title: Novel 19F activatable probe for the detection of matrix metalloprotease-2 activity by MRI/MRS.
abstract: Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable (19)F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP-2 activity by (19)F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing (19)F MRI agents and provides a simple but robust method for real-time (19)F MRI application.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) , Bethesda, Maryland 20892, United States.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunqi
authors.initials: C
authors.lastname: Qian
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000473:pathology; D003287:Contrast Media; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D057054:Molecular Imaging; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D003287:Contrast Media; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: 19F magnetic resonance imaging; 19F magnetic resonance spectroscopy; activatable probe; matrix metalloproteases