Advisory Committee Chair
Suzanne Lapi
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Imaging using nuclear medicine techniques has enabled non-invasive measurements of biomarkers for a wide range of diseases including cancer and neurodegenerative disorders. The production and characterization of new radioisotopes are crucial steps in designing radiopharmaceuticals for nuclear imaging applications. 45Ti is a novel radionuclide with desired physical characteristics for use in Positron Emission Tomography (PET) imaging. The half-life of 3.08 h is ideal for the imaging of small peptides. In addition, the 45Ti decay by positron emission (85 %) and a low mean positron energy (0.439 MeV) offers high spatial resolution. The production route of 45Ti is straightforward due to the presence of monoisotopic target material. The nuclear cross-section for the production of 45Ti via the 45Sc(p,n)45Ti is high and the bulk of the excitation function can be captured using a 13 MeV cyclotron. Coordination chemistry of 45Ti has been somewhat challenging since Ti has a high hydrolysis potential and poor water solubility. Translating a radiopharmaceutical based on a metal that has poor aqueous chemistry is challenging in both the preclinical and clinical setting. This work aimed to identify chelators suitable for the development of 45Ti radiopharmaceuticals. Toward this goal, this work investigated the characterization of radiochemistry and in vivo imaging studies of novel chelators for 45Ti. Chelators that form stable complexes with 45Ti were identified which can be radiolabeled with 45Ti under physiological conditions and remain stable in vivo. 3,4-hydroxypyridinone, catechol and 1,2-hydroxypyridinone functional moieties were screened and chelators namely THPMe, TREN-CAM, L12-(3,2,3)-HOPO/C8-HOPO, L12-(3,3,3)-HOPO/C9-HOPO, L12-(3,4,3)-HOPO/C10-HOPO and HOPO-O6-C4 were tested for radiochemistry, in vitro stability, and in vivo imaging studies. Though all the chelators were found to radiolabel under physiological labeling conditions, in vitro stability studies show that THPMe, TREN-CAM, and C9-HOPO had the highest stability. In vivo PET imaging studies supported prior stability studies illustrating that TREN-CAM and C9-HOPO complexes were metabolically inert while THPMe indicated some signs of decomplexation. Additionally, the evaluation of targeting conjugates with 45Ti were investigated and studies were conducted with 45Ti based radiopharmaceuticals (THP-PSMA), which can target prostate cancer-specific PSMA receptors for PET imaging of tumors in vivo were. Overall, this work indicates the potential of 45Ti in nuclear medicine. Future studies may involve screening of more chelators for high in vivo stability and investigation of octadentate chelators. Functionalization of chelators to further investigate targeting conjugates is also desirable.
Recommended Citation
Shefali, Fnu, "Titanium-45 Radiochemistry For The Development Of Pet Radiopharmaceuticals" (2024). All ETDs from UAB. 3855.
https://digitalcommons.library.uab.edu/etd-collection/3855
