Synthesis and Radiopharmacological Characterisation of a Fluorine-18-Labelled Azadipeptide Nitrile as a Potential PET Tracer for invivo Imaging of Cysteine Cathepsins

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 effi...

Full description

Saved in:
Bibliographic Details
Published in:ChemMedChem 2013-08, Vol.8 (8), p.1330
Main Authors: Loser, Reik, Bergmann, Ralf, Frizler, Maxim, Mosch, Birgit, Dombrowski, Lilli, Kuchar, Manuela, Steinbach, Jörg, Gutschow, Michael, Pietzsch, Jens
Format: Article
Language:English
Subjects:
Medical imaging
Tomography
Tumors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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-[18F]fluoroethylnosylate as a prosthetic agent. The pharmacokinetic properties of the resulting radiotracer compound were studied invitro, exvivo and invivo 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 18F-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 invivo despite their disadvantageous pharmacokinetics. [PUBLICATION ABSTRACT]
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201300135