Compact Luminol Chemiluminophores for In Vivo Detection and Imaging of β-Sheet Protein Aggregates

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Abstract
Protein aggregation has been found in a wide range of neurodegenerative protein-misfolding diseases. The demand for in vivo technologies to identify protein aggregation is at the leading edge for the pathogenic study, diagnostic development, and therapeutic intervention of these devastating disorders. Herein, we report a series of luminol analogues to construct a facile chemiluminescence (CL)-based approach for in vivo detection and imaging of β-sheet protein aggregates. The synthesized compounds exhibited a distinct chemiluminescent response with long emission wavelengths toward reactive oxygen species under physiological conditions and displayed signal amplification in the presence of β-sheet protein aggregates, including α-synuclein, β-amyloid, and tau. Among them, CyLumi-3 was further evaluated as a chemiluminescent probe in preclinical models. By intravenous administration into the model mice via the tail vein, in vivo CL imaging noninvasively detected the specific CL of the probe targeting the α-synuclein aggregates in the brains of living mice. Based on its structural characteristics, CyLumi-3 can readily interact with α-synuclein aggregates with significantly enhanced fluorescence and can identify α-synuclein aggregates in vivo via distinctive CL amplification, which could pave the way for a more comprehensive understanding of protein aggregation in preclinical studies and would provide new hints for developing small-molecule chemiluminophores for protein aggregates.
Funding Information
  • Sichuan University (2015SCU04A37)
  • China Postdoctoral Science Foundation (2014M560723)
  • Central University Basic Research Fund of China
  • National Natural Science Foundation of China (81402891)
  • Higher Education Discipline Innovation Project (B18035)
  • Health Department of Sichuan Province (16PJ225)
  • Sichuan Province Youth Science and Technology Innovation Team (2016TD0001)

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