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Front. Chem. | doi: 10.3389/fchem.2018.00121

Evaluation of fluorine-18-labelled alpha1(I)-N-telopeptide analogues as substrate-based radiotracers for PET imaging of melanoma-associated lysyl oxidase

 Reik Löser1, 2*, Manuela Kuchar1, 2, Christin Neuber1, Birgit Belter1, Ralf Bergmann1, Jens Lenk1, 2, Robert Wodtke1, 2, Torsten Kniess1, Jörg Steinbach1, 2 and  Jens Pietzsch1, 2
  • 1Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany
  • 2Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Germany

Accumulating evidence suggests an unequivocal role of lysyl oxidases as key players of tumour progression and metastasis, which renders this enzyme family highly attractive for targeted non-invasive functional imaging of tumours. Considering their function in matrix remodelling, malignant melanoma appears as particularly interesting neoplasia in this respect. For the development of radiotracers that enable PET imaging of the melanoma-associated lysyl oxidase activity, substrates derived from the type I collagen alpha1 N-telopeptide were labelled with fluorine-18 using succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) as prosthetic reagent. With regards to potential crosslinking to tumour-associated collagen in vivo, their interaction with triple-helical type I collagen was studied by SPR. A mouse model of human melanoma was established on the basis of the A375 cell line, for which the expression of the oncologically relevant lysyl oxidase isoforms LOX and LOXL2 was demonstrated in Western blot and immunohistochemical experiments. The radiopharmacological profiles of the peptidic radiotracers were evaluated in normal rats and A375 melanoma-bearing mice by ex vivo metabolite analysis, whole-body biodistribution studies and dynamic PET imaging. Out of three 18F-labelled telopeptide analogues, the one with the most favourable substrate properties has shown favourable tumour uptake and tumour-to-muscle ratio. Lysyl oxidase-mediated tumour uptake was proven by pharmacological inhibition using β-aminopropionitrile and by employing negative-control analogues of impeded or abolished targeting capability. The latter were obtained by substituting the lysine residue by ornithine and norleucine, respectively. Comparing the tumour uptake of the lysine-containing peptide with that of the non-functional analogues indicate the feasibility of lysyl oxidase imaging in melanoma using substrate-based radiotracers.

Keywords: lysyl oxidase, Collagen, Extracellular Matrix, Molecular Imaging, pharmacokinetics

Received: 12 Feb 2018; Accepted: 30 Mar 2018.

Edited by:

Simona Rapposelli, Università degli Studi di Pisa, Italy

Reviewed by:

Kyeongsoon Park, Chung-Ang University, South Korea
Heebeom Koo, Catholic University of Korea, South Korea  

Copyright: © 2018 Löser, Kuchar, Neuber, Belter, Bergmann, Lenk, Wodtke, Kniess, Steinbach and Pietzsch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Reik Löser, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany,