Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography: Comparison of full saturation and steady state methods

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2011-08, Vol.57 (3), p.928-937
• Main Authors: Syvänen, Stina, de Lange, Elizabeth C., Tagawa, Yoshihiko, Schenke, Maarten, Molthoff, Carla F.M., Windhorst, Albert D., Lammertsma, Adriaan A., Voskuyl, Rob A.
• Format: Article
• Language: English
• Subjects: ["C]verapamil; [11C]Flumazenil; active efflux; Animals; blood-brain barrier; Brain - diagnostic imaging; Carbon Radioisotopes - pharmacokinetics; cyclosporin; Drug dosages; Experiments; Flumazenil - pharmacokinetics; GABAA-receptor; Ligands; Male; Methods; modeling; p-glycoprotein; PET; pharmacokinetics; Plasma; Population pharmacokinetic/pharmacodynamic modelling; Positron emission tomography; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptor binding; Rodents
• ISSN: 1053-8119; 1095-9572; 1095-9572
• DOI: 10.1016/j.neuroimage.2011.05.022

The binding of PET radiotracer [11C]flumazenil to the GABAA receptors is described by the receptor density (Bmax) and binding affinity (KD). The estimation of Bmax and KD is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both Bmax and KD was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining Bmax and KD of [11C]flumazenil in the same group of male Sprague–Dawley rats. Fourteen rats underwent 3 consecutive [11C]flumazenil scans of 30min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500μg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABAA receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, Bmax and KD were then derived by compartmental modelling. Both methods yielded similar Bmax and KD estimates. The full saturation method yielded Bmax values of 37±5.8ng·mL−1 and KD values of 7.6±2.0ng·mL−1, whilst the steady state method yielded Bmax values of 33±5.4ng·mL−1 and KD values of 7.1±0.8ng·mL−1. The main advantage of the full saturation method is that Bmax and KD can be obtained from a single PET scan. ► Steady state and full saturation methods to characterise [11C]flumazenil binding. ► A single PET scan is enough for simultaneous estimation of Bmax and KD. ► Successful use of population pharmacokinetic modelling to analyse PET data.