6533b837fe1ef96bd12a2f27

RESEARCH PRODUCT

New site-specific bioconjugation strategies and their application to the development of molecular imaging agents for cancer diagnostic

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description

The preparation of targeted imaging agents suitable for cancer diagnostic involves the coupling of an imaging probe to a vector, generally a protein, able to specifically target cancerous tissues. Unfortunately, this bioconjugation step is often problematic. Indeed, proteins present a large variety of reactive functions that can potentially interfere with the coupling reaction. The purpose of this work is the design of innovative selective bioconjugation strategies that can facilitate the synthesis of molecular imaging agents.Our research led to the development of a simple and efficient approach allowing the modification of a protein with a fluorophore by using a site-specific bioconjugation reaction. Thanks to this technique, it is possible to obtain near infrared fluorescent agents in a single step.We also focused our work on the design of bimodal nuclear/fluorescent imaging tracers based on protein vectors. These bimodal imaging agents show high potential for numerous medical applications. However, their synthesis requires the coupling of two distinct imaging molecules to the protein, which makes the bioconjugation step even more challenging. In this context, we developed different strategies suitable for the site-specific dual-modification of proteins. These approaches are based on a highly modular trifunctional platform, dichlorotetrazine. Several bimodal nuclear/optical imaging agents were obtained and shown convenient in vivo diagnostic properties.This thesis also presents the elaboration of a new PSMA-specific radiotracer able to detect prostate cancer. The promising results obtained during the preclinical evaluation of this compound labeled with copper-64, make it an interesting candidate for the diagnosis of prostate cancer by positron emission tomography in human.