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.
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 Ga(3+) chelators, TRAP ligands (triazacyclononane phosphinic acids). Stepwise protonation constants of ligands and stability constants of their complexes with Ga(3+), selected divalent metal, and Ln(3+) 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 Ga(3+) over the other metal ions (log K(GaL) - log K(ML) = 7-9) and a selective complexation of smaller Mg(2+) over Ca(2+). Stabilities of the Ga(3+) complexes are dependent on the basicity of the donor atoms: [Ga(NOTA)] (log K(GaL) = 29.6) > [Ga(TRAP-OH)] (log K(GaL) = 23.3) > [Ga(TRAP-H)] (log K(GaL) = 21.9). The [Ga(TRAP-OH)] complex exhibits unusual reversible rearrangement of the "in-cage" N(3)O(3) complex to the "out-of-cage" O(6) complex. The in-cage complex is present in acidic solutions, and at neutral pH, Ga(3+) 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 Ga(3+) 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 Ga(3+) complexes are kinetically inert in both acidic and alkaline solutions. Complex formation studies in acidic solutions indicate that Ga(3+) complexes of the phosphinate ligands are formed quickly (minutes) and quantitatively even at pH <2. Compared to common Ga(3+) chelators (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)  derivatives), these novel ligands show fast complexation of Ga(3+) over a broad pH range. The discussed TRAP ligands are suitable alternatives for the development of (68)Ga radiopharmaceuticals.
Department of Inorganic Chemistry, Univerzita Karlova (Charles University), Hlavova 2030, 12843 Prague 2, Czech Republic.
Jakub
J
Šimeček
Martin
M
Schulz
Johannes
J
Notni
Jan
J
Plutnar
Vojtěch
V
Kubíček
Jana
J
Havlíčková
Petr
P
Hermann
D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D005708:Gallium / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring; D007477:Ions / Q000737:chemistry; D008024:Ligands; D008670:Metals / Q000737:chemistry; D010721:Phosphinic Acids / Q000737:chemistry*
D002614:Chelating Agents; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007477:Ions; D008024:Ligands; D008670:Metals; D010721:Phosphinic Acids; C075712:1,4,7-triazacyclononane; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D005708:Gallium