title: Development of fluorine-18 labeled peptidic PET tracers for imaging active tissue transglutaminase.
abstract: 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.
  
  
  
  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.
  
  
  
  [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.
  
  
  
  Whereas based on the intensive metabolism [18F]6f seems unsuitable as a TG2 PET tracer, the results warrant further evaluation of [18F]6gin vivo.
authors.affiliation: Radiology & Nuclear Medicine, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands; Anatomy & Neurosciences, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands. Electronic address: b.vanderwildt@vumc.nl.
authors.forename: Berend
authors.initials: B
authors.lastname: van der Wildt
authors.affiliation: Anatomy & Neurosciences, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Micha M M
authors.initials: MM
authors.lastname: Wilhelmus
authors.affiliation: Radiology & Nuclear Medicine, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Kooijman
authors.affiliation: Anatomy & Neurosciences, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: Jongenelen
authors.affiliation: Radiology & Nuclear Medicine, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.affiliation: ZEDIRA GmbH, D-64293, Darmstadt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Büchold
authors.affiliation: ZEDIRA GmbH, D-64293, Darmstadt, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Pasternack
authors.affiliation: Radiology & Nuclear Medicine, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Anatomy & Neurosciences, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drukarch
authors.affiliation: Radiology & Nuclear Medicine, VU University Medical Center, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000215:Acylation; D000818:Animals; D005462:Fluorine Radioisotopes; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007553:Isotope Labeling; D008297:Male; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D010455:Peptides; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Fluorine-18; Irreversible TG2 inhibitors; MDA-MB-231; TG2; Tissue transglutaminase