1. ¹Medical Department, Brookhaven National Laboratory, Upton, NY, USA
2. ²Psychiatry Department, Mt. Sinai School of Medicine, New York, NY, USA
3. ³AJA PharmaServices, Tarpon Springs, FL, USA
4. ⁴Biologistic Services, Boulder, Colorado, CO, USA
5. ⁵Department of Applied Mathematics and Statistics, SUNY at Stony Brook, Stony Brook, NY, USA
6. ⁶CeNeRx BioPharma, North Carolina, NC, USA
7. ⁷National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA

Correspondence: Dr JS Fowler, Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Tel: 631 344 4365, Fax: 631 344 5815; E-mail: fowler@bnl.gov

Received 23 June 2009; Revised 1 September 2009; Accepted 8 September 2009; Published online 4 November 2009.

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 [¹¹C]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 [¹¹C]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 (EC₅₀: 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.