Triethylenetetramine-N,N,N‘,N‘‘,N‘‘‘,N‘‘‘-hexaacetic Acid (TTHA) and TTHA-Bis(butanamide) as Chelating Agents Relevant to Radiopharmaceutical Applications

The N,N'-bis(butanamide) derivative of TTHA (TTHA = triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid), and its Ga(3+) and In(3+) complexes were synthesized and characterized. The crystal X-ray diffraction structure of [Ga(2)(OH)(2)(TTHA)][Na(2)(H(2)O)(6)].2H(2)O was determined. The complex crystallizes in the monoclinic space group P2(1)/n with a = 7.179(2) Å, b = 20.334(3) Å, c = 10.902(5) Å, beta = 101.90(2) degrees, and Z = 2. Each gallium atom is bonded to six donor atoms (N(2)O(4)) in a slightly distorted octahedral geometry. The values of the protonation constants and the protonation sequence were determined by potentiometry and NMR. The stability constants of the Al(3+), Ga(3+), Fe(3+), and In(3+) complexes of TTHA-(BuA)(2) and of the Ga(3+) complex of TTHA were determined by potentiometry. The structures, in solution, of the Al(3+), Ga(3+), and In(3+) complexes of TTHA-(BuA)(2) and TTHA were analyzed by (1)H, (13)C, (27)Al, (71)Ga, and (115)In NMR techniques. Derivatization of two terminal carboxylates by butanamide substituents leads to a significant decrease of the total ligand basicity (5.77 log units) and to a change of the solubility of the resulting complexes. The stability constant of the ML complexes of TTHA-(BuA)(2) with Fe(3+) exhibits the highest value of the series (10(23.92)). The In(3+) complex is more stable than that of Ga(3+) and almost as stable as that of the Fe(3+). However, the decrease in indium and iron complex stability is less drastic going from TTHA to TTHA-(BuA)(2) (about 3 log units) than for Al(3+) or Ga(3+) (about 6 log units). pM values calculated under physiological conditions for DTPA, TTHA, and the bis(butanamide) derivatives have shown that while DTPA remains a ligand of choice to chelate Fe(3+) and In(3+) ions in vivo compared to transferrin as competitor ligand, TTHA, surprisingly, appears to be the best of these four ligands (pM = 22.71) to chelate Ga(3+).