Radiometals possess an exceptional breadth of decay properties and have been applied to medicine with great success for several decades. The majority of current clinical use involves diagnostic procedures, which use either positron-emission tomography (PET) or single-photon imaging to detect anatomic abnormalities that are difficult to visualize using conventional imaging techniques (e.g., MRI and X-ray). The potential of therapeutic radiometals has more recently been realized and relies on ionizing radiation to induce irreversible DNA damage, resulting in cell death. In both cases, radiopharmaceutical development has been largely geared toward the field of oncology; thus, selective tumor targeting is often essential for efficacious drug use. To this end, the rational design of fourcomponent radiopharmaceuticals has become popularized. This Review introduces fundamental concepts of drug design and applications, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance. Also presented are detailed accounts of production, chelation chemistry, and biological use of selected main group and rare earth radiometals.

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (Hdpaa), phosphonate (Hdppa), and bisphosphonate (Hdpbpa), as well as their nonfunctionalized analogue (Hdpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of Hdpa, Hdpaa, and Hdppa, the 1:2 lanthanum(III) complex of Hdpa, and the 1:1 gallium(III) complex of Hdpaa were characterized, including via X-ray crystallography for [La(dppa)(HO)] and [Ga(dpaa)(HO)]. Hdpa, Hdpaa, and Hdppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (Hdpaa) or NMR spectrometric (Hdpa and Hdppa) titrations, which showed that the carboxylate (Hdpaa) and phosphonate (Hdppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log β and pM values) at physiological pH. In addition, potentiometric titrations with Hdpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log P values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides Ga, radiolabeling studies were performed withGa and Hdpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10 M, and human serum stability studies were undertaken.

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)­pharmaceuticals. Three ligands (H6phospa, H6dipedpa, H6eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H6phospa and H6dipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions. These methods were particularly useful in discerning structural information for Sc3+ and La3+ complexes. Solution studies were conducted to evaluate the complex stability of 15 metal complexes. As a general trend, H6phospa was noted to form the most stable complexes, and H6eppy associated with the least stable complexes. Moreover, In3+ complexes were determined to be the most stable, and complexes with La3+ were the least stable, across all metals. Density functional theory (DFT) was employed to calculate structures of H6phospa and H6dipedpa complexes with La3+ and Sc3+. A comparison of experimental 1H NMR spectra with calculated 1H NMR spectra using DFT-optimized structures was used as a method of structure validation. It was noted that theoretical NMR spectra were very sensitive to a number of variables, such as ligand configuration, protonation state, and the number/orientation of explicit water molecules. In general, the inclusion of an explicit second shell of water molecules qualitatively improved the agreement between theoretical and experimental NMR spectra versus a polarizable continuum solvent model alone. Formation constants were also calculated from DFT results using potential-energy optimized structures. Strong dependence of molecular free energies on explicit water molecule number, water molecule configuration, and protonation state was observed, highlighting the need for dynamic data in accurate first-principles calculations of metal–ligand stability constants.

Trivalent lanthanum (La) has the potential to treat bone resorption disorders (such as osteoporosis) by eliciting a bone-building response in the cells which control skeletal remodelling. Because La suffers from extremely poor intestinal absorption, specifically designed chelators are required in order that a biologically active form of lanthanum can be administered orally. Two such chelators, 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdpp) and bis-{[bis(carboxymethyl)amino]methy}phosphinic acid (HXT), have previously been the subjects of extensive physical, in vitro, and in vivo testing as the tris- and mono-lanthanum(iii) complexes La(dpp) and La(XT), respectively. In this manuscript, we expand upon those studies to include 4-week intravenous (IV) and oral La biodistribution profiles, which show that the metal ion initially accumulates in the liver followed by preferential redistribution and retention by bone. Of the two compounds, La(XT) demonstrates the more favourable in vivo characteristics, therefore dose-dependent oral biodistribution studies were carried out with this complex. These show drug saturation above a dose of 100 mg kg day, so liver histology was performed in order to assess any potential toxicity. Finally, we improve upon the physical characterization of La(dpp) to include a single crystal X-ray structure, which exhibits an 8-coorindate La centre with two bound water molecules, and a disordered exoclathrate-type hydrogen bonded network.

A 7-membered triprotic heterocycle, DEDA-(PO), was synthesized, characterized, and tested for its solution properties with three trivalent lanthanides (La, Gd, and Lu) and three biologically relevant divalent metal ions (Ca, Zn, and Cu). The ligand synthesis has been reported once before; however, the characterization results were previously misinterpreted to correspond to a larger, 14-membered heterocycle, TETA-(PO). This manuscript serves to correct the original paper. Potentiometric titrations were carried out with each of the metal ions, and the thermodynamic stability values in terms of log β and log K were calculated showing a 1:1 metal-to-ligand ratio preference for the divalent metal ions and a 1:2 ratio for the lanthanides. The stability of the 1:2 complexes decreased across the lanthanide series, presumed to be a steric effect. Further resolution to the potentiometry results was given via pH-dependent NMR spectrometry (with La) and pH-dependent UV-vis spectroscopy (with Cu), and the pM values were calculated for all metal ions. The solid-state structure of the 1:1 Cu-DEDA-(PO) complex was further characterized by X-ray crystallography.

A phosphinate-bearing picolinic acid-based chelating ligand (H6dappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In3+, Lu3+, Y3+, Sc3+, La3+, Bi3+). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of H6dappa with four metal ions (In3+, Lu3+, Y3+, Sc3+) was deeply investigated via potentiometric and spectrophotometric (UV–vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand–ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([111In]­In3+, [177Lu]­Lu3+, [90Y]­Y3+), and the serum stability of [111In]­[In­(dappa)]3– was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that H6dappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [111In]­In3+ and [177Lu]­Lu3+, respectively. For H6dappa, high thermodynamic stability did not correlate with kinetic inertnesslability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.

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Purpose The purpose of this study was to evaluate the efficacy and toxicity of a novel lanthanum compound, La(XT), in an ovariectomized (OVX) rat model of osteoporosis. Methods Twenty-four ovariectomized female Sprague Dawley rats were divided into 3 groups receiving a research diet with/without treatment compounds (alendronate: 3 mg/kg; La(XT) 100 mg/kg) for three months. At the time of sacrifice, the kidney, liver, brain, lung and spleen were collected for histological examination. The trabecular bone structure of the tibiae was evaluated using micro-CT and a three-point metaphyseal mechanical test was used to evaluate bone failure load and stiffness. Results No significant differences were noted in plasma levels of calcium, phosphorus, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) between the La(XT) treatment compared to the non-treated OVX group. Alendronate-treated animals (positive control) showed higher BV/TV, Tb.N and lower Tb.Th and Tb.Sp when compared to the non-treated OVX group. Mechanical analysis indicated that stiffness was higher in the alendronate (32.88%, p = 0.04) when compared to the non-treated OVX group. Failure load did not differ among the groups. Conclusions No kidney or liver toxicities of La(XT) treatments were found during the three-month study. The absence of liver and kidney toxicity with drug treatment for 3 months, as well as the increased trabecular bone stiffness are encouraging for the pursuit of further studies with La(XT) for a longer duration of time.