title: Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy.
abstract: An in vivo binding assay is characterized for [(3)H]M100907 binding to rat brain, as a measure of 5-HT(2A) receptor occupancy. Dose-response analyses were performed for various 5-HT(2A) antagonist reference agents, providing receptor occupancy ED(50) values in conjunction with plasma and brain concentration levels. Ketanserin and M100907 yielded dose-dependent increases in 5-HT(2A) receptor occupancy with ED(50)s of 0.316 mg/kg and 0.100 mg/kg, respectively. The atypical antipsychotics risperidone, olanzapine, and clozapine dose-dependently inhibited in vivo [(3)H]M100907 binding with ED(50) values of 0.051, 0.144, and 1.17 mg/kg, respectively. In contrast, the typical antipsychotic haloperidol exhibited only 20.1% receptor occupancy at 10 mg/kg despite producing dose-dependent increases in plasma and brain exposure levels. The novel psychopharmacologic agent asenapine dose-dependently occupied 5-HT(2A) receptors in rat brain with an ED(50) of 0.011 mg/kg, demonstrating higher 5-HT(2A) receptor potency compared with the other atypical antipsychotics tested. This enhanced potency was supported by a lower plasma exposure EC(50) of 0.477 ng/ml, compared with risperidone (1.57 ng/ml) and olanzapine (7.81 ng/ml) and was confirmed in time course studies. The validated [(3)H]M100907 rat in vivo binding assay allows for preclinical measurement of 5-HT(2A) receptor occupancy, providing essential data for understanding the pharmacological profile of novel antipsychotic agents. Additionally, the corresponding plasma and brain drug exposure data analyses provides a valuable data set for 5-HT(2A) reference agents by enabling direct comparison with any complementary studies performed in rats, thus providing a foundation for predictive pharmacokinetic/pharmacodynamic models and, importantly, allowing for translation to human receptor occupancy studies using [(11)C]M100907 positron emission tomography.
authors.affiliation: Pfizer Inc., Ann Arbor, MI 48105, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Knauer
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Campbell
authors.forename: Betsy
authors.initials: B
authors.lastname: Galvan
authors.forename: Christopher
authors.initials: C
authors.lastname: Bowman
authors.forename: Sarah
authors.initials: S
authors.lastname: Osgood
authors.forename: Susan
authors.initials: S
authors.lastname: Buist
authors.forename: Lisa
authors.initials: L
authors.lastname: Buchholz
authors.forename: Brian
authors.initials: B
authors.lastname: Henry
authors.forename: Erik H F
authors.initials: EH
authors.lastname: Wong
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shahid
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; C079049:volinanserin