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

Abstract

[Abstract] 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.