"LIVIMODE aims to develop specific tools for non invasive in vivo imaging of disease related molecular events. Such tools are of high relevance for disease detection, staging, developing animal models of human disease, and evaluating novel therapies. We propose to use optical imaging, which is optimally suited for this task as it provides excellent sensitivity and allows visualizing molecular events via a fluorescent signal. While optical imaging technology has rapidly evolved over the last years, the availability of SMART (activatable) imaging agents that change their fluorescence properties upon disease related events, remains a critical gap. The LIVIMODE project proposes to combine expertises in medicinal chemistry, pharmacology and imaging in a conceptually new approach in designing SMART agents. In particular, we will (i) translate established strategies in medicinal/pharmaceutical chemistry to design highly selective SMART probes and (ii) optimize the cell/tissue specificity of probes integrating concepts from polymer and protein based targeted drug delivery. We will generate a toolset of highly selective targeted SMART probes for at least 10 disease-relevant proteases. The selection of target proteases is based on their relevance in disease processes that cannot yet be monitored with non invasive technology. These include (i) the development of tumor microenvironment as a critical factor in oncogenesis, (ii) tumor hypoxia and angiogenesis, and (iii) inflammatory and degenerative processes in osteoarthritis. LIVIMODE has established animal models for these conditions and will use in vivo optical imaging to evaluate the novel SMART probes as tools for monitoring disease progression and drug efficacy. This will enhance our knowledge of disease mechanisms and our ability to rapidly characterize drug candidates for in vivo efficacy (proof-of-efficacy). Selected SMART probes will be optimized to assess their potential as clinical diagnostics."