Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative

• Published in: Journal of neuropathology and experimental neurology 2002-09, Vol.61 (9), p.797-805
• Main Authors: Klunk, William E, Bacskai, Brian J, Mathis, Chester A, Kajdasz, Stephen T, McLellan, Megan E, Frosch, Matthew P, Debnath, Manik L, Holt, Daniel P, Wang, Yanming, Hyman, Bradley T
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Alkenes - pharmacokinetics; Alzheimer Disease - diagnosis; Alzheimer Disease - pathology; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Animals; Benzene - chemistry; Benzene - pharmacokinetics; Benzene Derivatives; Binding, Competitive - drug effects; Blood-Brain Barrier; Carbon Radioisotopes; Coloring Agents - chemistry; Coloring Agents - pharmacokinetics; Congo Red - analogs & derivatives; Congo Red - chemistry; Disease Models, Animal; Imaging, Three-Dimensional; Male; Mice; Mice, Transgenic; Microscopy - methods; Peptide Fragments - chemistry; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Stilbenes
• ISSN: 0022-3069

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.