Challenging the Macrocycle Paradigm: Four-Arm, High-Denticity Acyclic Chelators for Radiopharmaceuticals Incorporating Actinium and Lanthanides

As an alternative to macrocyclic chelators, a family of high-denticity, acyclic chelating agents based on picolinate arms has been devised with the aim of finding versatile chelating agents for ²²⁵Ac, ¹⁶¹Tb, and ¹⁷⁷Lu. This family comprises six symmetrical four-arm decadentate chelators that differ in the nature of the backbone spacer, ethylene (H₄tpaen), o-phenylene (H₄tpaopd), 2,3-naphtylene (H₄tpaond), m-xylylene (H₄tpamxd), p-xylylene (H₄tpapxd), and 2-hydroxypropylene (H₄tpadapo), and two dissymmetrical octadentate ligands, H₃tripaen and H₄asyoctapa, structurally derived from H₄tpaen by the loss of one arm (the first) and the replacement of two vicinal picolinate pendent arms by acetate groups (the second). The coordination chemistry of each chelating ligand with nonradioactive Lu³⁺, Tb³⁺, and La³⁺ (the latter as a surrogate for [²²⁵Ac]Ac³⁺) has been explored to rationalize the findings in radiolabeling and human serum stability studies. With an RCY of 96% at 10⁻⁷ M, which is directly comparable to the gold standard macrocyclic chelators H₂macropa and H₄crown, H₄tpaond is an excellent candidate for the development of radiopharmaceuticals based on ²²⁵Ac. In addition, both H₄tpaen and H₄tpaopd are also an opportunity for the ²²⁵Ac/¹⁵⁵Tb theranostic pair. Meanwhile, H₄asyoctapa appears to be a great opportunity, not only for developing terbium radiopharmaceuticals, but also for the promising ¹⁷⁷Lu/¹⁵⁵Tb pair.