Rigidified 18-membered hexaaza macrocycle, H₄pyta (18-py₂N₄Ac₄), as an efficient chelator for large metal radionuclides

Complexes of macrocyclic ligands are commonly utilized in many medicinal applications, such as MRI contrast agents and radiopharmaceuticals. Due to their thermodynamic stability and kinetic inertness, they overcome toxicity of free heavy metal ions and, thus, enable their use in vivo. However, there is no “general” ligand suitable for any metal ion in the periodic table and, thus, useful chelator should be specially designed for each metal ion. Among metal radionuclides, there is an increasing interest in those of large elements (i.e. large metal ions) to be used for both, radiotherapy and imaging. The 18-memberred macrocycles are suitable scaffolds for the utilizations.
This contribution deals with chemistry and radiochemistry of H4pyta (18-py2N4Ac4), a parent rigidified macrocycle suitable for large metal ions. Although the ligand was synthesized in mid-nineties, there are almost no data focused on its possible utilization in radiopharmaceutical context.[2] The ligand forms thermodynamically stable complexes with Ln(III) ions. Its ten donor atoms completely wrap the large Ln(III) ions but one pendant arm is not coordinated for small Ln(III) ions. Thus, the early Ln(III) ions form more stable complexes. The Ln(III)-H4pyta complexes are 2–3 orders of magnitude more kinetically inert than those of H4dota and, thus, they will be fully stable in vivo.
Radiolabeling of H4pyta with 133La and 177Lu is, at different pH’s and temperatures, comparable with that of H4dota. Challenging experiments showed that these radiolabeled H4pyta complexes are fully resistant to transmetallation and transchelation, and show very high stability in human blood serum stability. For larger 133La, the results are much better if compared with data obtained for H4dota and macropa in the parallel experiments. For smaller 177Lu, the results are also more promising compared to those of H4dota and its analogues.
This ligand shows that the H4pyta (18-py2N4Ac4) scaffold offers new possibilities for design of chelators for radioisotopes of large metal ions from the bottom of the Periodic Table, e.g. 225Ac, and the data are promising for future conjugations and in vivo applications.