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

ABSTRACT 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, 19 F‐Cy5.5‐NP for “Turn‐On” 19 F magnetic resonance/near‐infrared fluorescence ( 19 F MR/NIR‐FL) imaging of the enzyme activity in AD in vivo. The “Turn‐On” 19 F 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, 19 F‐Cy5.5‐NP, with a silent 19 F MR/NIR‐FL signal is obtained from the precursor Cys(StBu)‐Glu‐Val‐Asn‐Leu‐Asp‐Ala‐Glu‐Phe(CF 3 )‐Lys(Cy5.5)‐CBT ( 19 F‐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 9 F NMR and NIR‐FL signals in vitro, respectively. Moreover, 19 F‐Cy5.5‐NP renders 4.6 ± 0.9‐fold/1.5 ± 0.1‐fold higher 19 F MRI/NIR‐FL signal in Aβ 25–35 ‐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 19 F‐Cy5.5‐NP could be applied for the early diagnosis of AD in clinics in the future.