<p> The use of high flux research reactors, such as the High Flux Isotope Reactor (HFIR), to produce a wide variety of both industrial and medical isotopes has been well documented and proven to be economically feasible. However, due to the lack of access to these high flux facilities by most countries, isotope production methods utilizing reactors with low to moderate flux levels are needed, especially for short lived medical isotopes whose production must be relatively close to the location where they will be administered. In recent years medical isotopes that can both be used for treatment and diagnostic uses have become of great interest. One of the most popular of these theragnostic radionuclides is lutetium-177. Production of high-grade Lu-177 can be achieved in both high and low flux reactors through two different production methods. The current work looks to determine the feasibility of producing Lu-177 via the indirect route, using the relatively low flux of PUR-1. This will be accomplished through the use of high-fidelity models and simulations to predict the resulting production rates of the desired products. The results of these models and simulations will then be compared to the results obtained from the experimental irradiation of various samples of ytterbium oxide in PUR-1. Many studies have successfully produced Lu-177 using moderate and high flux reactors and several papers have studied the predicted production rate for low to moderate flux reactors by using the reported thermal flux of various research reactors and the reported cross-section values for ytterbium. A Monte Carlo based model of PUR-1 will be developed to determine the radiative capture reaction rates for the ytterbium targets across all neutron energies. This model in conjunction with a simplified MATLAB model, to solve the series of partial differential equations describing the production and decay of each product isotope, will be used to predict isotope production rates and will be compared to experimentally obtained results. </p>

The most promising applications for targeted alpha-therapy with astatine-211 (At-211) include treatments of disseminated microscopic disease, the major medical problem for cancer treatment. The primary advantages of targeted alpha-therapy with At-211 are that the alpha-particle radiation is densely ionizing, translating to high relative biological effectiveness (RBE), and short-range, minimizing damage to surrounding healthy tissues. In addition, theranostic imaging with I-123 surrogates has shown promise for developing new therapies with At-211 and translating them to the clinic. Currently, Canada does not have a way of producing At-211 by conventional methods because it lacks alpha-particle accelerators with necessary beam energy and intensity. The work presented here was aimed at studying the Rn-211/At-211 generator system as an alternative production strategy by leveraging TRIUMF's ability to produce rare isotopes. Recognizing that TRIUMF provided production opportunities for a variety of astatine isotopes, this work also originally hypothesized and evaluated the use of At-209 as a novel isotope for preclinical Single Photon Emission Computed Tomography (SPECT) with applications to At-211 therapy research. At TRIUMF's Isotope Separator and Accelerator (ISAC) facility, mass separated ion beams of short­-lived francium isotopes were implanted into NaCl targets where Rn-211 or At-209 were produced by radioactive decay, in situ. This effort required methodological developments for safely relocating the implanted radioactivity to the radiochemistry laboratory for recovery in solution. For multiple production runs, Rn-211 was quantitatively transferred from solid NaCl to solution (dodecane) from which At-211 was efficiently extracted and evaluated for clinical applicability. This validated the use of dodecane for capturing Rn-211 as an elegant approach to storing and shipping Rn-211/At-211 in the future. Po-207 contamination (also produced by Rn-211 decay) was removed using a granular tellurium (Te) column before proceeding with biomolecule labelling. Although the produced quantities were small, the pure At-211 samples demonstrated these efforts to have a clear path of translation to animal studies. For the first time in history, SPECT/CT was evaluated for measuring At-209 radioactivity distributions using high energy collimation. The spectrum detected for At-209 by the SPECT camera presented several photopeaks (energy windows) for reconstruction. The 77-90 Po X­-ray photopeak reconstructions were found to provide the best images overall, in terms of resolution/contrast and uniformity. Collectively, these experiments helped establish guidelines for determining the optimal injected radioactivity, depending on scan parameters. Moreover, At-209-based SPECT demonstrated potential for pursuing image-­based dosimetry in mouse tumour models, in the future. Simultaneous SPECT imaging with At-209 and I-123 was demonstrated to be feasible, supporting the future evaluation of At-209 for studying/validating I-123 surrogates for clinical image-based At-211 dosimetry. This work also pursued a novel strategy for labelling cancer targeting peptides with At-211, using octreotate (TATE, a somatostatin analogue for targeting tumour cells, mostly neuroendocrine tumours) prepared with or without N-terminus PEGylation (PEG2), followed by conjugation with a closo-decaborate linking moiety (B10) for attaching At-211. Binding affinity and in vivo biodistributions for the modified peptides were determined using iodine surrogates. The results indicated that B10-PEG2-TATE retained target binding affinity but that the labelling reaction with iodine degraded this binding affinity significantly, and although having high in vivo stability, no I-123-B10-PEG2-TATE tumour uptake was observed by SPECT in a mouse tumour model positive for the somatostatin receptor (sstr2a). This suggested that further improvements are required for labelling. A new method for producing At-211 at TRIUMF is established, and At-209-­based SPECT imaging is now demonstrated as a new preclinical technology to measure astatine biodistributions in vivo for developing new radiopharmaceuticals with At-211. Combined with the theranostic peptide labelling efforts with iodine, these efforts provide a foundation for future endeavours with At-211-­based alpha-therapy at TRIUMF. All procedures were performed safely and rapidly, suitable for preclinical evaluations. All animal studies received institutional ethics approval from the University of British Columbia (UBC). / Graduate