1. Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer's disease brains
- Author
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Gerhard Mall, Christian Schön, Roland Heyny-von Haußen, Christian Czech, Jana Hölzer, Thomas Kramer, Jochen Herms, Boris Schmidt, Valerie Goetschy-Meyer, Ingrid Hilger, Jiamin Gu, Upendra Rao Anumala, and Fabio Lo Monte
- Subjects
Fluorescence-lifetime imaging microscopy ,Embryo, Nonmammalian ,toxicity [Fluorescent Dyes] ,Clinical Biochemistry ,Analytical chemistry ,Pharmaceutical Science ,Acetates ,Biochemistry ,pathology [Alzheimer Disease] ,chemistry.chemical_compound ,pathology [Brain] ,Thiazine ,chemical synthesis [Acetates] ,Drug Discovery ,metabolism [Peptide Fragments] ,Cytotoxicity ,Zebrafish ,chemistry [Fluorescent Dyes] ,Chemistry ,Brain ,drug effects [Embryo, Nonmammalian] ,amyloid beta-protein (1-42) ,Imaging agent ,chemistry [Acetates] ,Rhodanine ,Molecular Medicine ,toxicity [Acetates] ,metabolism [Alzheimer Disease] ,chemical synthesis [Fluorescent Dyes] ,Cell Survival ,drug effects [Cell Survival] ,metabolism [Amyloid beta-Peptides] ,MAPT protein, human ,tau Proteins ,In vivo ,Alzheimer Disease ,Cell Line, Tumor ,chemistry [Rhodanine] ,Animals ,Humans ,ddc:610 ,Binding site ,Molecular Biology ,Fluorescent Dyes ,Amyloid beta-Peptides ,chemistry [tau Proteins] ,Organic Chemistry ,amyloid beta-protein (1-40) ,growth & development [Zebrafish] ,Molecular biology ,metabolism [tau Proteins] ,In vitro ,Peptide Fragments ,Microscopy, Fluorescence ,metabolism [Brain] ,chemistry [Peptide Fragments] ,chemistry [Amyloid beta-Peptides] - Abstract
There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer's diagnosis. In the present study, a series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay. However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays. Probe 6 showed binding affinity (IC50=19nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC50 values of lower than 100nM to tau aggregates to displace Thiazine red R. Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity. The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72h post fertilization.
- Published
- 2013