Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes

Nuclear medicine leverages different
types of radiometals for disease
diagnosis and treatment, but these applications usually require them
to be stably chelated. Given the often-disparate chemical properties
of these radionuclides, it is challenging to find a single chelator
that binds all of them effectively. Toward addressing this problem,
we recently reported a macrocyclic chelator macrodipa with an unprecedented
“dual-size-selectivity” pattern for lanthanide (Ln3+) ions, characterized by its high affinity for both the large
and the small Ln3+ (J. Am. Chem. Soc, 2020, 142, 13500). Here, we describe a second-generation
“macrodipa-type” ligand, py-macrodipa. Its coordination
chemistry with Ln3+ was thoroughly investigated experimentally
and computationally. These studies reveal that the Ln3+–py-macrodipa complexes exhibit enhanced thermodynamic and
kinetic stabilities compared to Ln3+–macrodipa,
while retaining the unusual dual-size selectivity. Nuclear medicine
applications of py-macrodipa for chelating radiometals with disparate
chemical properties were assessed using the therapeutic 135La3+ and diagnostic 44Sc3+ radiometals
representing the two size extremes within the rare-earth series. Radiolabeling
and stability studies demonstrate that the rapidly formed complexes
of these radionuclides with py-macrodipa are highly stable in human
serum. Thus, in contrast to gold standard chelators like DOTA and
macropa, py-macrodipa can be harnessed for the simultaneous, efficient
binding of radiometals with disparate ionic radii like La3+ and Sc3+, signifying a substantial achievement in nuclear
medicine. This concept could enable the facile incorporation of a
breadth of medicinally relevant radiometals into chemically identical
radiopharmaceutical agents. The fundamental coordination chemistry
learned from py-macrodipa provides valuable insight for future chelator
development.