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.
Subject(s)
Acetates/chemistry , Fluorescent Dyes/chemistry , Rhodanine/chemistry , Acetates/chemical synthesis , Acetates/toxicity , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Brain/pathology , Cell Line, Tumor , Cell Survival/drug effects , Embryo, Nonmammalian/drug effects , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/toxicity , Humans , Microscopy, Fluorescence , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Zebrafish/growth & development , tau Proteins/chemistry , tau Proteins/metabolismABSTRACT
Shedding light on grey matter: Fluorescent trimethine cyanines were evaluated as imaging probes for neurofibrillary tangles in post-mortem brain sections of Alzheimer's disease patients. These probes bind to neurofibrillary tangles with high contrast and selectivity over amyloid ß plaques.
Subject(s)
Alzheimer Disease/metabolism , Antineoplastic Agents/chemistry , Brain/metabolism , Carbocyanines/chemistry , Fluorescent Dyes/chemistry , Olfactory Mucosa/chemistry , tau Proteins/analysis , Aged , Alzheimer Disease/pathology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Brain/pathology , Carbocyanines/chemical synthesis , Carbocyanines/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Hep G2 Cells , Humans , Male , Molecular Structure , Olfactory Mucosa/metabolism , Olfactory Mucosa/pathology , Structure-Activity Relationship , Zebrafish/embryologyABSTRACT
We evaluated 2-styrylindolium derivatives (6-11) as novel and selective probes for neurofibrillary tangles (NFTs) on brain sections of AD patients. The staining experiments indicated that these compounds may bind selectively to NFTs in the presence of ß-amyloid (Aß) plaques. Cell free binding assays confirmed that 2-[2-[4-(1-pyrrolidinyl)phenyl]ethenyl]-1,3,3-trimethyl-3H-indolium iodide (9) and 2-[2-[4-(diethylamino)phenyl]ethenyl]-1-butyl-3,3-dimethyl-3H-indolium iodide (11) display excellent affinities to Tau-aggregates (IC(50) values of 5.1 and 1.4 nM, respectively) in the displacement of Thiazin Red R. These probes have good solubility in distilled water and low or no cytotoxicity in zebrafish embryo and liver hepatocellular carcinoma cell assays.
