The general goal of this research is to develop positron emission tomography (PET) and magnetic resonance imaging (MRI) based molecular imaging systems to image cancer-specific enzymatic acfivity of proteases in vivo. To date the imaging of protease activity has primarily involved the development of fluorescent probes which exploit quenching and acfivation mechanisms offered by fiuorescence resonance energy transfer (FRET). Opfical imaging unfortunately has a serious limitafion, especially for clinical translation, which is the limited tissue penetrafion of light photons and high tissue autofluorescence background, hindering its ability to image deep tissues. To address this challenge, we propose a new platform for imaging protease activity in vivo. Here we outline developments to make this new platform compatible with modalities that have deep tissue penetrafion, specifically: PET and MRI. We propose to establish and validate a general platform for imaging specific protease activity in cancer cells. The platform is based on the protease activity triggered polymerization between two chemical moieties (the amino and thiol groups of cysteine and 2-cyanobenzothiazole) incorporated into a small-molecule imaging probe. This polymerization process will convert the small-molecule probe into larger molecules (or even nanoparticles) to achieve probe concentration and retention at the target site and to generate amplified readout signals. In particular, we will exploit the highly specific condensation reaction between 1,2-aminomercapto and 2-cyanobenzothlazole groups as the base mechanism for polymerization, adding other functionalities to impart specificity to different enzymes or to enhance the effectiveness of our approach. Probes for two clinical imaging modalities, PET and MRI, will be designed, prepared and evaluated. The nature of the small-molecule PET and MRI probes, combined with the amplified activation signal, should maximize the likelihood of moving these probes into the clinic. In this project, we have chosen furin as the target enzyme because of its important role as a """"""""master switch"""""""" at different levels or stages during the process of cancer development and progression. The approach, however, should be generally applicable to other cancer- and disease-specific proteases, in particular, any endoproteases that perform C-terminal cleavage. This again may greatly improve the prospects for eventual clinical translafion of this platform technology.

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National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-SRLB-9)
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Stanford University
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