153Sm and 166Ho complexes with tetraaza macrocycles containing pyridine and methylcarboxylate or methylphosphonate pendant arms

Abstract

A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac(3)py14) or methylphosphonate (MeP(2)py14 and P(3)py14) pendant arms were prepared and their stability constants with La(3+), Sm(3+), Gd(3+) and Ho(3+) determined by potentiometry at 25 degrees C and 0.10 M ionic strength in NMe(4)NO(3). The metal:ligand ratio for (153)Sm and (166)Ho and for ac(3)py14, MeP(2)py14 and P(3)py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24 h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP(2)py14 and P(3)py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.

Lanthanide complexes of macrocyclic derivatives useful for medical applications

“…The later ligands exhibit larger K ML values for the complexes with lanthanide ions than the corresponding acetate derivative [6][7][8]. Differently, the Ni 2+ , Cu 2+ , and Zn 2+ complexes of the same ligands present K ML of the same order for the acetate and methylphosphonate derivatives, see in Table 2 the values for the Cu(II) complexes [6][7][8]. However, as the direct comparison of stability constants involving ligands with rather different overall basicity can lead to erroneous conclusions, because the competition of metals and proton for ligands is not taken into account, the pM val-…”

“…Indeed, the electrostatic effect of the double negative charge on the phosphonate groups prevails over the inductive electron-withdrawal effect of these groups, making the nearby amine more basic [6,7]. The different overall basicity of the studied ligands has direct repercussion in their complexation properties and in their biological applications [7].…”

“…, which are dependent of the protonation constants, were determined and collected in Table 3 [7]. It shows that the highest pM values were found for solutions containing the ligand with three methylphosphonate arms, immediately followed by those of the ligand with two methylphosphonate groups, and finally those of the compound containing acetate arms.…”

“…Table 1 shows the protonation constants of the first series of compounds studied, represented in Fig. 1, determined in aqueous solutions of tetramethylammonium nitrate (NMe 4 NO 3 ) at 298.0 K [6,7].…”

Chelating agents for radiolanthanides: Applications to imaging and therapy

“…8). 70 The stability constants of the Sm(III) and Ho(III) complexes 71 12-membered tetraaza macrocycles with integrated pyridine rings are also well known.…”