While widely used in bioassays, the spectrofluorimetric method described here uses the antenna effect as a tool to probe the thermodynamic parameters of ligands that sensitize lanthanide luminescence. The Eu3+ coordination chemistry, solution thermodynamic stability and photophysical properties of the spermine-based hydroxypyridonate octadentate chelator 3,4,3-LI(1,2-HOPO) are reported. The complex [EuIII(3,4,3-LI(1,2-HOPO))]- luminesces with a long lifetime (805 mu s) and a quantum yield of 7.0percent in aqueous solution, at pH 7.4. These remarkable optical properties were exploited to determine the high (and proton-independent) stability of the complex (log beta 110 = 20.2(2)) and to define the influence of the ligand scaffold on the stability and photophysical properties.

In the past few decades, targeted radionuclide therapy has emerged as a potential strategy for combatting cancer. Through the delivery of alpha, beta-minus, or Auger electron emitting radionuclides to diseased tissue via targeting vectors, targeting radiopharmaceuticals can deal cytotoxic damage to cancerous cells while minimizing damage to healthy tissue. Furthermore, applying the theranostic approach, where a diagnostic radionuclide is delivered using the same targeting vector, allows targeted radionuclide therapy to become more personalized, potentially making these treatments more effective. This strategy allows for using the same targeting radiopharmaceutical for both diagnostics and therapy. This enables patient-specific dosimetry, the ability to predict the response for a given therapy, improved treatment planning, and monitoring of the ongoing treatment. Unfortunately, widespread use of the theranostic approach faces a variety of challenges in order to make theranostics more obtainable. This dissertation seeks to advance targeting radiopharmaceuticals for theranostic applications by investigating a novel companion diagnostic radionuclide, 134Ce, as a companion diagnostic for both 225Ac and 227Th. In addition, the use of the chelator 3,4,3-LI(1,2-HOPO) (HOPO) was investigated with 134Ce, the 90Y/86Y theranostic pair, and 225Ac. HOPO has the potential to be a “theranostic chelator” due to its affinity for a variety of strategic trivalent and tetravalent radiometals. Furthermore, a novel elution strategy for 224Ra/212Pb generators was benchmarked which could facilitate the use of the 212Pb/203 Pb theranostics in clinical settings. Lastly, the use of Siderocalin fusion proteins, which could pave the doorway for the development of antibody-based “cold-kits” thereby allowing for the rapid, room temperature labeling of monoclonal antibodies for targeted radionuclide therapy, was explored. The actinide radionuclides 225Ac and 227Th have recently shown great clinical and preclinical success for targeted radionuclide therapy due to their long decay chain which emits 4 or 5 α particles and their lack of a long-lived decay product. Unfortunately, neither of these radionuclides can be suitably imaged by contemporary molecular imaging modalities including positron emission tomography (PET) or single photon emission computed tomography (SPECT). Furthermore, there is not an actinium or thorium isotope that allows for PET or SPECT imaging. To address this need a surrogate diagnostic radionuclide with chemically similar properties using the in vivo generator system 134Ce/134La was investigated since it can be imaged by PET and has an unique redox chemistry that allows 134Ce to be stabilized as 134CeIII to mimic 225AcIII or as 134CeIV to mimic 227ThIV. The surrogacy of 134Ce/134La is investigated by assaying the biodistribution and in vivo stability of 134Ce complexes (134CeIII-DTPA, 134CeIII-DOTA, and 134CeIV-HOPO) through microPET imaging of a murine model. All of these complexes displayed high in vivo stability and rapid pharmacokinetics, and they all had negligible residual activity 24 hours after administration. Furthermore, the long half-life of 134Ce (3.2 days) allows for it to be compatible with antibody drug conjugates. This compatibility is investigated through microPET imaging 134CeIII-DOTA-Trastuzumab in a SK-OV-3 tumor-bearing murine model. Because of the high in vivo stability of 134Ce-DOTA and long half-life of 134Ce, 134Ce-DOTA-Trastuzumab displayed elevated tumor uptake for up to 9 days after administration and has a similar biodistribution to 225Ac -DOTA -Trastuzumab. These proof of concept studies open the doorway for the development of targeting radiopharmaceuticals incorporating 134Ce. 86YIII (a positron emitter) and 90YIII (a β- emitter) are rare earth metal theranostic pairs that facilitate the implementation of the theranostic approach due to both the therapeutic and diagnostic radionuclides having identical chemistry. Due to HOPO’s affinity for trivalent radiometals, HOPO can rapidly form highly stable yttrium complexes at room temperature, unlike DTPA or DOTA which are commonly used for 90Y/86Y theranostics. Through in vivo microPET imaging, the biodistribution and in vivo stability of 86Y-HOPO are assayed in a murine model. 86Y-HOPO displayed high in vivo stability and rapid pharmacokinetics, and it had negligible residual activity 24 hours after administration which is valuable for future work investigating yttrium-based targeting radiopharmaceuticals. 212Pb, another promising α emitting radionuclide, is available in a convenient 224Ra/212Pb generator and has a diagnostic matched pair available, 203Pb, which allows for SPECT imaging. A new elution strategy that directly yields 212Pb in a more favorable electrolytic solution (1.0 M sodium acetate) for radiolabeling, circumventing the need for long evaporation and redissolution processes, is benchmarked by a series of radiolabeling experiments comparing this new strategy to the conventional one. Through two weeks of labeling experiments, this elution strategy minimized the time needed to elute the 225Ra/212Pb, and it maintained a high radiochemical yield and radiochemical purity while labeling 212Pb to TCMC-Trastuzumab conjugates. This novel elution strategy can facilitate the use of 224Ra/212Pb generators in clinical settings allowing a more widespread implementation of 212Pb/203Pb theranostics. Siderocalin fusion proteins allow for a novel way to deliver therapeutic radionuclides to diseased sites. Because of Siderocalin’s ability to non-covalently bind to highly stable, negatively charged metal-HOPO complexes, these fusion proteins can allow for rapid, room temperature radiolabeling compared to DOTA which requires high temperatures in order for quantitative radiolabeling. In order to investigate their tumor targeting and tumor control properties, ex vivo biodistribution and tumor control experiments are performed with 225Ac and 90Y labeled fusion proteins in a SK-OV-3 tumor-bearing murine model. While 225Ac labeled fusion proteins were not able to display elevated uptake in tumors due to the low in vivo stability of 225Ac-HOPO, the 90Y fusion proteins were able to display tumor uptake within 50 hours. With further development, these Siderocalin fusion proteins can potentially become the blueprint for antibody-based “cold-kits”.

