The aggregation of amyloid beta (Aβ) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aβ-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two-photon microscopy (TPM) has emerged as one of the most powerful. To date, several near-infrared-emissive two-photon dyes with a high affinity for Aβ fibrils have been developed, but there has often been a tradeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)-based de-excitation pathway, which results in a remarkable fluorescence increase of around 167-fold in the presence of Aβ fibrils, while maintaining an excellent two-photon cross section, thereby enabling high-contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal-to-background ratio.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702, J.S.K.), and the Korea Research Fellowship Program funded by the Ministry of Science and ICT through the NRF of Korea (2016H1D3A1938052, P.V.). This work was also supported by Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (NRF-2018R1A6A1A03025124, NRF-2018R1D1A1B07043383, D.K.; NRF-2017R1D1A1B03032561, P.V.; and NRF-2018R1A2B6002275, J.H.) and by the Bio & Medical Technology Development Program of the NRF of Korea funded by the Ministry of Science and ICT (NRF-2018M3A9H3021707, D.K.), as well as the Brain Research Program (NRF-2015M3C7A1028790, I.M.-J.) through the NRF of Korea. This study was supported by Korea Basic Science Institute Grant (T38662, J.S.K.).
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
- Alzheimer's disease
- fluorescent probes
- imaging agents
- molecular rotation
- two-photon probes
ASJC Scopus subject areas
- General Chemistry