P4–312: Preclinical characterization of RO4602522, a novel, selective and orally active monoamine oxidase type B inhibitor for the treatment of Alzheimer's disease

Expression of monoamine oxidase type B (MAO-B) is increased in the brain of Alzheimer's disease (AD) patients. Quantitative autoradiography studies using selective inhibitors indicate that MAO-B is highly over expressed (>3 fold) in reactive astrocytes in the vicinity of amyloid plaques. MAO-B catalyzes the inactivation of monoamines neurotransmitters (e.g., dopamine, 2-phenylethylamine, (PEA)). Its enzymatic activity is coupled to the formation of H 2 O 2 and thereby to the production of reactive oxygen species. Dopaminergic dysfunctions have been reported in AD patients and suggested to correlate to behavioral impairments such as apathy and reduced activities of daily living. Inhibition of MAOB may ameliorate dopamine-related behavioral impairments and reduce oxidative stress. Here we present the pharmacological properties of RO4602522, a novel MAO-B inhibitor specifically developed for the treatment of AD. MAO enzymatic activity was measured using a fluorimetric assay. MAO-B-dependent H 2 O 2 formation in AD brain section (stage Braak VI) was detected by use of horseradish peroxidases and diaminobenzidine. RO4602522 inhibited the enzymatic activity of human recombinant and rat native MAO-B with an IC50 of 5.9 and 14.7 nM, respectively, with a selectivity of >500 fold over MAO-A. At 10 μM RO4602522 did not display any affinity for > 100 different receptors, enzymes and ion channels. After oral administration to rats, RO4602522 dose-dependently inhibited MAO-B in the brain and in peripheral organs (liver) with an IC 50 of 0.1 and 0.03 mg/kg, respectively whereas complete inhibition was achieved at dose of 0.3–1 mg/kg. No effect on MAO-A was observed at doses up to 10 mg/kg. In vivo, RO4602522 was potently active in a test predictive for MAO-B inhibition (potentiation of PEA hyperlocomotor activity) being without any effect in tests indicating inhibition of MAO-A (potentiation of 5-HTP-induced stereotypies and of tyramine pressor effect). AD brain sections incubated with a MAO-substrate showed formation of H 2 O 2 in the vicinity of amyloid plaques which was completely blocked after incubation with RO4602522. RO4602522 is an orally active, potent and selective MAO-B inhibitor. The compound has completed extensive toxicology and safety pharmacology studies and it is now in Phase II trial in patients with Alzheimer's disease.