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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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

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