H₂CHXdedpa and H₄CHXoctapaChiral Acyclic Chelating Ligands for ^67/68Ga and ¹¹¹In Radiopharmaceuticals

The chiral acyclic ligands H₂CHXdedpa (N₄O₂), H₂CHXdedpa-bb (N₄O₂), and H₄CHXoctapa (N₄O₄) (CHX = cyclohexyl/cyclohexane, H₂dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]­ethane, bb = N,N′-dibenzylated, H₄octapa = N,N′-bis­(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-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 H₂dedpa and octadentate H₄octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga­(CHXdedpa)]⁺ showed very similar properties to those of [Ga­(dedpa)]⁺, with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga­(dedpa)]⁺, [Ga­(CHXdedpa)]⁺ exhibited exceptionally high thermodynamic stability constants (log K_ML = 28.11(8)), and the chelate retained the ability to label ⁶⁷Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10^–5 M. In vitro kinetic inertness assays demonstrated the [⁶⁷Ga­(CHXdedpa)]⁺ complex to be more stable than [⁶⁷Ga­(dedpa)]⁺ in a human serum competition, with 90.5% and 77.8% of ⁶⁷Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H₄CHXoctapa with In­(III) demonstrated [In­(CHXoctapa)]⁻ to have an equivalently high thermodynamically stable constant as [In­(octapa)]⁻, with log K_ML values of 27.16(9) and 26.76(14), respectively. The [¹¹¹In­(CHXoctapa)]⁻ complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [¹¹¹In­(octapa)]⁻ 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 H₂CHXdedpa and octadentate H₄CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.