Brain concentrations of mGluR5 negative allosteric modulator MTEP in relation to receptor occupancy - Comparison to MPEP

Background to verify relation between brain free levels,receptor occupancy in vivo and in vitro affinity at the target for mglur5 negative allosteric modulator (nam) mtep. methods we evaluated plasma and brain extra-cellular fluid (ecf) concentration of mtep at behaviourally active dose (5 mg/kg) using in vivo microdialysis. these values were compared it to the affinity in vitro (receptor binding and flipr) and to receptor occupancy in vivo. another,related substance,mpep was used for comparison. results mtep and mpep respectively inhibited mglur5 receptors function in vitro with an affinity of 25.4 and 12.3 nm respectively. accordingly peak ecf (extracellular fluid) levels were 1.3 and 0.14 μm,and peak total plasma levels were 7-11 and 2.6 μm. the ed50 for in vivo receptor occupancy was for both agents in the range of 0.8-0.7 mg/kg. conclusions at behaviourally active dose mtep produced complete mglur5 receptor occupancy but over 50 times higher ecf concentrations than affinity for mglur5 receptor in vitro. this difference is seems lower for other mglur5 nam compounds such as mpep. a possibly explanation could be different distribution in body compartments of both agents leading to errors of estimation with the microdialysis technique or different pharmacological activity at the receptor. © 2015 institute of pharmacology,polish academy of sciences.