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SPECT Quantification of Benzodiazepine Receptor Concentration Using a Dual-Ligand Approach

¹ Psychiatric Neuroimaging Unit, Division of Neuropsychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland; and ² INSERM, E340, Grenoble, France

Correspondence: For correspondence or reprints contact: Philippe Millet, PhD, Psychiatric Neuroimaging Unit, Division of Neuropsychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, chemin du Petit-Bel-Air, CH-1225 Chêne-Bourg, Geneva, Switzerland. E-mail: Philippe.Millet{at}sim.hcuge.ch

The distribution of benzodiazepine receptors in the human brain has been widely studied with SPECT using ¹²³I-iomazenil and semiquantitative approaches, but these methods do not allow quantification of the total receptor site concentration available for binding (B'_max) and of the apparent equilibrium dissociation constant (K_d/V_R). One of the major obstacles to full quantitative studies is that pharmacologic effects preclude the administration to humans of the high doses of iomazenil required to displace the labeled ligand from the receptors. In this study, we applied a dual-ligand protocol using the unlabeled ligand flumazenil, which lacks pharmacologic effects, to quantify all binding parameters of the benzodiazepine receptor–¹²³I-iomazenil interactions. Methods: ¹²³I-Iomazenil SPECT and MRI were acquired in 8 healthy volunteers, one of whom had participated in a ¹¹C-flumazenil PET experiment. The experimental protocol consisted of injections of ¹²³I-iomazenil and/or unlabeled flumazenil. We developed a kinetic model to integrate the different pharmacokinetics of these 2 ligands. To simplify the model, we assumed linear relationships between iomazenil and flumazenil parameters and adjusted them using a coupled fitting procedure. The resulting constrained 5-parameter model was then used to quantify the biologic parameters. Results: Across regions, we obtained B'_max values ranging from 7 to 69 pmol/mL and K_dV_R values for IMZ from 2.3 to 3.7 pmol/mL. There was a close correlation in the B'_max values calculated in the same volunteer using ¹²³I-iomazenil SPECT and ¹¹C-flumazenil PET. Conclusion: The dual-ligand approach can be used to quantify all model parameters with acceptable SEs. This work demonstrates a theoretic framework and initial application of SPECT to quantify binding parameters.

Key Words: SPECT • benzodiazepine • iomazenil • mathematic modeling