Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301.
Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.
Hirvonen
J
J
Turku PET Centre, University of Turku and Turku University Central Hospital, Turku, Finland.
Kailajärvi
M
M
Haltia
T
T
Koskimies
S
S
Någren
K
K
Virsu
P
P
Oikonen
V
V
Sipilä
H
H
Ruokoniemi
P
P
Virtanen
K
K
Scheinin
M
M
Rinne
J O
JO
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000187:drug effects* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D012642:Selegiline / Q000494:pharmacology
D002250:Carbon Radioisotopes; D008314:Malonates; D008996:Monoamine Oxidase Inhibitors; C540298:N-(4-(3-fluorobenzyloxy)phenyl)malonamide; D012642:Selegiline; D008995:Monoamine Oxidase