A 19F MRI/NIR-FL Nanoprobe for "Turn-On" Imaging of β-Secretase (BACE1) Activity in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder with very few therapeutic methods; thus, its early detection is urgently important. β-secretase (BACE1) is a well-recognized biomarker of early-stage AD, but its in vivo imaging-based diagnostic method is rarely reported. Herein, we report a BACE1-disassemblable nanoprobe, 19F-Cy5.5-NP for "Turn-On" 19F magnetic resonance/near-infrared fluorescence (19F MR/NIR-FL) imaging of the enzyme activity in AD in vivo. The "Turn-On" 19F MRI signals are employed for imaging BACE1 activity with high specificity, while the "Turn-On" NIR-FL signals are used for double checking the enzyme activity with high spatial resolution. Specifically, 19F-Cy5.5-NP, with a silent 19F MR/NIR-FL signal is obtained from the precursor Cys(StBu)-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe(CF3)-Lys(Cy5.5)-CBT (19F-Cy5.5) through a CBT-Cys click reaction. Upon BACE1 cleavage, the nanoprobe disassembles, resulting in 6.8 ± 1.3-fold and 9.5 ± 0.3-fold increases of 1 9F NMR and NIR-FL signals in vitro, respectively. Moreover, 19F-Cy5.5-NP renders 4.6 ± 0.9-fold/1.5 ± 0.1-fold higher 19F MRI/NIR-FL signal in Aβ25-35-treated PC12 cells than that in normal PC12 cells. In vivo experimental results show that this nanoprobe enables the precise imaging of BACE1 activity in AD zebrafish models. We anticipate that 19F-Cy5.5-NP could be applied for the early diagnosis of AD in clinics in the future.