title: A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease.
abstract: This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.
authors.affiliation: Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Peter
authors.initials: P
authors.lastname: Dal-Bianco
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.forename: Aiman
authors.initials: A
authors.lastname: Abrahim
authors.forename: Rupert
authors.initials: R
authors.lastname: Lanzenberger
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.forename: Christian
authors.initials: C
authors.lastname: Joukhadar
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Orlando
authors.initials: O
authors.lastname: Ghirardi
authors.forename: Paola
authors.initials: P
authors.lastname: Piovesan
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Mario E
authors.initials: ME
authors.lastname: Corrado
authors.forename: Nadège
authors.initials: N
authors.lastname: Lods
authors.forename: Robert
authors.initials: R
authors.lastname: Dudczak
authors.forename: Eduard
authors.initials: E
authors.lastname: Auff
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019540:Area Under Curve; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D009284:Naphthols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000682:Amyloid; D002250:Carbon Radioisotopes; D009284:Naphthols; D018696:Neuroprotective Agents; C010635:1,1'-methylenedi-2-naphthol