13- and 14-membered macrocyclic ligands containing methylcarboxylate or methylphosphonate pendant arms: Chemical and biological evaluation of their 153Sm and 166Ho complexes as potential agents for therapy or bone pain palliation

The stability constants of La3+, Sm3+ and Ho3+ complexes with 13- and 14-membered macrocycles having methylcarboxylate (trita and teta) or methylphosphonate (tritp and tetp) arms were determined. All the ligands were labelled with 153Sm and 166Ho in order to evaluate the effect of the macrocyclic cavity size and type of appended arms on their in vitro and in vivo behaviour. The radiolabelling efficiency was found to be higher than 98% for all the complexes, except for those of tetp. All radiocomplexes studied are hydrophilic with an overall negative charge and low plasmatic protein binding. Good in vitro stability in physiological media and human serum was found for all complexes, except the 153Sm/166Ho-teta, which are unstable in phosphate buffer (pH 7.4). In vitro hydroxyapatite (HA) adsorption studies indicated that 153Sm/166Ho-tritp complexes bind to HA having the 166Ho complex the highest degree of adsorption (>80%, 10 mg). Biodistribution studies in mice demonstrated that 153Sm/166Ho-trita complexes have a fast tissue clearance with more than 95% of the injected activity excreted after 2 h, value that is comparable to the corresponding dota complexes. In contrast, the 153Sm-teta complex has a significantly lower total excretion. 153Sm/166Ho-tritp complexes are retained by the bone, particularly 166Ho-tritp that has 5-6% (% I.D./g) bone uptake and also a high rate of total excretion. Thus, these studies support the potential interest of 153Sm/166Ho-trita complexes for therapy when conjugated to a biomolecule and the potential usefulness of the 166Ho-tritp complex in bone pain palliation.