科研之友
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摘要
Introduction: Tissue transglutaminase (TG2) is a ubiquitously expressed enzyme capable of forming metabolically and mechanically stable crosslinks between the gamma-carboxamide of a glutamine acyl-acceptor substrate and the epsilon-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 I, 2 and 3, were successfully radiolabeled with carbon-11 on the acrylamide carbonyl position using a palladium mediated [C-11]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: [C-11]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 [C-11] and [C-11]2 were rapidly metabolized, whereas [C-11]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 [C-11]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 [C-11]3 as the most promising of the three compounds tested for development as PET radiotracer for the in vivo investigation of TG2 activity.
- 出版日期2016-4
