A comparative investigation of two
structurally related potentially
nonadentate chelating ligands, H4neunpa-NH2 and
H4noneunpa, has been undertaken to examine the influence
of bifunctionalization on their coordination chemistry and metal ion
selectivity. Significantly improved synthetic routes for each compound
have been developed, employing straightforward high-yielding strategies.
Radiolabeling studies with [44Sc]Sc3+, [111In]In3+, [177Lu]Lu3+, and
[225Ac]Ac3+ revealed a sharp contrast between
the affinity of each chelator for large radiometal ions. H4noneunpa demonstrated highly effective coordination of [177Lu]Lu3+ and [225Ac]Ac3+ achieving
quantitative radiochemical yields (>98%) at ligand concentrations
of 10–6 M (room temperature (RT), 10 min), with
excellent stability when challenged in human serum, while H4neunpa-NH2 was unable to complex either metal ion effectively.
Nuclear magnetic resonance (NMR) spectroscopy was employed to explore
the coordination chemistry of each chelating ligand with nonradioactive
metal ions, spanning a range of ionic radii and coordination numbers.
A comprehensive conformational analysis of each metal complex was
undertaken using density functional theory (DFT) calculations to explore
the coordination geometries and explain the discrepancy in binding
characteristics. Theoretical simulations revealed notable differences
in the coordination geometry and apparent denticity of each ligand,
which together account for the observed selectivity in metal binding
and have important implications for the future design of complexes
based upon this framework to target large radiometal ion coordination.
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