaike information criterion, F test, and residual plots. Graphical models were assessed qualitatively. Results: Metrics indicated that the 2-tissue model was superior to the 1-tissue model for the current dataset. The 2-tissue model allowed adequate decoupling of 18 F-FET perfusion and internalization by cells in the different regions of interest. Of the 2 graphical models tested, the Patlak plot provided adequate results for the tumor and brain, whereas the Logan plot was appropriate for muscles. Conclusion: The 2-tissue-compartment model is appropriate to quantify the perfusion and internalization of 18 F-FET by cells in various tissues of the rat, whereas graphical models provide a global measure of uptake. Ther adiolabeled artificial amino acid O-(2-18 F-fluoroethyl)-Ltyrosine ( 18 F-FET) has proven useful for the PET assessment of brain tumors in preclinical and clinical settings (1-3). Its high uptake in tumor tissue compared with normal brain and inflamed tissues allows for efficient tumor delineation (4), but the typical SUVs and tumor-to-brain ratios are of limited use for tumor grading (5,6). In contrast, the shape of time-activity curves are indicative of tumor grade and aggressiveness (7). For example, in untreated or recurring gliomas, continuously ascending curves are associated with a better prognosis than curves that reach a maximum a few minutes after injection (6,8), but the underlying mechanisms remain to be clarified (7,9,10). A pharmacokinetic model could help explain these differences and would allow quantitative comparison of cohorts.There have been few reports on 18 F-FET pharmacokinetic modeling (11,12), and a consensus on the most appropriate models has not been proposed. The present study aims at identifying the best models in different tissue types. MATERIALS AND METHODS Animal ModelExperiments were conducted in accordance with the recommendations of the Canadian Council on Animal Care and the local Ethics Committee. F98 glioblastoma cells were implanted in the right hemisphere of 17 male Fischer rats (254.6 6 15.9 g, Charles River Laboratories) according to a previously published protocol (13). The animals underwent dynamic PET scans 9-15 d after implantation. All imaging procedures were performed under isoflurane anesthesia with breathing rate and temperature continuously monitored. An automatic in...

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