Complexation of Metal Ions with TRAP (1,4,7-Triazacyclononane Phosphinic Acid) Ligands and 1,4,7-Triazacyclononane-1,4,7-triacetic Acid: Phosphinate-Containing Ligands as Unique Chelators for Trivalent Gallium

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Abstract
Three phosphinic acid 1,4,7-triazacyclononane (TACN) derivatives bearing methylphosphinic (TRAP-H), methyl(phenyl)phosphinic (TRAP-Ph), or methyl(hydroxymethyl)phosphinic acid (TRAP-OH) pendant arms were investigated as members of a new family of efficient Ga3+ chelators, TRAP ligands (triazacyclononane phosphinic acids). Stepwise protonation constants of ligands and stability constants of their complexes with Ga3+, selected divalent metal, and Ln3+ ions were determined by potentiometry. For comparison, equilibrium data for the metal ion–NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) systems were redetermined. These ligands exhibit high thermodynamic selectivity for Ga3+ over the other metal ions (log KGaL – log KML = 7–9) and a selective complexation of smaller Mg2+ over Ca2+. Stabilities of the Ga3+ complexes are dependent on the basicity of the donor atoms: [Ga(NOTA)] (log KGaL = 29.6) > [Ga(TRAP-OH)] (log KGaL = 23.3) > [Ga(TRAP-H)] (log KGaL = 21.9). The [Ga(TRAP-OH)] complex exhibits unusual reversible rearrangement of the “in-cage” N3O3 complex to the “out-of-cage” O6 complex. The in-cage complex is present in acidic solutions, and at neutral pH, Ga3+ ion binds hydroxide anion, induces deprotonation and coordination of the P-hydroxymethyl group(s), and moves out of the macrocyclic cavity; the hypothesis is supported by a combination of results from potentiometry, multinuclear nuclear magnetic resonance spectrometry, and density functional theory calculations. Isomerism of the phosphinate Ga3+ complexes caused by a combination of the chelate ring conformation, the helicity of coordinated pendant arms, and the chirality of the coordinated phosphinate groups was observed. All Ga3+ complexes are kinetically inert in both acidic and alkaline solutions. Complex formation studies in acidic solutions indicate that Ga3+ complexes of the phosphinate ligands are formed quickly (minutes) and quantitatively even at pH 3+ chelators (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives), these novel ligands show fast complexation of Ga3+ over a broad pH range. The discussed TRAP ligands are suitable alternatives for the development of 68Ga radiopharmaceuticals.