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

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 (B9max) and of the apparent equilibrium dissociation constant (Kd/VR). 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 healthyvolunteers, oneofwhomhadparticipated in a 11C-flumazenil PET experiment. The experimental protocol consisted of injec-tions of 123I-iomazenil and/or unlabeled flumazenil. We developed akineticmodel to integrate thedifferent pharmacokineticsof 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 con-strained 5-parametermodel was thenused toquantify the biologic parameters. Results: Across regions, we obtained B9max values ranging from 7 to 69 pmol/mL and KdVR values for IMZ from 2.3 to 3.7 pmol/mL. There was a close correlation in the B9max 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 ap-plication of SPECT to quantify binding parameters. Key Words: SPECT; benzodiazepine; iomazenil; mathematic modelin