title: Synthesis, radiolabeling, and in vivo pharmacokinetic evaluation of the amyloid beta radioligand [11C]AZD4694 in nonhuman primates.
abstract: OBJECTIVE
  [(18)F]AZD4694 (2-(2-(18)F-fluoro-6-(methylamino)-3-pyridyl)benzofuran-5-ol) is a radioligand suitable for imaging of amyloid beta deposits in the living human brain using positron emission tomography (PET). Here, we report the preparation and pharmacokinetic profile of its carbon-11 (t1/2 = 20.4 min) labeled isotopolog [(11)C]AZD4694 and compare [(11)C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [(11)C]Pittsburgh Compound B (PiB).
  
  
  METHODS
  The immediate unlabeled precursor to [(11)C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N-(11)C-methylation of this precursor with [(11)C]methyl iodide yielded [(11)C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [(11)C]AZD4694 and [(11)C]PiB was measured using PET.
  
  
  RESULTS
  [(11)C]AZD4694 was prepared in a 60 % incorporation yield. In a head to head comparison with [(11)C]PiB, it appeared that [(11)C]AZD4694 displayed slightly lower nonspecific binding in white matter than [(11)C]PiB as well as more rapid pharmacokinetics in the brain.
  
  
  CONCLUSIONS
  The advantageous pharmacokinetic profile and low nonspecific binding render [(11)C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.
authors.affiliation: AstraZeneca Translational Science Centre, PET Centre of Excellence, Department of Clinical Neuroscience, Karolinska University Hospital, Karolinska Institutet, 171 76, Stockholm, Sweden, magnus.schou@astrazeneca.com.
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.forename: Johan
authors.initials: J
authors.lastname: Sandell
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Cselenyi
authors.forename: Samuel
authors.initials: S
authors.lastname: Svensson
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.forename: Linda
authors.initials: L
authors.lastname: Bergman
authors.forename: Anna
authors.initials: A
authors.lastname: Sumic
authors.forename: Balazs
authors.initials: B
authors.lastname: Gulyas
authors.forename: Eva
authors.initials: E
authors.lastname: Lindström-Böö
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D016229:Amyloid beta-Peptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D001572:Benzofurans / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D008252:Macaca fascicularis / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C552498:AZD4694; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001572:Benzofurans; D002250:Carbon Radioisotopes; D006845:Hydrocarbons, Fluorinated; D019275:Radiopharmaceuticals; D013844:Thiazoles