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

Abstract

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⁺ ( <i>J. Am. Chem. Soc</i>, 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.