ro-16-0154 and nimetazepam

The in vivo benzodiazepine (BZ) receptor occupancy in mouse brain was measured by employing 3H-flumazenil (FMZ) in comparison with 125I-iomazenil (IMZ), in order to obtain fundamental data for PET and SPECT studies, respectively. Mice were pretreated with various doses of flunitrazepam (FNP) 40 min prior to the tracer injection. At 20 min after the tracer injection, mice were killed by decapitation and receptor occupancy in cerebral cortex, hippocampus, cerebellum and pons-medulla were determined by the modified method reported by Goeders and Kuhar (1985). In all regions studied, BZ receptor occupancy by FNP measured with 3H-FMZ was significantly higher than that of 125I-IMZ. For instance, 0.1 mg/kg of FNP inhibited almost 50% of the specific binding of 3H-FMZ, on the other hand almost no inhibition of 125I-IMZ with the same dose of FNP was seen. This type of discrepancy was also observed in other types of benzodiazepine agonists, nimetazepam and triazolam, or inverse agonist ethyl-beta-carboline-3-carboxylate (CCE). It is of interest that in in vitro binding study using brain homogenate, almost the same competitive inhibition curve was observed between these two radioligands, which strongly suggested that discrepancy of receptor occupancy is likely observed in intact brain. The mechanism for such discrepancy is unknown, although the different kinetics properties of these two radioligand seems to be an important factor.

Topics: Animals; Binding, Competitive; Brain; Carbolines; Flumazenil; Flunitrazepam; In Vitro Techniques; Iodine Radioisotopes; Kinetics; Male; Mice; Nitrazepam; Receptors, GABA-A; Triazolam; Tritium