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Octadentate chelators for zirconium- and other metal-based radiopharmaceuticals Buchwalder, Christian


Metal-based radiopharmaceuticals are critical in nuclear medicine for non-invasive diagnosis and treatment of serious diseases such as cancer. To be successfully deployed in such radioactive drugs, radiometal ions need to be stably sequestered by a suitable chelating agent. This work investigates a new class of octadentate chelating agents containing four 3-hydroxy-4-pyridinone (3,4-HOPO) entities with a focus on the development of new zirconium(IV) chelates. The diagnostic radionuclide zirconium-89 (89Zr, t1/2 78.41 h, Iβ+ 22.7%, Eβ+ mean 395.5 keV) is of particular interest for antibody-targeted positron emission tomography (immunoPET). The developed tetrakis(3,4-HOPO) chelator is capable of quantitatively sequestering 89Zr within 10 min at ambient temperature. The resultant Zr(IV) complex was found to be of exceptional thermodynamic stability (log β 50.3), showed a favourable pharmacokinetic profile in vivo, and exceeded the current standard Zr-chelator in direct in vitro stability tests. The tetrapodal chelator was derivatized in a multi-step synthesis for covalent attachment to targeting vectors or other carriers. The conjugation and ⁸⁹Zr-radiolabeling of the bifunctional chelator (BFC) was subsequently optimized and investigated in detail with two monoclonal antibodies, a model protein, and with polymeric nanoparticles. The long-term in vivo stability of the ⁸⁹Zr-radiochelate was assessed in a novel way over six days by utilizing long-circulating hyperbranched polyglycerol (HPG) nanoparticles. The radiochelate-nanocarrier conjugates were examined over six days by non-invasive positron emission tomography (PET) and in a biodistribution study. Although in vitro exams demonstrated extended plasma stability, these data revealed a physiologic susceptibility of the tetrakis(HOPO) complex attributed to kinetic lability. In addition to investigations with Zr(IV), the new ligand system was briefly explored with Fe(III), Ga(III), Y(III), Sm(III), Gd(III), Tb(III), Lu(III), and Bi(IIII) and indicated to be a promising chelator for iron(III), gallium(III), yttrium(III), and lanthanide ion coordination.

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