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000136683 0247_ $$2doi$$a10.1021/jm300653b
000136683 0247_ $$2pmid$$apmid:22913544
000136683 0247_ $$2ISSN$$a0022-2623
000136683 0247_ $$2ISSN$$a0095-9065
000136683 0247_ $$2ISSN$$a1520-4804
000136683 0247_ $$2ISSN$$a1943-2992
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000136683 037__ $$aDZNE-2020-03005
000136683 041__ $$aEnglish
000136683 082__ $$a610
000136683 1001_ $$0P:(DE-HGF)0$$aBoländer, Alexander$$b0
000136683 245__ $$aBis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for tau fibrils and β-amyloid plaques in Alzheimer's disease models.
000136683 260__ $$aWashington, DC$$bACS$$c2012
000136683 264_1 $$2Crossref$$3online$$bAmerican Chemical Society (ACS)$$c2012-08-31
000136683 264_1 $$2Crossref$$3print$$bAmerican Chemical Society (ACS)$$c2012-11-08
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000136683 3367_ $$2BibTeX$$aARTICLE
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000136683 520__ $$aThe in vivo diagnosis of Alzheimer's disease (AD) is of high socioeconomic interest and remains a demanding field of research. The biopathological hallmarks of the disease are extracellular plaques consisting of aggregated β-amyloid peptides (Aβ) and tau protein derived intracellular tangles. Here we report the synthesis and evaluation of fluorescent pyrazine, pyrimidine,and pyridazine derivatives in vitro and in vivo aiming at a tau-based diagnosis of AD. The probes were pre-evaluated on human brain tissue by fluorescence microscopy and were found to label all known disease-related alterations at high contrast and specificity. To quantify the binding affinity, a new thiazine red displacement assay was developed and selected candidates were toxicologically profiled. The application in transgenic mouse models demonstrated bioavailability and brain permeability for one compound. In the course of histological testing, we discovered an AD-related deposition of tau aggregates in the Bowman's glands of the olfactory epithelium, which holds potential for an endoscopic diagnosis of AD in the olfactory system.
000136683 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000136683 650_7 $$2NLM Chemicals$$aFluorescent Dyes
000136683 650_7 $$2NLM Chemicals$$aPyrazines
000136683 650_7 $$2NLM Chemicals$$aPyridazines
000136683 650_7 $$2NLM Chemicals$$aPyrimidines
000136683 650_7 $$2NLM Chemicals$$atau Proteins
000136683 650_2 $$2MeSH$$aAged, 80 and over
000136683 650_2 $$2MeSH$$aAlzheimer Disease: diagnosis
000136683 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000136683 650_2 $$2MeSH$$aAnimals
000136683 650_2 $$2MeSH$$aBiological Availability
000136683 650_2 $$2MeSH$$aBrain: metabolism
000136683 650_2 $$2MeSH$$aFluorescent Dyes: chemical synthesis
000136683 650_2 $$2MeSH$$aFluorescent Dyes: chemistry
000136683 650_2 $$2MeSH$$aFluorescent Dyes: pharmacokinetics
000136683 650_2 $$2MeSH$$aHumans
000136683 650_2 $$2MeSH$$aMice
000136683 650_2 $$2MeSH$$aMice, Transgenic
000136683 650_2 $$2MeSH$$aMicroscopy, Fluorescence
000136683 650_2 $$2MeSH$$aOlfactory Mucosa: metabolism
000136683 650_2 $$2MeSH$$aOrgan Specificity
000136683 650_2 $$2MeSH$$aPermeability
000136683 650_2 $$2MeSH$$aPlaque, Amyloid: metabolism
000136683 650_2 $$2MeSH$$aPyrazines: chemical synthesis
000136683 650_2 $$2MeSH$$aPyrazines: chemistry
000136683 650_2 $$2MeSH$$aPyrazines: pharmacokinetics
000136683 650_2 $$2MeSH$$aPyridazines: chemical synthesis
000136683 650_2 $$2MeSH$$aPyridazines: chemistry
000136683 650_2 $$2MeSH$$aPyridazines: pharmacokinetics
000136683 650_2 $$2MeSH$$aPyrimidines: chemical synthesis
000136683 650_2 $$2MeSH$$aPyrimidines: chemistry
000136683 650_2 $$2MeSH$$aPyrimidines: pharmacokinetics
000136683 650_2 $$2MeSH$$aStereoisomerism
000136683 650_2 $$2MeSH$$aStructure-Activity Relationship
000136683 650_2 $$2MeSH$$atau Proteins: metabolism
000136683 7001_ $$0P:(DE-HGF)0$$aKieser, Daniel$$b1
000136683 7001_ $$0P:(DE-HGF)0$$aVoss, Constantin$$b2
000136683 7001_ $$0P:(DE-HGF)0$$aBauer, Silvia$$b3
000136683 7001_ $$0P:(DE-2719)9000402$$aSchön, Christian$$b4$$udzne
000136683 7001_ $$0P:(DE-2719)2811261$$aBurgold, Steffen$$b5$$udzne
000136683 7001_ $$0P:(DE-2719)9000029$$aBittner, Tobias$$b6$$udzne
000136683 7001_ $$0P:(DE-HGF)0$$aHölzer, Jana$$b7
000136683 7001_ $$0P:(DE-HGF)0$$aHeyny-von Haußen, Roland$$b8
000136683 7001_ $$0P:(DE-HGF)0$$aMall, Gerhard$$b9
000136683 7001_ $$0P:(DE-HGF)0$$aGoetschy, Valérie$$b10
000136683 7001_ $$0P:(DE-HGF)0$$aCzech, Christian$$b11
000136683 7001_ $$0P:(DE-HGF)0$$aKnust, Henner$$b12
000136683 7001_ $$0P:(DE-HGF)0$$aBerger, Robert$$b13
000136683 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b14$$udzne
000136683 7001_ $$0P:(DE-HGF)0$$aHilger, Ingrid$$b15
000136683 7001_ $$0P:(DE-HGF)0$$aSchmidt, Boris$$b16$$eCorresponding author
000136683 77318 $$2Crossref$$3journal-article$$a10.1021/jm300653b$$b : American Chemical Society (ACS), 2012-08-31$$n21$$p9170-9180$$tJournal of Medicinal Chemistry$$v55$$x0022-2623$$y2012
000136683 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/jm300653b$$gVol. 55, no. 21, p. 9170 - 9180$$n21$$p9170-9180$$q55:21<9170 - 9180$$tJournal of medicinal chemistry$$v55$$x0022-2623$$y2012
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