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

## TL;DR

Researchers developed new acyclic chelators that could replace traditional macrocyclic ones for radiopharmaceuticals involving actinium and lanthanides.

## Contribution

A new family of four-arm, high-denticity acyclic chelators is introduced as an alternative to macrocyclic chelators for radiopharmaceuticals.

## Key findings

- H4 tpaond achieved 96% radiolabeling efficiency comparable to gold standard macrocyclic chelators.
- H4 tpaen and H4 tpaopd are suitable for 225Ac/155Tb theranostic pairs.
- H4 asyoctapa is promising for terbium and 177Lu/155Tb radiopharmaceuticals.

## 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 (H4
tpaen), o-phenylene (H4
tpaopd), 2,3-naphtylene (H4
tpaond), m-xylylene (H4
tpamxd), p-xylylene
(H4
tpapxd), and 2-hydroxypropylene (H4
tpadapo), and two dissymmetrical octadentate
ligands, H3
tripaen and H4
asyoctapa, structurally derived from H4
tpaen 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 H2
macropa and H4
crown, H4
tpaond is an excellent candidate for the development of radiopharmaceuticals
based on 225Ac. In addition, both H4
tpaen and H4
tpaopd are also an opportunity for
the 225Ac/155Tb theranostic pair. Meanwhile,
H4
asyoctapa appears to be a great opportunity,
not only for developing terbium radiopharmaceuticals, but also for
the promising 177Lu/155Tb pair.