Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for tau fibrils and β-amyloid plaques in Alzheimer's disease models.

Abstract

The in vivo diagnosis of Alzheimer's disease (AD) is of high socioeconomic interest and remains a demanding field of research. The biopathological hallmarks of the disease are extracellular plaques consisting of aggregated β-amyloid peptides (Aβ) and tau protein derived intracellular tangles. Here we report the synthesis and evaluation of fluorescent pyrazine, pyrimidine,and pyridazine derivatives in vitro and in vivo aiming at a tau-based diagnosis of AD. The probes were pre-evaluated on human brain tissue by fluorescence microscopy and were found to label all known disease-related alterations at high contrast and specificity. To quantify the binding affinity, a new thiazine red displacement assay was developed and selected candidates were toxicologically profiled. The application in transgenic mouse models demonstrated bioavailability and brain permeability for one compound. In the course of histological testing, we discovered an AD-related deposition of tau aggregates in the Bowman's glands of the olfactory epithelium, which holds potential for an endoscopic diagnosis of AD in the olfactory system.

• Authors: Alexander Boländer, Daniel Kieser, Constantin Voss, Silvia Bauer, Christian Schön, Steffen Burgold, Tobias Bittner, Jana Hölzer, Roland Heyny-von Haußen, Gerhard Mall, Valérie Goetschy, Christian Czech, Henner Knust, Robert Berger, Jochen Herms, Ingrid Hilger, Boris Schmidt
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 21 Pg. 9170-80 (Nov 08 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22913544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorescent Dyes
• Pyrazines
• Pyridazines
• Pyrimidines
• tau Proteins

Topics

• Aged, 80 and over
• Alzheimer Disease (diagnosis, metabolism)
• Animals
• Biological Availability
• Brain (metabolism)
• Fluorescent Dyes (chemical synthesis, chemistry, pharmacokinetics)
• Humans
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• Olfactory Mucosa (metabolism)
• Organ Specificity
• Permeability
• Plaque, Amyloid (metabolism)
• Pyrazines (chemical synthesis, chemistry, pharmacokinetics)
• Pyridazines (chemical synthesis, chemistry, pharmacokinetics)
• Pyrimidines (chemical synthesis, chemistry, pharmacokinetics)
• Stereoisomerism
• Structure-Activity Relationship
• tau Proteins (metabolism)