The utility of biological ligands attached to radionuclides for in vivo applications depends on the ability of a bifunctional chelator (BFC) to retain the metal ion of interest. Chemists increase the stability of metal chelates by selecting appropriate metal coordinating groups and by pre-organizing the metal binding chelator into a conformation that has been optimized for metal binding. Coordinating groups are chosen based on their affinity for the metal cation of interest, the “bite angle” subtended by the individual atoms in the group, and the number of groups needed to form an optimal coordination geometry. Our chelators exploit two factors that confer conformational rigidity: The use of aromatic coordinating groups and the positioning of these upon macrocyclic scaffolds.<br/><br/>Recently, we reported the properties of aromatic macrocyclic BFCs made from 1-hydroxypyridin-2-one (1,2-HOPO) coordinating groups. These groups are useful both as sensitizers of europium(III) luminescence and as remarkably effective ligands for lanthanides and related tetravalent metal ions of radiopharmaceutical interest. These macrocyclic chelators form bright (Φ = 0.37) europium(III) complexes that are up to 1000-fold more kinetically stable with respect to challenge by DTPA compared to acyclic 1,2-HOPO analogs. Crystallographic characterization of the parent europium(III) complex confirms that the inner coordination sphere of europium(III) cation is fully saturated by the 1,2-HOPO binding units (<b>Fig. 1</b>). Both the europium(III) and the corresponding calcium(II) BFCs can be coupled to a variety of targeting moieties (e.g. antibodies) using amide-forming NHS coupling chemistry. The calcium(II) form of the BFC has been shown to label with lutetium(III), zirconium(IV), and thorium(IV) quickly at room temperature, which can facilitate the development of temperature sensitive radiopharmaceuticals containing these metal ions.

Aromatic macrocyclic bifunctional chelators for radiopharmaceutical applications

ACS Spring 2022

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