title: Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties.
abstract: Brivaracetam is a novel synaptic vesicle protein 2A (SV2A) ligand reported to be 10 fold more potent than levetiracetam in animal models of epilepsy. This study reports the binding profile of brivaracetam in the brain of several species in relation to its anticonvulsant properties. The affinity, kinetics and selectivity of brivaracetam and its tritiated form [(3)H]ucb 34714 have been determined by in vitro binding experiments in rat, human and mouse brain and on recombinant human SV2A. Brivaracetam and levetiracetam ex vivo binding to SV2A and anticonvulsant activities in audiogenic mice were compared in relation to dose and time. Brivaracetam bound selectively with 20 fold higher affinity than levetiracetam to SV2A. [(3)H]ucb 34714 bound reversibly and with high affinity to an homogenous population of binding sites in rat and human brain and to human SV2A expressed in CHO cells. The binding sites labeled by [(3)H]ucb 34714 in brain had the pharmacological characteristics of SV2A and no specific binding could be detected in the brain of SV2A(-/-) knock-out mice. The time- and dose-dependency of brivaracetam and levetiracetam for binding to brain SV2A and for providing seizure protection in audiogenic mice correlated well; brivaracetam being more potent and faster than levetiracetam. Brivaracetam is a potent and selective SV2A ligand. From its affinity and pharmacokinetics, simulations predicted that at therapeutically relevant doses, brivaracetam should occupy more than 80% of SV2A in human brain, in line with levels of occupancy observed in pre-clinical models of epilepsy.
authors.affiliation: CNS Research, UCB Pharma SA, Braine L'Alleud, Belgium. michel.gillard@ucb.com
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuks
authors.forename: Karine
authors.initials: K
authors.lastname: Leclercq
authors.forename: Alain
authors.initials: A
authors.lastname: Matagne
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D020195:Epilepsy, Reflex / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D011760:Pyrrolidinones / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D012640:Seizures / Q000378:metabolism / Q000517:prevention & control*; D013379:Substrate Specificity
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011760:Pyrrolidinones; C076414:SV2A protein, human; C482793:brivaracetam