H<sub>2</sub><i>CHX</i>dedpa and H<sub>4</sub><i>CHX</i>octapaChiral Acyclic Chelating Ligands for <sup>67/68</sup>Ga and <sup>111</sup>In Radiopharmaceuticals

The chiral acyclic ligands H<sub>2</sub><i>CHX</i>dedpa (N<sub>4</sub>O<sub>2</sub>), H<sub>2</sub><i>CHX</i>dedpa-bb (N<sub>4</sub>O<sub>2</sub>), and H<sub>4</sub><i>CHX</i>octapa (N<sub>4</sub>O<sub>4</sub>) (<i>CHX</i> = cyclohexyl/cyclohexane, H<sub>2</sub>dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]­ethane, bb = <i>N</i>,<i>N</i>′-dibenzylated, H<sub>4</sub>octapa = <i>N</i>,<i>N</i>′-bis­(6-carboxy-2-pyridylmethyl)-ethylenediamine-<i>N</i>,<i>N</i>′-diacetic acid) were synthesized, complexed with Ga­(III) and/or In­(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H<sub>2</sub>dedpa and octadentate H<sub>4</sub>octapa ligands to determine the effect adding a chiral 1<i>R</i>,2<i>R</i>-<i>trans</i>-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga­(<i>CHX</i>dedpa)]<sup>+</sup> showed very similar properties to those of [Ga­(dedpa)]<sup>+</sup>, with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga­(dedpa)]<sup>+</sup>, [Ga­(<i>CHX</i>dedpa)]<sup>+</sup> exhibited exceptionally high thermodynamic stability constants (log <i>K</i><sub>ML</sub> = 28.11(8)), and the chelate retained the ability to label <sup>67</sup>Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10<sup>–5</sup> M. In vitro kinetic inertness assays demonstrated the [<sup>67</sup>Ga­(<i>CHX</i>dedpa)]<sup>+</sup> complex to be more stable than [<sup>67</sup>Ga­(dedpa)]<sup>+</sup> in a human serum competition, with 90.5% and 77.8% of <sup>67</sup>Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H<sub>4</sub><i>CHX</i>octapa with In­(III) demonstrated [In­(<i>CHX</i>octapa)]<sup>−</sup> to have an equivalently high thermodynamically stable constant as [In­(octapa)]<sup>−</sup>, with log <i>K</i><sub>ML</sub> values of 27.16(9) and 26.76(14), respectively. The [<sup>111</sup>In­(<i>CHX</i>octapa)]<sup>−</sup> complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [<sup>111</sup>In­(octapa)]<sup>−</sup> values, and an improved stability compared to the current industry “gold standards” 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H<sub>2</sub><i>CHX</i>dedpa and octadentate H<sub>4</sub><i>CHX</i>octapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.