Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa

Abstract

Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal-ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln³⁺), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for ¹³⁵La³⁺, ²¹³Bi³⁺, and ⁴⁴Sc³⁺ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py₂-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln³⁺ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py₂-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln³⁺ compared to py-macrodipa. By contrast, the kinetic stability of Ln³⁺ complexes with py₂-macrodipa is only improved for the light, large Ln³⁺ ions. Based upon these observations, we further assessed the suitability of py₂-macrodipa for use with ²²⁵Ac³⁺, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py₂-macrodipa to efficiently incorporate ²²⁵Ac³⁺ and to form a complex that is inert in human serum over 3 weeks. Although py₂-macrodipa does not surpass the state-of-the-art chelator macropa for ²²⁵Ac³⁺ chelation, it does provide another effective ²²⁵Ac³⁺ chelator. These studies shed light on the fundamental coordination chemistry of the Ln³⁺ series and may inspire future chelator design efforts.

Figure 1.

Crystal structures of (a) [La(py₂-macrodipa)]⁺ and (b) [Sc(py₂-macrodipa)(OH₂)]⁺ complexes. Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity.

Figure 2.

¹H NMR spectra of La³⁺−, Y³⁺−, Lu³⁺−, and Sc³⁺−py₂-macrodipa complexes (600 MHz, D₂O, pD 7, 25 °C). The yellow asterisks in the spectra of the La³⁺ and Y³⁺ complexes highlight the decrease in symmetry of Conformation A in moving from larger to smaller ions. The purple (Conformation A) and red (Conformation B) asterisks in the spectrum of the Lu³⁺ complex indicate the two conformers present in solution.

Figure 3.

DFT-computed standard free energy differences (ΔG°) between Conformations A and B for Ln³⁺−py₂-macrodipa complexes, plotted versus ionic radii.

Figure 4.

Stability constants of Ln³⁺ complexes formed with py₂-macrodipa, py-macrodipa, macrodipa, and macropa plotted versus ionic radii.

Figure 5.

Radiochemical yields (RCYs) of ²²⁵Ac³⁺ radiolabeling with py₂-macrodipa, macropa, and DOTA at different ligand concentrations (pH 6.0, 25 °C). (a) 5-min reaction time; (b) 60-min reaction time.

Figure 6.

The stability of [²²⁵Ac]Ac³⁺−py₂-macrodipa and [²²⁵Ac]Ac³⁺−macropa in human serum at 37 °C.

Scheme 1.

Depiction of the Conformational Toggle Present in Dual-Size-Selective Chelators when Binding Ln³⁺ Ions with Different Sizes.^{a a}Reproduced from J. Am. Chem. Soc. 2020, 142, 13500. Copyright 2020 American Chemical Society.

Scheme 2.

Synthetic Route to py₂-macrodipa.

Chart 1.

Structures of Ligands Discussed in This Work.