Rapid Thermodynamically Stable Complex Formation of [In]In, [Y]Y, and [Lu]Lu with Hdappa.

A phosphinate-bearing picolinic acid-based chelating ligand (Hdappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In, Lu, Y, Sc, La, Bi). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of Hdappa with four metal ions (In, Lu, Y, Sc) was deeply investigated via potentiometric and spectrophotometric (UV-vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand-ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([In]In, [Lu]Lu, [Y]Y), and the serum stability of [In][In(dappa)] was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that Hdappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [In]In and [Lu]Lu, respectively. For Hdappa, high thermodynamic stability did not correlate with kinetic inertness-lability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.