TY  - JOUR
AU  - Boländer, Alexander
AU  - Kieser, Daniel
AU  - Voss, Constantin
AU  - Bauer, Silvia
AU  - Schön, Christian
AU  - Burgold, Steffen
AU  - Bittner, Tobias
AU  - Hölzer, Jana
AU  - Heyny-von Haußen, Roland
AU  - Mall, Gerhard
AU  - Goetschy, Valérie
AU  - Czech, Christian
AU  - Knust, Henner
AU  - Berger, Robert
AU  - Herms, Jochen
AU  - Hilger, Ingrid
AU  - Schmidt, Boris
TI  - Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for tau fibrils and β-amyloid plaques in Alzheimer's disease models.
JO  - Journal of medicinal chemistry
VL  - 55
IS  - 21
SN  - 0022-2623
CY  - Washington, DC
PB  - ACS
M1  - DZNE-2020-03005
SP  - 9170-9180
PY  - 2012
AB  - 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.
KW  - Aged, 80 and over
KW  - Alzheimer Disease: diagnosis
KW  - Alzheimer Disease: metabolism
KW  - Animals
KW  - Biological Availability
KW  - Brain: metabolism
KW  - Fluorescent Dyes: chemical synthesis
KW  - Fluorescent Dyes: chemistry
KW  - Fluorescent Dyes: pharmacokinetics
KW  - Humans
KW  - Mice
KW  - Mice, Transgenic
KW  - Microscopy, Fluorescence
KW  - Olfactory Mucosa: metabolism
KW  - Organ Specificity
KW  - Permeability
KW  - Plaque, Amyloid: metabolism
KW  - Pyrazines: chemical synthesis
KW  - Pyrazines: chemistry
KW  - Pyrazines: pharmacokinetics
KW  - Pyridazines: chemical synthesis
KW  - Pyridazines: chemistry
KW  - Pyridazines: pharmacokinetics
KW  - Pyrimidines: chemical synthesis
KW  - Pyrimidines: chemistry
KW  - Pyrimidines: pharmacokinetics
KW  - Stereoisomerism
KW  - Structure-Activity Relationship
KW  - tau Proteins: metabolism
KW  - Fluorescent Dyes (NLM Chemicals)
KW  - Pyrazines (NLM Chemicals)
KW  - Pyridazines (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22913544
DO  - DOI:10.1021/jm300653b
UR  - https://pub.dzne.de/record/136683
ER  -