ABSTRACT
BACKGROUND: Positron emission tomography (PET) is a powerful, non-invasive preclinical and clinical nuclear imaging technique used in disease diagnosis and therapy assessment. Fluorine-18 is the predominant radionuclide used for PET tracer synthesis. An impressive variety of new 'late-stage' radiolabeling methodologies for the preparation of 18F-labeled tracers has appeared in order to improve the efficiency of the labeling reaction. MAIN BODY: Despite these developments, one outstanding challenge into the early key steps of the process remains: the preparation of reactive [18F]fluoride from oxygen-18 enriched water ([18O]H2O). In the last decade, significant changes into the trapping, elution and drying stages have been introduced. This review provides an overview of the strategies and recent developments in the production of reactive [18F]fluoride and its use for radiolabeling. CONCLUSION: Improved, modified or even completely new fluorine-18 work-up procedures have been developed in the last decade with widespread use in base-sensitive nucleophilic 18F-fluorination reactions. The many promising developments may lead to a few standardized drying methodologies for the routine production of a broad scale of PET tracers.
ABSTRACT
INTRODUCTION: Tissue transglutaminase (TG2) is a ubiquitously expressed enzyme capable of forming metabolically and mechanically stable crosslinks between the γ-carboxamide of a glutamine acyl-acceptor substrate and the ε-amino functionality of a lysine acyl-donor substrate resulting in protein oligomers. High TG2 crosslinking activity has been implicated in the pathogenesis of various diseases including celiac disease, cancer and fibrotic and neurodegenerative diseases. Development of a PET tracer specific for active TG2 provides a novel tool to further investigate TG2 biology in vivo in disease states. Recently, potent irreversible active site TG2 inhibitors carrying an acrylamide warhead were synthesized and pharmacologically characterized. METHODS: Three of these inhibitors, compound 1, 2 and 3, were successfully radiolabeled with carbon-11 on the acrylamide carbonyl position using a palladium mediated [(11)C]CO aminocarbonylation reaction. Ex vivo biodistribution and plasma stability were evaluated in healthy Wistar rats. Autoradiography was performed on MDA-MB-231 tumor sections. RESULTS: [(11)C]1, -2 and -3 were obtained in decay corrected radiochemical yields of 38-55%. Biodistribution showed low uptake in peripheral tissues, with the exception of liver and kidney. Low brain uptake of <0.05% ID/g was observed. Blood plasma analysis demonstrated that [(11)C]1 and [(11)C]2 were rapidly metabolized, whereas [(11)C]3 was metabolized at a more moderate rate (63.2 ± 6.8 and 28.7 ± 10.8% intact tracer after 15 and 45 min, respectively). Autoradiography with [(11)C]3 on MDA-MB-231 tumor sections showed selective and specific binding of the radiotracer to the active state of TG2. CONCLUSIONS: Taken together, these results identify [(11)C]3 as the most promising of the three compounds tested for development as PET radiotracer for the in vivo investigation of TG2 activity.
