Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative.
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.
Klunk
William E
WE
Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
Bacskai
Brian J
BJ
Mathis
Chester A
CA
Kajdasz
Stephen T
ST
McLellan
Megan E
ME
Frosch
Matthew P
MP
Debnath
Manik L
ML
Holt
Daniel P
DP
Wang
Yanming
Y
Hyman
Bradley T
BT
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
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