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: Joanna S Fowler, Jean Logan, Albert J Azzaro, Robert M Fielding, Wei Zhu, Amy K Poshusta, Daniel Burch, Barry Brand, James Free, Mahnaz Asgharnejad, Gene-Jack Wang, Frank Telang, Barbara Hubbard, Millard Jayne, Payton King, Pauline Carter, Scott Carter, Youwen Xu, Colleen Shea, Lisa Muench, David Alexoff, Elena Shumay, Michael Schueller, Donald Warner, Karen Apelskog-Torres
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 35 Issue 3 Pg. 623-31 (Feb 2010) ISSN: 1740-634X [Electronic] England
• PMID: 19890267 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CX157
• Heterocyclic Compounds
• Monoamine Oxidase Inhibitors
• Nerve Tissue Proteins
• Monoamine Oxidase
• Clorgyline

Topics

• Adult
• Brain (drug effects, enzymology)
• Clorgyline (metabolism)
• Heterocyclic Compounds (chemistry, metabolism, pharmacology)
• Humans
• Male
• Middle Aged
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (metabolism, pharmacology)
• Nerve Tissue Proteins (antagonists & inhibitors, metabolism)
• Positron-Emission Tomography (methods)
• Protein Binding (drug effects, physiology)
• Young Adult