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

详细信息    查看全文

• 作者：Berend van der Wildt^a ; ^b ; ^{b.vanderwildt@vumc.nl} ; Micha M.M. Wilhelmus^b ; Esther J.M. Kooijman^a ; Cornelis A.M. Jongenelen^b ; Robert C. Schuit^a ; Christian Bü ; chold^c ; Ralf Pasternack^c ; Adriaan A. Lammertsma^a ; Benjamin Drukarch^b ; Albert D. Windhorst^a
• 关键词：Tissue transglutaminase ; TG2 ; Fluorine-18 ; Irreversible TG2 inhibitors ; MDA-MB-231
• 刊名：Nuclear Medicine and Biology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：44
• 期：Complete
• 页码：90-104
• 全文大小：1274 K
• 卷排序：44

文摘

The protein–protein crosslinking activity of the enzyme tissue transglutaminase (TG2; EC 2.3.2.13) 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.MethodsInitially, 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.ConclusionsWhereas based on the intensive metabolism [18F]6f seems unsuitable as a TG2 PET tracer, the results warrant further evaluation of [18F]6gin vivo.