Journal Article

DZNE-2020-03005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for tau fibrils and β-amyloid plaques in Alzheimer's disease models.

Boländer, A. ; Kieser, D. ; Voss, C. ; Bauer, S. ; Schön, C.DZNE* ; Burgold, S.DZNE* ; Bittner, T.DZNE* ; Hölzer, J. ; Heyny-von Haußen, R. ; Mall, G. ; Goetschy, V. ; Czech, C. ; Knust, H. ; Berger, R. ; Herms, J.DZNE* ; Hilger, I. ; Schmidt, B. (Corresponding author)

2012
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/jm300653b

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.

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

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2012

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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