Reversible inhibitors of monoamine oxidase-A (RIMAs): Robust, reversible inhibition of human brain MAO-A by CX157

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 MuenchDavid Alexoff, Elena Shumay, Michael Schueller, Donald Warner, Karen Apelskog-Torres

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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 Cclorgyline 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 Cclorgyline 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.

Original languageEnglish
Pages (from-to)623-631
Number of pages9
Issue number3
StatePublished - Feb 2010


  • CX157
  • MAO-A inhibitor
  • Major depressive disorder
  • PET
  • RIMA


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