The role of Np(v) concentration as a potential chemical driver of Np(v) disproportionation was investigated by probing Np redox chemistry in two different acid media using visible-near-infrared absorbance spectroscopy. In situ spectroscopy of chemically and electrochemically manipulated Np oxidation states at molar concentrations of Np underscores the difficulty in stabilizing pure Np(v), even in dilute acid. A Np(vi) component coexisting with the majority Np(v) component was observed in both HNO3 and HCl. Electrochemical tuning and subsequent spectroscopic analysis of the Np(VI/V) ratio revealed neptunyl self-complexation as a key mechanism occurring in both acid media. Chemical reduction of the Np(vi) component and stabilization of a minor Np(iv) component in HNO3 were observed; however, spectral data indicated that these two oxidation states were not observed to coexist, and pure Np(v) was stabilized only briefly. These findings demonstrate that high Np concentrations significantly affect the redox chemistry of Np in acidic solutions. Finally, the occurrence of Np(v) disproportionation could not be definitely determined by spectral data, but other mechanisms such as self-complexation and radiolysis, which potentially compete with disproportionation, must be considered.

Trivalent lanthanides and actinides are difficult to separate, often relying on subtle differences in bonding between the 4f- and 5f-orbitals. However, trivalent Cm poses additional complexity owing to its half-filled 5f7 shell. This configuration causes Cm to have very similar properties to several of the early lanthanides, more specifically, similarly sized Pm. In this study, similarities were probed through isolating an isostructural series between the early lanthanides (La-Eu) and Cm with the oligoamine 2,2':6'2″-terpyridine in the presence of acid. Single-crystal X-ray diffraction studies highlighted the similarities of Pm and Cm under these conditions and further demonstrated the difficulty in separating these elements. Despite the similarities, differences exist between interactions of Pm and Cm with terpyridine in the solid state. Interestingly, Cm appears to be more similar to Sm than to Pm. Furthermore, this study continues to probe the fundamental chemistry of Pm and Cm with respect to slight differences that can be leveraged in their separation from each other.

Curium and promethium share similar chemical and physical properties thereby complicating their separation. Co-located processing at Oak Ridge National Laboratory results in curium contamination of the fission product stream containing promethium. To gain insight into the difficulty of this separation, the fundamental properties of these elements are experimentally and computationally probed in a 2,2':6',2"-terpyridine crystal system. Analysis of the isostructural compounds via single crystal X-ray diffraction and quantum theory of atoms in molecules reveals that bonding between promethium and curium is quite similar in this particular structure type. The small differences in the analysis of these two elements in this isostructural series sheds light on the difficulty required to separate the elements from each other. More so, this study develops the fundamental chemistries of two rare elements in the solid state and experimentally portrays the often-omitted position of promethium within the lanthanide series.

Antimony-119 (119Sb) is one of the most attractive Auger-electron emitters identified to date, but it remains practically unexplored for targeted radiotherapy because no chelators have been identified to stably bind this metalloid in vivo. In a departure from current studies focused on chelator development for Sb(III), we explore the chelation chemistry of Sb(V) using the tris-catecholate ligand TREN-CAM. Through a combination of radiolabeling, spectroscopic, solid-state, and computational studies, the radiochemistry and structural chemistry of TREN-CAM with 1XX/natSb(V) were established. The resulting [1XXSb]Sb-TREN-CAM complex remained intact for several days in human serum, signifying high stability under biological conditions. Finally, the first in vivo single photon emission computed tomography and positron emission tomography imaging studies were carried out using 117Sb, the diagnostic analogue of 119Sb. These studies revealed marked differences in the uptake and distribution of activity in mice administered unchelated [117Sb]Sb(OH)6 - versus [117Sb]Sb-TREN-CAM, suggesting that 117Sb is largely retained by TREN-CAM over the time course of the study. Collectively, these findings demonstrate the most physiologically stable complex of no-carrier-added 1XXSb yet reported, offering new promise for the clinical implementation of radioantimony in nuclear medicine. Our results also establish the feasibility of 117Sb as an elementally matched partner to 119Sb for theranostic applications.

