¹⁵³Sm and ¹⁶⁶Ho complexes with two series of tetraazamacrocyclic ligands containing methylcarboxylate and/or methylphosphonate pendant arms were synthesized and their charge, lipophilicity, protein binding and in vitro and in vivo behaviour evaluated. The first series has the same backbone, a 14-membered tetraazamacrocycle containing a pyridine unit with different pendant arms, namely methylcarboxylates (ac₃py14) or methylphosphonates (MeP₂py14 and P₃py14). The second series comprises 12- to 14-membered tetraazamacrocycles having methylcarboxylates and/or methylphosphonates as pendant arms (trans-DO2A2P, TRITA, TRITP, TETA and TETP). The ¹⁵³Sm/¹⁶⁶Ho complexes with the 14-membered tetraazamacrocycles containing the pyridine unit are neutral, hydrophilic, have a significant plasmatic protein binding, are unstable in vivo and present a slow rate of radioactivity excretion and high hepatic retention. ¹⁵³Sm/¹⁶⁶Ho complexes with the 12- to 14-membered tetraazamacrocycles are quantitatively prepared, except those with TETP. These complexes are hydrophilic, have an overall negative charge and present a medium to low plasmatic protein binding. The ¹⁵³Sm/¹⁶⁶Ho- trans-DO2A2P, ¹⁵³Sm/¹⁶⁶Ho-TRITA and ¹⁶⁶Ho-TRITP complexes are stable in vitro and in vivo, presenting a rapid clearance from main organs and a high rate of whole body radioactivity excretion. Biological profile of ¹⁵³Sm/¹⁶⁶Ho-TRITA complexes makes them promising candidates for therapy when conjugated to a biomolecule, while ¹⁶⁶Ho-TRITP is potentially useful for bone targeting due to its considerable uptake by bone.