title: Synthesis and radiopharmacological characterisation of a fluorine-18-labelled azadipeptide nitrile as a potential PET tracer for in vivo imaging of cysteine cathepsins.
abstract: A fluorinated cathepsin inhibitor based on the azadipeptide nitrile chemotype was prepared and selected for positron emission tomography (PET) tracer development owing to its high affinity for the oncologically relevant cathepsins L, S, K and B. Labelling with fluorine-18 was accomplished in an efficient and reliable two-step, one-pot radiosynthesis by using 2-[(18) F]fluoroethylnosylate as a prosthetic agent. The pharmacokinetic properties of the resulting radiotracer compound were studied in vitro, ex vivo and in vivo in normal rats by radiometabolite analysis and small-animal positron emission tomography. These investigations revealed rapid conjugate formation of the tracer with glutathione in the blood, which is associated with slow blood clearance. The potential of the developed (18) F-labelled probe to image tumour-associated cathepsin activity was investigated by dynamic small-animal PET imaging in nude mice bearing tumours derived from the human NCI-H292 lung carcinoma cell line. Computational analysis of the obtained image data indicated the time-dependent accumulation of the radiotracer in the tumours. The expression of the target enzymes in the tumours was confirmed by immunohistochemistry with specific antibodies. This indicates that azadipeptide nitriles have the potential to target thiol-dependent cathepsins in vivo despite their disadvantageous pharmacokinetics.
authors.affiliation: Institut für Radiopharmazeutische Krebsforschung, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany. r.loeser@hzdr.de
authors.forename: Reik
authors.initials: R
authors.lastname: Löser
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Maxim
authors.initials: M
authors.lastname: Frizler
authors.forename: Birgit
authors.initials: B
authors.lastname: Mosch
authors.forename: Lilli
authors.initials: L
authors.lastname: Dombrowski
authors.forename: Manuela
authors.initials: M
authors.lastname: Kuchar
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging; D009570:Nitriles / Q000737:chemistry*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D001372:Aza Compounds; D004151:Dipeptides; D005462:Fluorine Radioisotopes; D009570:Nitriles; D019275:Radiopharmaceuticals; D002403:Cathepsins
keywords: cathepsins; fluorine; glutathione; imaging agents; positron emission tomography; radiochemistry