Curium (244Cm) from the plutonium (238Pu) waste stream at Oak Ridge National Laboratory is coextracted with promethium (147Pm) because of similar chemical and physical properties. To gain insight for improving this separation, their fundamental properties are experimentally and computationally probed in a 2,2’:6’,2”-terpyridine crystal system. Analysis of the isostructural compounds via single crystal X-ray diffraction and quantum theory of atoms in molecules (QTAIM) revealed that although promethium (147Pm) and 244Cm share the same predicted VI-coordinate ionic radius, they have minute structural differences. Although the differences between Pm and Cm are subtle in this crystal system, insights for potentially optimizing the separation between 147Pm and 244Cm are gained. Furthermore, this study develops the chemistries of two rare elements in the solid state and experimentally portrays promethium’s often omitted position within the lanthanide series.

The structure and bonding of radium (Ra) is poorly understood because of challenges arising from its scarcity and radioactivity. Here we report the synthesis of a molecular Ra2+ complex using 226Ra and the organic ligand dibenzo-30-crown-10, and its characterization in the solid state by single-crystal X-ray diffraction. The crystal structure of the Ra2+ complex shows an 11-coordinate arrangement comprising the 10 donor O atoms of dibenzo-30-crown-10 and that of a bound water molecule. Under identical crystallization conditions, barium (Ba2+) yielded a 10-coordinate 'Pac-Man'-shaped structure lacking water. Furthermore, the bond distance between the Ra centre and the O atom of the coordinated water is substantially longer than would be predicted from the ionic radius of Ra2+ and by analogy with Ba2+, supporting greater water lability in Ra2+ complexes than in their Ba2+ counterparts. Barium often serves as a non-radioactive surrogate for radium, but our findings show that Ra2+ chemistry cannot always be predicted using Ba2+. Radium complexes are of interest for use as cancer therapeutic agents, but the structure and bonding are poorly understood. Here, the synthesis of a Ra2+ complex is reported, and the structure and bonding characteristics are elucidated using single-crystal X-ray diffraction.

To clinically advance the growing arsenal of radiometals available to image and treat cancer, chelators with versatile binding properties are needed. Herein, we evaluated the ability of the py2[18]dieneN6 macrocycle PYTA to interchangeably bind and stabilize 225Ac3+, [177Lu]Lu3+, [111In]In3+ and [44Sc]Sc3+, a chemically diverse set of radionuclides that can be used complementarily for targeted alpha therapy, beta therapy, single-photon emission computed tomography (SPECT) imaging, and positron emission tomography (PET) imaging, respectively. Through NMR spectroscopy and X-ray diffraction, we show that PYTA possesses an unusual degree of flexibility for a macrocyclic chelator, undergoing dramatic conformational changes that enable it to optimally satisfy the disparate coordination properties of each metal ion. Subsequent radiolabeling studies revealed that PYTA quantitatively binds all 4 radiometals at room temperature in just minutes at pH 6. Furthermore, these complexes were found to be stable in human serum over 2 half-lives. These results surpass those obtained for 2 state-of-the-art chelators for nuclear medicine, DOTA and macropa. The stability of 225Ac-PYTA and [44Sc]Sc-PYTA, the complexes having the most disparity with respect to metal-ion size, was further probed in mice. The resulting PET images (44Sc) and ex vivo biodistribution profiles (44Sc and 225Ac) of the PYTA complexes differed dramatically from those of unchelated [44Sc]Sc3+ and 225Ac3+. These differences provide evidence that PYTA retains this size-divergent pair of radionuclides in vivo. Collectively, these studies establish PYTA as a new workhorse chelator for nuclear medicine and warrant its further investigation in targeted constructs. PYTA is demonstrated to rapidly and stably complex 225Ac, 177Lu, 111In, and 44Sc, a "superfecta" of complementary but chemically distinct radiometals for targeted theranostic applications.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223Ra and 224Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra2+. A moderate log KML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind 223Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra2+ ion and contributes to the small, but growing, number of chelator development efforts for 223Ra-based TAT.

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 coordination chemistry of Ra2+ is poorly defined, hampering efforts to design effective chelators for 223Ra-based targeted alpha therapy. Here, we report the complexation thermodynamics of Ra2+ with the biomedically-relevant chelators DOTA and macropa. Our work reveals the highest affinity chelator to date for Ra2+ and advances our understanding of key factors underlying complex stability and selectivity for this underexplored ion.