Session: Bioinorganic Chemistry:

The theranostic isotope pairs, ⁶⁴Cu (t_1/2= 12.7 h, β+ = 653 keV) and ⁶⁷Cu (t_1/2= 61.9 h, β- =141 keV), have received considerable attention due to increased availability and production. Central to these efforts is the design of bio-conjugatable chelates capable of forming inert metal complexes under benign metalation conditions. Polyaminocarboxylates based on cyclen are well known chelators for copper radiopharmaceuticals (e.g. TETA, DOTA, DO3A, NOTA), where N-alkylation and introduction of cross-bridged functionalization can lead to a dramatic increase in stability at the cost of sluggish metal uptake. In this work, we report that the introduction of a spirocyclic quaternary ammonium fragment to the DO3A core results in large structural perturbations to the cyclen framework and provides access to thermodynamically stable and neutral Cu^II and Zn^II compounds. The structures of these complexes are thoroughly characterized by single-crystal X-ray diffraction, EPR, NMR, potentiometry, cyclic voltammetry, and supporting computational studies. Furthermore, we demonstrate that DO3A^C4H8 rapidly chelates to ⁶⁴Cu at room temperature and displays high blood plasma stability. Our findings point towards the potential of DO3A^C4H8 based scaffolds and the benefits of charge neutral and electrochemically reversible ⁶⁴Cu radiopharmaceuticals.

Jerome R. Robinson

Assistant Professor of Chemistry, Brown University

Appearances