F-18 Labelled cathepsin inhibitors as potential radiotracers for tumour imaging


F-18 Labelled cathepsin inhibitors as potential radiotracers for tumour imaging

Löser, R.; Frizler, M.; Bergmann, R.; Dombrowski, L.; Knieß, T.; Gütschow, M.; Steinbach, J.

Ziel/Aim:

The enzyme class of thiol-dependent cathepsins has been shown to be linked to the progression of cancer in multiple ways. Particularly crucial is their involvement in proteolytic pathways that are related to tumour invasion and metastasis (1).
The aim was the design of a fluorine-containing inhibitor of the azadipeptide nitrile chemotype (2) and the labelling with the radionuclide F-18 to evaluate the potential of this inhibitor class for functional tumour imaging by PET and to gain insight into the pharmacokinetic behaviour of these inhibitors.

Methodik/Methods:

The fluorine atom was connected by an ethylene bridge to the inhibitor core structure and the affinities of the resulting compound to its targets were determined in kinetic enzyme assays. Labelling with F-18 was achieved by fluoroethylation with different substituted [18F]2-fluoroethyl benzenesulfonates (3). The stability of the tracer against chemical and enzymatic degradation as well as its metabolic fate in rat blood was investigated and its biodistribution was studied in vivo by small animal PET.

Ergebnisse/Results:

The fluorine containing azadipeptide nitrile Gue2011 exhibits inhibition constant in the single-digit to subnanomolar range against the oncologically relevant cathepsins L, S, and B. Among the various F-18 fluoroethylating agents tested, [18F]2-fluoroethyl nosylate revealed as the most efficient one. This enabled the two-step radiosynthesis of [18F]Gue2011 in an average RCY (dc) of 24 % (n = 6). Metabolite analysis in rat blood showed the rapid conversion of the tracer into its glutathione conjugate as indicated by HPLC. Studies towards the pharmacological prevention of this conjugate formation are under current investigation.

Schlussfolgerungen/Conclusions:

With Gue2011 a highly potent fluorine-containing cathepsin inhibitor was found and its labelling with fluorine-18 could be successfully established. The compounds suitability as PET tracer for functional tumour imaging seems to be limited due to its inherent thiol reactivity. The radiolabelling of other cathepsin inhibitors is underway.

Literatur/References:

(1) Mohamed, M. M.; Sloane B. F. Nat. Rev. Cancer 2006, 6, 764-775
(2) Löser, R. et al. Angew. Chem. Int. Ed. 2008, 47, 4331-4334
(3) Musachio, J. L.; Shah, J.; Pike V. W. J. Label. Compd. Radiopharm. 2005, 48, 735-747

  • Poster
    Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Nuklearmedizin 2011, 13.-16.04.2011, Bregenz, Österreich
  • Abstract in refereed journal
    Nuklearmedizin 50(2011), A118
    ISSN: 0029-5566

Permalink: https://www.hzdr.de/publications/Publ-15545
Publ.-Id: 15545