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.

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

“…Importantly, the DFT-optimized structure of [Ba­(macropa-XL)] is generally consistent with the experimentally determined X-ray and EXAFS structural parameters described above (Table S5). Collectively, the results of our DFT optimizations indicate that macropa-XL can significantly rearrange its binding pocket and toggle between conformations to accommodate different cation sizes. − This rearrangement points to a somewhat more flexible and less preorganized scaffold for metal binding in comparison to macropa.…”

Size Selective Ligand Tug of War Strategy to Separate Rare Earth Elements

“…In general, ligands with donor groups connected to freely rotating single bonds that can achieve high complementarity with metal ions (e.g., DGAs) exhibit high affinities for lanthanides that are more Lewis acidic. − A combination of lipophilic DGA with hydrophilic dioxaoctanediamide results in improved selectivity for Gd over La (SF Gd/La = 100 or 1130 based on the size of N-alkyl substituents on DGAs). , This improvement is driven by dioxaoctanediamide exhibiting opposite selectivity to that of DGA, but is limited due to dioxaoctanediamide being a weaker extractant than DGA . Other ligands that show opposite selectivity across the trivalent lanthanide (Ln) series include substrates that incorporate conformational rigidity. ,− For example, lipophilic bis-lactam-1,10-phenanthrolines (BLPhen) , and macrocycles (macropa, , macrophosphi, and py-macrodipa) show high affinity for trivalent lanthanides having larger ionic radius. The latter are efficient chelators for radioisotopes in nuclear medicine applications at physiological pH. ,, Using neutral extractants allows for operating at a more comprehensive pH range.…”

“…Other ligands that show opposite selectivity across the trivalent lanthanide (Ln) series include substrates that incorporate conformational rigidity. ,− For example, lipophilic bis-lactam-1,10-phenanthrolines (BLPhen) , and macrocycles (macropa, , macrophosphi, and py-macrodipa) show high affinity for trivalent lanthanides having larger ionic radius. The latter are efficient chelators for radioisotopes in nuclear medicine applications at physiological pH. ,, Using neutral extractants allows for operating at a more comprehensive pH range. The extraction of REEs is sensitive to changes in anion concentration when using neutral ligands, as the anions accompany Ln ions in the partition process.…”

“… 50 Other ligands that show opposite selectivity across the trivalent lanthanide (Ln) series include substrates that incorporate conformational rigidity. 48 , 51 − 59 For example, lipophilic bis-lactam-1,10-phenanthrolines (BLPhen) 51 , 52 and macrocycles (macropa, 53 , 54 macrophosphi, 57 and py-macrodipa 58 ) show high affinity for trivalent lanthanides having larger ionic radius. The latter are efficient chelators for radioisotopes in nuclear medicine applications at physiological pH.…”

“…The latter are efficient chelators for radioisotopes in nuclear medicine applications at physiological pH. 58 , 60 , 61 Using neutral extractants allows for operating at a more comprehensive pH range. The extraction of REEs is sensitive to changes in anion concentration when using neutral ligands, as the anions accompany Ln ions in the partition process.…”