Development of Triphenylmethane Dyes for In Vivo Fluorescence Imaging of Aß Oligomers.
ACS Chem Neurosci
; 15(11): 2233-2242, 2024 06 05.
Article
in En
| MEDLINE
| ID: mdl-38753435
ABSTRACT
Detection of amyloid ß (Aß) oligomers, regarded as the most toxic aggregated forms of Aß, can contribute to the diagnosis and treatment of Alzheimer's disease (AD). Thus, the development of imaging probes for in vivo visualization of Aß oligomers is crucial. However, the structural uncertainty regarding Aß oligomers makes it difficult to design imaging probes with high sensitivity to Aß oligomers against highly aggregated Aß fibrils. In this study, we developed Aß oligomer-selective fluorescent probes based on triphenylmethane dyes through screening of commercially available compounds followed by structure-activity relationship (SAR) studies on cyclic or acyclic 4-dialkylamino groups. We synthesized 11 triarylmethane-based Aß oligomer probe (TAMAOP) derivatives. In vitro evaluation of fluorescence properties, TAMAOP-9, which had bulky 4-diisobutylamino groups introduced into three benzenes of a twisted triphenylmethane backbone, showed marked fluorescence enhancement in the presence of Aß oligomers and demonstrated high selectivity for Aß oligomers against Aß fibrils. In docking studies using the Aß trimer model, TAMAOP-9 bound to the hydrophobic surface and interacted with the side chain of Phe20. In vitro section staining revealed that TAMAOP-9 could visualize Aß oligomers in the brains of AD model mice. An in vivo fluorescence imaging study using TAMAOP-9 showed significantly higher fluorescence signals from the brains of AD model mice than those of age-matched wild-type mice, confirmed by ex vivo section observation. These results suggest that TAMAOP-9 is a promising Aß oligomer-targeting fluorescent probe applicable to in vivo imaging.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trityl Compounds
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Amyloid beta-Peptides
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Alzheimer Disease
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Optical Imaging
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Fluorescent Dyes
Limits:
Animals
/
Humans
Language:
En
Journal:
ACS Chem Neurosci
Year:
2024
Document type:
Article