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Synthesis and Radiopharmacological Characterisation of a Fluorine‐18‐Labelled Azadipeptide Nitrile as a Potential PET Tracer for in vivo Imaging of Cysteine Cathepsins
Author(s) -
Löser Reik,
Bergmann Ralf,
Frizler Maxim,
Mosch Birgit,
Dombrowski Lilli,
Kuchar Manuela,
Steinbach Jörg,
Gütschow Michael,
Pietzsch Jens
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300135
Subject(s) - in vivo , cathepsin , positron emission tomography , chemistry , radiosynthesis , ex vivo , imaging agent , nitrile , preclinical imaging , in vitro , biochemistry , nuclear medicine , enzyme , medicine , biology , microbiology and biotechnology , organic chemistry
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.