Innovative strategies for PET-radiotracer discovery and development
Innovative strategies for PET-radiotracer discovery and development
Positron emission tomography (PET) is an essential molecular imaging technique for clinical diagnosis, pharmacological research, and drug development. Its broader application, however, remains constrained by the limited availability of suitable radiotracers, the short half-lives of commonly used radionuclides, inefficient precursor utilization, time-consuming purification, and the high cost of tracer production. This thesis of Siyu Xiao explores innovative radiochemical strategies to accelerate PET-radiotracer discovery and improve production efficiency, with a particular focus on carbon-11 and fluorine-18 chemistry.
First, multicomponent reactions (MCRs) are reviewed and investigated as rapid, modular, and atom-economical tools for isotope labeling and precursor synthesis. Using the Ugi-azide reaction, libraries of boronic acid pinacol ester tetrazoles were synthesized as potential precursors for brain PET tracers. Building on this strategy, a multiplexed fluorine-18 radiolabeling workflow was developed, enabling multiple arylBpin precursors to be radiolabeled in a single one-pot reaction and purified by one HPLC procedure, thereby increasing throughput and reducing resource consumption. In addition, this thesis describes the development of carbon-11-labeled PLX5622 for brain imaging, providing mechanistic insight into selective radiolabeling of tautomeric pyridone/pyridinol systems. Finally, a reusable react-and-release precursor strategy was established using solid-supported precursors, allowing repeated radiolabeling cycles and simplifying purification.
Together, these studies demonstrate practical approaches to make PET-radiotracer development faster, more efficient, and more sustainable, while supporting systematic evaluation of new tracer candidates for molecular imaging.