Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.
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.
Fowler
Joanna S
JS
Medical Department, Brookhaven National Laboratory, Upton, NY, USA.
Logan
Jean
J
Azzaro
Albert J
AJ
Fielding
Robert M
RM
Zhu
Wei
W
Poshusta
Amy K
AK
Burch
Daniel
D
Brand
Barry
B
Free
James
J
Asgharnejad
Mahnaz
M
Wang
Gene-Jack
GJ
Telang
Frank
F
Hubbard
Barbara
B
Jayne
Millard
M
King
Payton
P
Carter
Pauline
P
Carter
Scott
S
Xu
Youwen
Y
Shea
Colleen
C
Muench
Lisa
L
Alexoff
David
D
Shumay
Elena
E
Schueller
Michael
M
Warner
Donald
D
Apelskog-Torres
Karen
K
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
C551866:CX157; D006571:Heterocyclic Compounds; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D008995:Monoamine Oxidase; D003010:Clorgyline