Synthesis and radiopharmacological characterisation of a fluorine-18 labelled azadipeptide nitrile as potential PET Tracer for in vivo imaging of cysteine cathepsins


Synthesis and radiopharmacological characterisation of a fluorine-18 labelled azadipeptide nitrile as potential PET Tracer for in vivo imaging of cysteine cathepsins

Löser, R.; Bergmann, R.; Frizler, M.; Mosch, B.; Dombrowski, L.; Kuchar, M.; Steinbach, J.; Gütschow, M.; Pietzsch, J.

A fluorinated cathepsin inhibitor based on the azadipeptide nitrile chemotype was prepared and selected for 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 using 2-[18F]fluoroethyl nosylate as 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 (PET). These investigations revealed the rapid conjugate formation of the tracer with glutathione in the blood associated with a 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 using specific antibodies. This indicates that azadipeptide nitriles have the potential to target thiol-dependent cathepsins in vivo despite their disadvantageous pharmacokinetics.

Keywords: cathepsins; glutathione; molecular imaging; small animal positron emission tomography; tumour-associated proteolysis

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Publ.-Id: 18783