Development of an optimized activatable MMP-14 targeted SPECT imaging probe

作者：Watkins Gregory A; Jones Ella Fung^*; Shell M Scott; VanBrocklin Henry F; Pan Mei Hsiu; Hanrahan Stephen M; Feng Jin Jin; He Jiang; Sounni Nor Eddine; Dill Ken A; Contag Christopher H; Coussens Lisa M; Franc Benjamin L

来源：Bioorganic & Medicinal Chemistry, 2009, 17(2): 653-659.

DOI：10.1016/j.bmc.2008.11.078

• Cancer
• MMP-14
• Protease sensitive probe
• SPECT imaging

Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r(8)) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two-fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity. Published by Elsevier Ltd.

• 出版日期2009-1-15