MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Bergström, Mats; Westerberg, Göran; Németh, György; Traut, M; Groß, Gerhard; Greger, G.; Müller-Peltzer, Herbert; Safer, Abdel-Majed; Eckernäs, S.‐Å.; Grahnér, A.; Långström, Bengt

doi:10.1007/s002280050260

Cited by 43 publications

(18 citation statements)

References 13 publications

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“…This feature was also found in humans using an irreversible MAO-A specific ligand [ 11 C]harmine after a 7-day treatment with a MAO-A inhibitors (Bergström et al, 1997c). It is therefore obvious that brain TACs of [ 11 C]befloxatone, which are highly dependent of the plasma input function, have to be corrected by this parameter (see Materials and Methods).…”

Section: Discussionmentioning

confidence: 57%

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone

Bottlaender¹,

Dollé²,

Guenther³

et al. 2003

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 57%

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone

Bottlaender¹,

Dollé²,

Guenther³

et al. 2003

J Pharmacol Exp Ther

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“…PET has been used to show CNS target engagement by inhibitors of monoamine oxidases A and B, catechol-O-methyltransferase and acetylcholinesterase. 14, 15, 16, 17, 18, 19 PET provides regional activity information, which detection of a mass-labeled tracer in CSF cannot. However, there are several limitations to PET.…”

Section: Discussionmentioning

confidence: 99%

Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

et al. 2013

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ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-2H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1–50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ⩾2 mg daily maintained peripheral HSD-1 inhibition ⩾88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ⩾81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ⩾2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

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“…These studies have been conducted with both reversibly binding radiotracers, such as the MAO-A radiotracer [ 11 C]harmine (Bergström et al , 1997; Ginovart et al , 2006), and irreversibly binding radiotracers such as the MAO-A and MAO-B radiotracers [ 11 C]clorgyline and [ 11 C]L-deprenyl-D2, respectively (Fowler et al , 1993, 1994, 1996, 2001a; Bench et al , 1991). Irreversibly binding radiotracers such as [ 11 C]N-methylspiperone have also been used to measure dopamine D2/D3 receptor occupancy by neuroleptic drugs (Wong et al , 1986).…”

Section: Discussionmentioning

confidence: 99%

Reversible Inhibitors of Monoamine Oxidase-A (RIMAs): Robust, Reversible Inhibition of Human Brain MAO-A by CX157

Fowler

Logan

Azzaro³

et al. 2009

Neuropsychopharmacol

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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.

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MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Cited by 43 publications

References 13 publications

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone

Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

Reversible Inhibitors of Monoamine Oxidase-A (RIMAs): Robust, Reversible Inhibition of Human Brain MAO-A by CX157

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MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Cited by 43 publications

References 13 publications

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [11C]Befloxatone

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [11C]Befloxatone

Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

Reversible Inhibitors of Monoamine Oxidase-A (RIMAs): Robust, Reversible Inhibition of Human Brain MAO-A by CX157

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Product

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Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone

Mapping the Cerebral Monoamine Oxidase Type A: Positron Emission Tomography Characterization of the Reversible Selective Inhibitor [¹¹C]Befloxatone