A New Generation of Bifunctional Bispidine Chelators for Imaging and Therapeutic Applications

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The bispidine platform is a very rigid tetradentate ligand with a relatively large cavity, and a modular synthesis has been developed to produce up to decadentate ligands with variable donor sets. Methods have been developed for an easy functionalization of the ligands with biological vectors and/or fluorescence dyes. Two types of hexadentate and a macrocyclic tetradentate ligands have been used for 64CuII PET tracers and the corresponding conjugates with biological vectors and, for the macrocyclic tracer, an additional cyanine group are ready for animal experiments. Preliminary experiments with hepta-, octa- and nonadentate bispidines and 111InIII, 213BiIII, 177LuIII and 225AcIII for radio-imaging and therapy have been performed, photophysical properties of LnIII complexes have been studied and the MnII selectivity of two new bispidines has been evaluated together with the collection of preliminary data on the proton relaxivity in view of MRI contrast agents. The aim of this follow-up project is to thoroughly study complexation and decomplexation mechanisms in order to optimize the ligand systems specifically for 213BiIII, 177LuIII and 225AcIII radiotracers with the aim of efficient and relatively fast complexation at physiological conditions as well as inertness under biological conditions. The currently available bispidine systems already outperform the current “gold standards” but we have observed the fast formation of relatively labile complexes in a pre-equilibrium and this needs to be understood in detail and prevented as far as possible. The inertness of the bispidine systems is a result of very efficient encapsulation and this needs to be optimized for each tracer system on the basis of structural work and kinetic studies in presence of excess of biologically relevant metal ions. In addition, we propose to further develop the LnIII systems towards lanthanide-based fluorescence probes and optimize the unique MnII selectivity of our ligands and develop corresponding applications such as for MRI contrast agents and in-cell optical and structural probes.