Pharmacokinetics Of The Cannabinoid Receptor Ligand [F-18]Mk-9470 In The Rat Brain - Evaluation Of Models Using Micropet

Purpose: The positron emission tomography ligand [F-18]MK-9470 is an inverse agonist that binds reversibly and with high affinity to the cannabinoid type 1 receptor. Due to its slow brain kinetics, care is required in the definition of its dissociation rates from the receptor. The goal of this study was to investigate pharmacokinetic analysis methods using an arterial input function.Methods: Five Sprague-Dawley rats received injections of 13 to 25 MBq of [F-18]MK-9470 and were scanned over a period of 90 min. Arterial blood samples were collected throughout the scan. Data were analyzed using four different compartmental models: a reversible one-tissue model, reversible two tissue models with and without parameter constraints and an irreversible two-tissue model. The outcome values were goodness of fit measures (Akaike information criterion; standard error), pharmacokinetic modeling parameters (volume of distribution; irreversible uptake constant) and intersubject variability.Results: Goodness of fit measures indicated that the experimental data are more adequately described by a two-tissue model than a one-tissue model. Differences in mean Akaike information criterion values between all two-tissue models were < 5%. Mean standard errors of model parameters were lowest for the irreversible model (range: 1% to 6%). The irreversible model delivered plausible results for all animals that were less variable compared to results of the other two-tissue models.Conclusions: A reversible two-tissue model may not deliver stable results for all animals and regions within a 90-min microPET study protocol. Stable parameters for all animals and regions are obtained when an irreversible model is used. If the acquisition time of the experiment is limited, an irreversible model provides a consistent distribution of composite outcome parameters, suggesting its suitability for use in future studies. (C) 2017 American Association of Physicists in Medicine