Radiolanthanide complexes with tetraazamacrocycles bearing methylphosphonate pendant arms as bone seeking agents

Radiolanthanide complexes with ligands bearing phosphonate groups have demonstrated their usefulness as bone seeking agents. Herein, we report on the synthesis of 153Sm and 166Ho complexes with 12- to 14-membered macrocycles containing different number of methylphosphonate pendant arms and their in vitro and in vivo evaluation in order to assess the effect of the cavity size and type of appended arms on their biological behavior.

Radioactive macrocycle complexes were prepared by reaction of (153)Sm/(166)Ho nitrates with four different tetraazamacrocycles bearing methylphosphonate groups. Radiochemical behavior, in vitro stability and charge of complexes were studied by chromatography and electrophoresis. The lipophilicity, plasmatic protein binding and adsorption onto hydroxyapatite (HA) were evaluated by in vitro assays. Biodistribution was assessed in CD-1 mice. Radiolabeling efficiency depends both on radionuclide and ligand structure. All the complexes are hydrophilic with an overall negative charge and relatively low protein binding. High in vitro stability in human serum and adsorption onto HA was found for all the complexes.

Biodistribution and in vivo stability studies have demonstrated promising biological profile for targeted radiotherapy, namely a rapid tissue clearance from most organs and rapid total excretion. Additionally, 166Ho-tritp has a high bone uptake, which led to high bone/ blood and bone/muscle ratios.

Our results clearly demonstrate that 12- and 13-membered macrocyclic ligands led to stable complexes with biological profile adequate to radionuclide therapy. The favorable in vivo behavior highlights the interest to further investigate these or closely related complexes to be used as bone seeking agents.