Nuclear medicine leverages radioisotopes of a wide range of elements, a significant portion of which are metals, for the diagnosis and treatment of disease. To optimally use radioisotopes of the metal ions, or radiometals, for these applications, a chelator that efficiently forms thermodynamically and kinetically stable complexes with them is required. The chelator also needs to attach to a biological targeting vector that locates pathological tissues. Numerous chelators suitable for small radiometals have been established to date, but chelators that work well for large radiometals are significantly less common. In this Account, we describe recent progress by us and others in the advancement of ligands for large radiometal chelation with emerging applications in nuclear medicine.First, we discuss and analyze the coordination chemistry of the chelator macropa, a macrocyclic ligand that contains the 18-crown-6 backbone and two picolinate pendent arms, with large metal ions in the context of nuclear medicine. This ligand is known for its unusual reverse size selectivity, the preference for binding large over small metal ions. The radiolabeling properties of macropa with large radiometals 225Ac3+, 132/135La3+, 131Ba2+, 223Ra2+, 213Bi3+, and related in vivo investigations are described. The development of macropa derivatives containing different pendent donors or rigidifying groups in the macrocyclic core is also briefly reviewed.Next, efforts to transform macropa into a radiopharmaceutical agent via covalent conjugation to biological targeting vectors are summarized. In this discussion, two types of bifunctional analogues of macropa reported in the literature, macropa-NCS and mcp-click, are presented. Their implementation in different radiopharmaceutical agents is discussed. Bioconjugates containing macropa attached to small-molecule targeting vectors or macromolecular antibodies are presented. The in vitro and in vivo evaluations of these constructs are also discussed.Lastly, chelators with dual size selectivity are described. This class of ligands exhibits good affinities for both large and small metal ions. This property is valuable for nuclear medicine applications that require the simultaneous chelation of both large and small radiometals with complementary therapeutic and diagnostic properties. Recently, we reported an 18-membered macrocyclic ligand called macrodipa that attains this selectivity pattern. This chelator, its second-generation analogue py-macrodipa, and their applications for chelating the medicinally relevant large 135La3+, 225Ac3+, 213Bi3+, and small 44Sc3+ ions are also presented. Studies with these radiometals show that py-macrodipa can effectively radiolabel and stably retain both large and small radiometals. Overall, this Account makes the case for innovative ligand design approaches for novel emerging radiometal ions with unusual coordination chemistry properties.

Lanthanides (Ln3+) are critical materials used for many important applications, often in the form of coordination compounds. Tuning the thermodynamic stability of these compounds is a general concern, which is not readily achieved due to the similar coordination chemistry of lanthanides. Herein, we report two 18-membered macrocyclic ligands called macrodipa and macrotripa that show for the first time a dual selectivity toward both the light, large Ln3+ ions and the heavy, small Ln3+ ions, as determined by potentiometric titrations. The lanthanide complexes of these ligands were investigated by NMR spectroscopy and X-ray crystallography, which revealed the occurrence of a significant conformational toggle between a 10-coordinate Conformation A and an 8-coordinate Conformation B that accommodates Ln3+ ions of different sizes. The origin of this selectivity pattern was further supported by density functional theory (DFT) calculations, which show the complementary effects of ligand strain energy and metal-ligand binding energy that contribute to this conformational switch. This work demonstrates how novel ligand design strategies can be applied to tune the selectivity pattern for the Ln3+ ions.

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.

The radionuclides 225Ac3+ and 213Bi3+ possess favorable physical properties for targeted alpha therapy (TAT), a therapeutic approach that leverages α radiation to treat cancers. A chelator that effectively binds and retains these radionuclides is required for this application. The development of ligands for this purpose, however, is challenging because the large ionic radii and charge-diffuse nature of these metal ions give rise to weaker metal-ligand interactions. In this study, we evaluated two 18-membered macrocyclic chelators, macrodipa and py-macrodipa, for their ability to complex 225Ac3+ and 213Bi3+. Their coordination chemistry with Ac3+ was probed computationally and with Bi3+ experimentally via NMR spectroscopy and X-ray crystallography. Furthermore, radiolabeling studies were conducted, revealing the efficient incorporation of both 225Ac3+ and 213Bi3+ by py-macrodipa that matches or surpasses the well-known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that ∼90% of the 225Ac3+-py-macrodipa complex dissociates after 1 d. The Bi3+-py-macrodipa complex possesses remarkable kinetic inertness reflected by an EDTA transchelation challenge study, surpassing that of Bi3+-macropa. This work establishes py-macrodipa as a valuable candidate for 213Bi3+ TAT, providing further motivation for its implementation within new radiopharmaceutical agents.

Coordination compounds of the lanthanide ions (Ln3+) have important applications in medicine due to their photophysical, magnetic, and nuclear properties. To effectively use the Ln3+ ions for these applications, chelators that stably bind them in vivo are required to prevent toxic side effects that arise from localization of these ions in off-target tissue. In this study, two new picolinate-containing chelators, a heptadentate ligand OxyMepa and a nonadentate ligand Oxyaapa, were prepared, and their coordination chemistries with Ln3+ ions were thoroughly investigated to evaluate their suitability for use in medicine. Protonation constants of these chelators and stability constants for their Ln3+ complexes were evaluated. Both ligands exhibit a thermodynamic preference for small Ln3+ ions. The log KLuL = 12.21 and 21.49 for OxyMepa and Oxyaapa, respectively, indicating that the nonadentate Oxyaapa forms complexes of significantly higher stability than the heptadentate OxyMepa. X-ray crystal structures of the Lu3+ complexes were obtained, revealing that Oxyaapa saturates the coordination sphere of Lu3+, whereas OxyMepa leaves an additional open coordination site for a bound water ligand. Solution structural studies carried out with NMR spectroscopy revealed the presence of two possible conformations for these ligands upon Ln3+ binding. Density functional theory (DFT) calculations were applied to probe the geometries and energies of these conformations. Energy differences obtained by DFT are small but consistent with experimental data. The photophysical properties of the Eu3+ and Tb3+ complexes were characterized, revealing modest photoluminescent quantum yields of <2%. Luminescence lifetime measurements were carried out in H2O and D2O, showing that the Eu3+ and Tb3+ complexes of OxyMepa have two inner-sphere water ligands, whereas the Eu3+ and Tb3+ complexes of Oxyaapa have zero. Lastly, variable-temperature 17O NMR spectroscopy was performed for the Gd-OxyMepa complex to determine its water exchange rate constant of kex298 = (2.8 ± 0.1) × 106 s-1. Collectively, this comprehensive characterization of these Ln3+ chelators provides valuable insight for their potential use in medicine and garners additional understanding of ligand design strategies.