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.