title: Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand.
abstract: Positron emission tomography (PET) radioligands that bind selectively to beta-amyloid plaques (Abeta) are promising imaging tools aimed at supporting the diagnosis of Alzheimer's disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for beta-amyloid fibrils in vitro (K(d) = 2.3 +/- 0.3 nM). In cortical sections from human Alzheimer's disease brain [(3)H]AZD4694 selectively labeled beta-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [(3)H]AZD4694 showed selective binding to beta-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [(3)H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral beta-amyloid deposits in the living human brain.
authors.affiliation: Department of Neuroscience, AstraZeneca R&D Södertälje, Södertälje, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Juréus
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Johan
authors.initials: J
authors.lastname: Sandell
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Allan E
authors.initials: AE
authors.lastname: Johnson
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Neelissen
authors.forename: Dan
authors.initials: D
authors.lastname: Sunnemark
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Samuel P S
authors.initials: SP
authors.lastname: Svensson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology; D005260:Female; D017611:Fluorine Compounds; D005462:Fluorine Radioisotopes; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C552498:AZD4694; D016229:Amyloid beta-Peptides; D001572:Benzofurans; D017611:Fluorine Compounds; D005462:Fluorine Radioisotopes; D006845:Hydrocarbons, Fluorinated