Target-enabled bioorthogonal reaction
and self-assembly of a small-molecule
probe into supramolecules have shown promise for molecular imaging.
In this paper, we report a new stimuli-responsive bioorthogonal reaction
scaffold (SF) for controlling in situ self-assembly by engineering the condensation reaction between 2-cyanobenzothiazole
and cysteine. For probes with the SF scaffold, intramolecular
cyclization took place soon after activation, which could efficiently
outcompete free cysteine even at a low concentration and result in
efficient aggregation in the target. Through integration with different
enzyme-responsive substrates and an ammoniomethyl-trifluoroborate
moiety (AmBF3), two radioactive positron emission tomography
(PET) tracers, [18F]SF-DEVD and [18F]SF-Glu, were designed, which showed high stability
under physiological conditions and could produce clear PET signal
in tumors to detect enzyme activity (e.g., caspase-3, γ-glutamyltranspeptidase)
timely and accurately. Our results demonstrated that the scaffold SF could serve as a general molecular scaffold in the development
of smart PET tracers for noninvasive imaging of enzyme activity, which
could contribute to tumor detection and treatment efficacy evaluation.
Legumain has been found overexpressed in several cancers, which serves as an important biomarker for cancer diagnosis. In this research, a novel fluorine-18 labeled radioactive tracer [18F]SF-AAN targeting legumain was designed and synthesized for positron emission tomography (PET) imaging. Nonradioactive probe [19F]SF-AAN was obtained through chemical and solid phase peptide synthesis. After a simple one-step 18F labeling, the radiotracer [18F]SF-AAN was obtained with a high radiochemical conversion rate (>85%) and radiochemical purity (99%) as well as high molar activity (12.77 ± 0.50 MBq/nmol). The targeting specificity of [18F]SF-AAN for detecting legumain activity was investigated systematically in vitro and in vivo. In vitro cellular uptake assay showed that the uptake of [18F]SF-AAN in legumain-positive MDA-MB-468 cells was twice as much as that in legumain-negative PC-3 cells at 4 h. In vivo PET imaging revealed that the tumor uptake of [18F]SF-AAN in MDA-MB-468 tumor-bearing mice was about 2.7 times of that in PC-3 tumor-bearing mice at 10 min post injection. The experimental results indicated that [18F]SF-AAN could serve as a promising PET tracer for detecting the legumain expression sensitively and specifically, which would be beneficial for the diagnosis of legumain-related diseases.
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