Abstract

The binding of the 11C-labeled benzodiazepine antagonist Ro 15-1788 (flumazenil) was measured in the neocortex of live Papio papio baboons by positron emission tomography. This allowed us to calculate in vivo (i.e., at physiological temperature, neurotransmitters concentrations, and ionic environment) the apparent density of available benzodiazepine receptors (B'max) and the dissociation constant of Ro 15-1788 (Kd). By coadministering increasing doses of unlabeled Ro 15-1788 with [11C]Ro 15-1788 and assuming that nonsaturable radioactivity indicated the free ligand concentration, we were able to obtain saturation isotherms. We showed that a state of quasiequilibrium was reached 50 min after the administration of the radioligand. Linear Scatchard plots allowed us to calculate B'max at 78 and 50 pmol/ml of cerebral tissue in the occipital and frontal cortices, respectively. In both these areas, Kd is on the order of 6 nM, with a Hill number very close to unity. This indicates that Ro 15-1788 binds in vivo with high affinity to an homogeneous population of saturable sites. A similar measurement was carried out on a naturally photosensitive P. papio baboon. Absolute values of B'max, Kd, and Hill number were similar to those of the control baboons. Although results concerning this baboon can only be considered as a case report, this similarity may suggest that its epileptic syndrome is not related to a large change in B'max or Kd, at least in occipital and frontal cortices. Our results showed that quantitative estimation by positron emission tomography of some characteristics of benzodiazepine receptors is possible in live baboons and may represent a supplementary tool for investigating further the molecular mechanisms of benzodiazepine receptor function in physiological and physiopathological conditions. We suggest that a similar method of quantification of classic in vivo [3H]Ro 15-1788 binding could be usefully adapted when studying rodent models of epilepsy, stress, and other neuropsychological disorders. On the other hand, the similarity between the B'max and Kd values we obtained in baboons and those recently reported in humans using similar methods emphasizes that most of the in vivo characteristics of the benzodiazepine receptors of baboons are very close to those of human benzodiazepine receptors. This confirms that P. papio baboons are a suitable animal model for studying the pharmacology of benzodiazepine receptor ligands before clinical applications in humans.