Development of fluorine-18 labeled peptidic PET tracers for imaging active tissue transglutaminase

Berend van der Wildt, Micha M.M. Wilhelmus, Esther J.M. Kooijman, Cornelis A.M. Jongenelen, Robert C. Schuit, Christian Büchold, Ralf Pasternack, Adriaan A. Lammertsma, Benjamin Drukarch, Albert D. Windhorst

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Introduction The protein-protein crosslinking activity of the enzyme tissue transglutaminase (TG2; EC is associated with the pathogenesis of various diseases, including celiac disease, lung-, liver- and kidney fibrosis, cancer and neurodegenerative diseases. This study aims at developing a TG2 PET tracer based on the peptidic irreversible TG2 inhibitor Z006. Methods Initially, the carbon-11 labeling of Z006 at the diazoketone position was explored. Subsequently, a set of analogues that allow for fluorine-18 labeling was synthesized. Two potent analogues, 6f and 6g, were radiolabeled with fluorine-18 and biodistribution and metabolite analysis in Wistar rats was performed. The identity of the main metabolite of [18F]6g was elucidated using LC-MS/MS. In vitro binding to isolated TG2 and in vitro autoradiography on MDA-MB-231 breast cancer tissue using [18F]6g was performed. Results [18F]6f and [18F]6g were obtained in 20 and 9% yields, respectively. Following administration to healthy Wistar rats, rapid metabolism of both tracers was observed. Remarkably, full conversion to just one single metabolite was observed for one of the tracers, [18F]6g. By LC-MS/MS analysis this metabolite was identified as C-terminally saponified [18F]6g. This metabolite was also found to be a potent TG2 inhibitor in vitro. In vitro binding to isolated TG2 and in vitro autoradiography on MDA-MB-231 tumor sections using [18F]6g demonstrated high specific and selective binding of [18F]6g to active TG2. Conclusions Whereas based on the intensive metabolism [18F]6f seems unsuitable as a TG2 PET tracer, the results warrant further evaluation of [18F]6g in vivo.

Original languageEnglish
Pages (from-to)90-104
Number of pages15
JournalNuclear medicine and biology
Publication statusPublished - 1 Jan 2017


  • Fluorine-18
  • Irreversible TG2 inhibitors
  • MDA-MB-231
  • TG2
  • Tissue transglutaminase

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