Dipicolinate Complexes of Gallium(III) and Lanthanum(III)

Abstract

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H₃dpaa), phosphonate (H₄dppa), and bisphosphonate (H₇dpbpa), as well as their nonfunctionalized analogue (H₂dpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of H₂dpa, H₃dpaa, and H₄dppa, the 1:2 lanthanum(III) complex of H₂dpa, and the 1:1 gallium(III) complex of H₃dpaa were characterized, including via X-ray crystallography for [La₄(dppa)₄(H₂O)₂] and [Ga(dpaa)(H₂O)]. H₂dpa, H₃dpaa, and H₄dppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (H₃dpaa) or NMR spectrometric (H₂dpa and H₄dppa) titrations, which showed that the carboxylate (H₃dpaa) and phosphonate (H₄dppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log β_ML and pM values) at physiological pH. In addition, potentiometric titrations with H₃dpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log P_o/w values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides ^67/68Ga, radiolabeling studies were performed with ⁶⁷Ga and H₃dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10^-5 M, and human serum stability studies were undertaken.