Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for tau fibrils and β-amyloid plaques in Alzheimer's disease models.
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.
Clemens Schoepf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstrasse 22, 64287 Darmstadt, Germany.
Alexander
A
Boländer
Daniel
D
Kieser
Constantin
C
Voss
Silvia
S
Bauer
Christian
C
Schön
Steffen
S
Burgold
Tobias
T
Bittner
Jana
J
Hölzer
Roland
R
Heyny-von Haußen
Gerhard
G
Mall
Valérie
V
Goetschy
Christian
C
Czech
Henner
H
Knust
Robert
R
Berger
Jochen
J
Herms
Ingrid
I
Hilger
Boris
B
Schmidt
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009831:Olfactory Mucosa / Q000378:metabolism; D009928:Organ Specificity; D010539:Permeability; D058225:Plaque, Amyloid / Q000378:metabolism*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism*
D005456:Fluorescent Dyes; D011719:Pyrazines; D011724:Pyridazines; D011743:Pyrimidines; D016875:tau Proteins