Developing a broadly applicable and facile radiolabeling method for PET imaging

Positron emission tomography (PET) is on the forefront of cancer diagnosis, clinical drug evaluation, and patient management. Among the numbers of β+-emitting nuclides, ¹⁸F (t₁/₂=109.8 min) is a mainstay isotope for PET imaging owing to its excellent nuclear properties and on-demand production at Curie levels. Despite the success of PET and increasing interests of ¹⁸F-radiochemistry, a facile ¹⁸F-labeling method that can be broadly applied to biomolecules has been a long-standing challenge. Most known ¹⁸F-labeling methods are relatively onerous and lengthy processes, which is a particularly serious problem given the short half-life of ¹⁸F. This thesis describes the design, synthesis and in vivo evaluation of novel ¹⁸F-radioprosthetics based on B-¹⁸F formation, and aims at developing a facile and broadly applicable ¹⁸F-labeling method for PET imaging. Previously, the Perrin group has established ¹⁸F-aryltrifluoroborates as a promising radiosynthon to radiolabel bioligands. In light of this success, this thesis has dedicated to expand B-¹⁸F labeling method from a scientific design to a generic clinical-friendly tool for developing new PET tracers. The first highlight of this thesis is to create new labeling methods (Chapter 4 and Chapter 5) to increase the specific activity of ¹⁸F-radiotracers to 15 Ci/μmol, which is about a magnitude higher than normal maximum. The second highlight is to discover a heretofore-unknown linear correlation between the solvolytic stability for a given organotrifluoroborate and the pKa of the corresponding carboxylic acids (Chapter 3). This discovery has fundamental interests for Suzuki-Miyaura coupling and also leads me to find a novel B-¹⁸F radiosynthon that combines high in vivo stability and “kit-like” ¹⁸F-labelling technology, which is the third highlight and also the core of this body of work (Chapter 6). Along with this, numbers of bioligands have been biologically evaluated, and some of them demonstrate excellent in vivo performance. Particularly, TATE-AMBF₃, which is an octreotate derivative, showing the best performance of any ligands for imaging somatostatin receptors in several decades (Chapter 7). In addition, for seamless bench-to-bed translation, a dual-modal strategy of synthesizing fluorescent PET tracer is presented (Chapter 8).Science, Faculty ofChemistry, Department ofGraduat