title: Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's disease and elderly controls after oral administration of sembragiline.
abstract: OBJECTIVE
  In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD.
  
  
  METHODS
  This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [11C]-L-deprenyl-D2radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6-15 days.
  
  
  RESULTS
  At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an Emaxof ∼80-90 % across brain regions of interest and in an EC50of 1-2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition.
  
  
  CONCLUSIONS
  This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.
authors.affiliation: Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland. stefan.sturm@roche.com.|F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland. stefan.sturm@roche.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sturm
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Forsberg
authors.affiliation: Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland.
authors.forename: Stephane
authors.initials: S
authors.lastname: Nave
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Stenkrona
authors.affiliation: AstraZeneca Translational Science Center, Stockholm, Sweden.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Fazio
authors.affiliation: Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland.
authors.forename: Candice
authors.initials: C
authors.lastname: Jamois
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Internal Disease and Gastroenterology, Miedzyleski Specialistic Hospital, Warsaw, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Ejduk
authors.affiliation: Karolinska Trial Alliance Phase 1 Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nabil
authors.initials: N
authors.lastname: Al-Tawil
authors.affiliation: Karolinska Institutet Alzheimer Disease Research Centre and Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Akenine
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Karolinska Institutet Alzheimer Disease Research Centre and Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Ricci
mesh_terms: D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000284:Administration, Oral; D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D008996:Monoamine Oxidase Inhibitors; D011760:Pyrrolidinones; D008995:Monoamine Oxidase; C000614721:sembragiline
keywords: Alzheimer’s disease; MAO-B; Monoamine oxidase inhibitor; Positron emission tomography; Sembragiline