title: Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.
abstract: Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [(11)C]clorgyline in 15 normal men after oral dosing of CX157 (20-80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47-72%) of [(11)C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC(50): 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Azzaro
authors.forename: Robert M
authors.initials: RM
authors.lastname: Fielding
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Amy K
authors.initials: AK
authors.lastname: Poshusta
authors.forename: Daniel
authors.initials: D
authors.lastname: Burch
authors.forename: Barry
authors.initials: B
authors.lastname: Brand
authors.forename: James
authors.initials: J
authors.lastname: Free
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Asgharnejad
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Telang
authors.forename: Barbara
authors.initials: B
authors.lastname: Hubbard
authors.forename: Millard
authors.initials: M
authors.lastname: Jayne
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: Scott
authors.initials: S
authors.lastname: Carter
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.forename: Elena
authors.initials: E
authors.lastname: Shumay
authors.forename: Michael
authors.initials: M
authors.lastname: Schueller
authors.forename: Donald
authors.initials: D
authors.lastname: Warner
authors.forename: Karen
authors.initials: K
authors.lastname: Apelskog-Torres
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D003010:Clorgyline / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: C551866:CX157; D006571:Heterocyclic Compounds; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D008995:Monoamine Oxidase; D003010:Clorgyline