A comparative investigation of two structurally related potentially nonadentate chelating ligands, H(4)neunpa-NH2 and H(4)noneunpa, 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 [Sc-44]Sc3+, [In-111]-In3+, [Lu-177]Lu3+, and [Ac-225]Ac3+ revealed a sharp contrast between the affinity of each chelator for large radiometal ions. H(4)noneunpa demonstrated highly effective coordination of [Lu-177]Lu3+ and [Ac-225]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 H(4)neunpa-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.