Paul Schaffer

Targeted alpha therapies using actinium-225 (²²⁵Ac, t₁/₂ = 9.9 d) can treat advanced metastatic disease, yet insufficient ²²⁵Ac availability limits their development (63 GBq/year is produced globally via ²²⁹Th generators). This thesis describes efforts to produce ²²⁵Ac and apply multi-nuclide SPECT imaging in preclinical evaluation of ²²⁵Ac-radiopharmaceuticals. Initial ²²⁵Ac production used ᴺᵃᵗU-spallation-produced and mass-separated ion beams, producing up to 8.6 MBq of ²²⁵Ra (an ²²⁵Ac parent) and 18 MBq of ²²⁵Ac. This material helped characterize the performance of ²²⁵Ac decay chain imaging on a microSPECT/PET/CT scanner in terms of contrast recovery, spatial resolution, and noise. Larger ²²⁵Ac quantities were produced via thorium target irradiation with a 438 MeV, 72 μA proton beam for 36 hours, producing (521 ±18) MBq of ²²⁵Ac and (91 ± 14) MBq of ²²⁵Ra. These irradiations enabled ²³²Th(p,x) cross sections measurements for ²²⁵Ac, ²²⁵Ra, and ²²⁷Ac: (13.3 ± 1.2) mb, (4.2 ± 0.4) mb, and (17.7 ± 1.7) mb, respectively. Thirty-five other cross sections were measured and compared to FLUKA simulations; measured and calculated values generally agree within a factor of two. Ac separation from irradiated thorium and co-produced radioactive by-products used a thorium peroxide precipitation followed by cation exchange and extraction chromatography. Studies showed this method separates Ac from most elements, providing a directly-produced Ac product (²²⁷˒²²⁵Ac†) with measured ²²⁷Ac content of (0.15 ± 0.04)%, a hazardous long-lived (t₁/₂ = 21.8 y) impurity with prohibitively low waste disposal limits. A second, indirectly-produced ²²⁵Ra/²²⁵Ac-generator-derived Ac product (²²⁵Ac*) with ²²⁷Ac content of
View record

Cancer progression and metastasis are driven by certain molecular features that are either non-existent or abnormally active in normal cells. These features are often exploited by medical scientists for the development of targeted therapies and/or imaging probes to better diagnose and stratify patients. In this thesis, we report the investigation of novel radiotracers designed to measure oxidative stress and the use of amino acids as alternative sources of energy, both associated with malignant transformation and resulting in upregulation of different amino acid transporters (AATs). Oxidative stress has been implicated as a feature of aggressive cancer types, particularly those with poor prognosis. System xC- is an antiporter of cystine and glutamate, which is upregulated under oxidative stress and overexpressed in many cancers including triple-negative breast cancer and glioblastoma. System xC- provides cells with a substrate for antioxidant synthesis. This transporter can be studied by positron emission tomography (PET) using ¹⁸F-fluoroaminosuberic acid ([¹⁸F]FASu). [¹⁸F]FASu is hypothesized to be a specific substrate for system xC- activity. The work herein explores the relationship between [¹⁸F]FASu uptake and system xC- transporter activity, and whether this can be used for cancer diagnosis and treatment response monitoring. We studied system xC- activity and overexpression in vitro and used [¹⁸F]FASu in vivo to monitor intratumoural changes following radiotherapy. We evaluated a novel [¹⁸F]FASu analogue, [¹⁸F]ASu-BF3, synthesized via an alternative radiolabelling method. Additionally, we compared [¹⁸F]FASu to two other PET radiopharmaceuticals in vivo, one of which also targets system xC-. Finally, this thesis also explores a novel radiolabelling methodology and biological characterisation of a number of radiofluorinated leucine derivatives, substrates for another AAT, LAT1. LAT1 is highly upregulated in several cancers and at metastatic sites. LAT1 is a poor prognostic biomarker in cancer patients. It is associated with mTOR pathway activation, through which amino acids are being imported and used as substrates for protein biosynthesis. This research presents effective methodology for producing LAT1 substrates for the purposes of cancer imaging with PET. Collectively, this research provides a non-invasive platform for the characterization of two AAT proteins, both of which play a role in cancer development and progression.

View record