title: Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative.
abstract: The identification of amyloid deposits in living Alzheimer disease (AD) patients is important for both early diagnosis and for monitoring the efficacy of newly developed anti-amyloid therapies. Methoxy-X04 is a derivative of Congo red and Chrysamine-G that contains no acid groups and is therefore smaller and much more lipophilic than Congo red or Chrysamine-G. Methoxy-X04 retains in vitro binding affinity for amyloid beta (Abeta) fibrils (Ki = 26.8 nM) very similar to that of Chrysamine-G (Ki = 25.3 nM). Methoxy-X04 is fluorescent and stains plaques, tangles, and cerebrovascular amyloid in postmortem sections of AD brain with good specificity. Using multiphoton microscopy to obtain high-resolution (1 microm) fluorescent images from the brains of living PSI/APP mice, individual plaques could be distinguished within 30 to 60 min after a single i.v. injection of 5 to 10 mg/kg methoxy-X04. A single i.p. injection of 10 mg/kg methoxy-X04 also produced high contrast images of plaques and cerebrovascular amyloid in PSI/APP mouse brain. Complementary quantitative studies using tracer doses of carbon- 11-labeled methoxy-X04 show that it enters rat brain in amounts that suggest it is a viable candidate as a positron emission tomography (PET) amyloid-imaging agent for in vivo human studies.
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Klunk
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Chester A
authors.initials: CA
authors.lastname: Mathis
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Kajdasz
authors.forename: Megan E
authors.initials: ME
authors.lastname: McLellan
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Manik L
authors.initials: ML
authors.lastname: Debnath
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000493:pharmacokinetics*; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001554:Benzene / Q000737:chemistry / Q000493:pharmacokinetics*; D001555:Benzene Derivatives; D001667:Binding, Competitive / Q000187:drug effects; D001812:Blood-Brain Barrier; D002250:Carbon Radioisotopes; D004396:Coloring Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003224:Congo Red / Q000031:analogs & derivatives* / Q000737:chemistry; D004195:Disease Models, Animal; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008853:Microscopy / Q000379:methods*; D010446:Peptide Fragments / Q000737:chemistry; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013267:Stilbenes
chemical_list: C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D000475:Alkenes; D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D002250:Carbon Radioisotopes; D004396:Coloring Agents; D010446:Peptide Fragments; D013267:Stilbenes; C078592:amyloid beta-protein (1-40); D003224:Congo Red; D001554:Benzene