Purifying the f-elements is necessary for nuclear waste remediation, diagnostic or therapeuticmedical applications, and to enable fundamental chemistry with these relatively rare elements. These separations are challenging because the lanthanides (Ln) and minor actinides (An) often share an oxidation state (M(III)) and have similar ionic radii, precluding common techniques like size exclusion chromatography. This dissertation considers the separations and fundamental chemistry of specific f-elements in two decay chains - 227Ac and 254Es - as well as lower-Z analogs Gd, Ce and Cs. Ac is interesting to study because it has the largest ionic radius of all the f-elements and is more difficult to chelate, but an effective chelator in biological systems is necessary to facilitate 225Ac targeted alpha therapies. A series of solution thermodynamic experiments using liquid/liquid extraction (LLE) probes the efficacy of eleven linear molecules as Ac chelators and compares those results to Gd as an analogous lanthanide. In general, the ligands chelates Gd more strongly than Ac, although the two phosphonic acids studied effectively retain Ac in the aqueous phase at lower concentrations than necessary for Gd retention. The octadentate hydroxypyridinone-based ligand 3,4,3-LI(1,2-HOPO) (343HOPO), which has been widely used for separations and fundamental investigations of the actinides, demonstrates similar behavior to diethylenetriamine pentaacetate (DTPA), a commonly used ligand in nuclear waste LLE systems. 343HOPO outperforms three catecholamide-containing ligands with the same backbone, and also outperforms the other carboxylic acids evaluated. In addition to this Ac solution chemistry, fundamental properties of the last two Group 1 metals, Cs and Fr, were explored using 137Cs and 223Fr via a different LLE system. Three crown ethers with increasing cavity sizes were compared for each element, and the results indicate a surprisingly similar size match between the two metals. These experiments present the first set of solution thermodynamic measurements conducted with a pure stream of Fr, and the first with 223Fr (t1/2 = 22 min); previous experiments have used 225Ac as an in situ generator of the short-lived 221Fr (t1/2 = 4.7 min). To produce this pure stream, a column-based scheme for rapid separation of 227Ac from its daughters 227Th, 223Fr, and 223Ra was developed, which can be used to obtain radio- and chemically-pure 223Fr as frequently as every 3 hours for at least 14 days. In addition, the procedure provides clean streams of the other 227Ac daughters, 227Th and 223Ra, both of which could be used as other targeted alpha therapy agents. A final set of column separation experiments consider schemes to separate Es/Bk/Cf, including a novel ionic exchange resin-based separation of Bk from Cf using 343HOPO's unique oxidizing power to change the overall charge of the Bk(343HOPO) complex. Furthering characterization of f-element-343HOPO complexes, 254Es(343HOPO) luminescence was measured, corroborating previous measurements of a blue shift upon Es complexation in contrast with the other actinides, which are red-shifted upon complexation. X-ray absorption spectroscopy (XAS) measurements of 254Es(343HOPO) and Ce(IV/III)(343HOPO) are also presented. The 254Es(343HOPO) XAS measurements include the first measurement of the elemental white line (closely corresponding to theory) and unexpectedly short M-O bond lengths, indicating a potential break in the An series. The Ce(343HOPO) measurements show beam-induced reduction of the complexed metal, demonstrating 343HOPO's remarkable oxidizing power, and providing a potential explanation for the challenges experienced in measuring Bk(IV)(343HOPO) via XAS despite solutions-based measurements that clearly demonstrate that oxidation state. Some initial forays into other ligands that mimic 343HOPO's oxidation of Ce are also presented, again with an eye toward biologically-relevant ligands and/or systems where Ce can be replaced with Bk. A final chapter considers the history of nuclear isotope production, evaluating the extent to which super heavy element researchers and research facilities can be considered science diplomacy, rather than 'mere' international science. While the common taxonomies of science diplomacy emphasize scientists' actions instead of state participation, a state-centered analysis that evaluates the dichotomy of competition and cooperation in the field concludes that some nations pursue the discovery of new elements for the science while others have international agendas.