Research Papers:

Development of a ghrelin receptor inverse agonist for positron emission tomography

Ralf Bergmann _, Constance Chollet, Sylvia Els-Heindl, Martin Ullrich, Nicole Berndt, Jens Pietzsch, Domokos Máthé, Michael Bachmann and Annette G. Beck-Sickinger

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Oncotarget. 2021; 12:450-474. https://doi.org/10.18632/oncotarget.27895

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Ralf Bergmann1,2,*, Constance Chollet3,*, Sylvia Els-Heindl3, Martin Ullrich1, Nicole Berndt1, Jens Pietzsch1,6, Domokos Máthé2, Michael Bachmann1,4,5 and Annette G. Beck-Sickinger3

1 Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany

2 Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary

3 Institute of Biochemistry, Faculty of Life Sciences, Universität Leipzig, Leipzig, Germany

4 Tumor Immunology, University Cancer Center, Carl Gustav Carus Technische Universität Dresden, Dresden, Germany

5 National Center for Tumor Diseases, Carl Gustav Carus Technische Universität Dresden, Dresden, Germany

6 Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany

* These authors contributed equally to this work

Correspondence to:

Ralf Bergmann,email: [email protected]

Keywords: cancer; prostate cancer; growth hormone secretagogue receptor (GHS-R); small animal imaging; copper-64

Received: November 05, 2020     Accepted: February 01, 2021     Published: March 02, 2021

Copyright: © 2021 Bergmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Imaging of Ghrelin receptors in vivo provides unique potential to gain deeper understanding on Ghrelin and its receptors in health and disease, in particular, in cancer. Ghrelin, an octanoylated 28-mer peptide hormone activates the constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) with nanomolar activity. We developed novel compounds, derived from the potent inverse agonist K-(D-1-Nal)-FwLL-NH2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), palmitic acid and/or diethylene glycol (PEG2) to allow radiolabeling and improve pharmacokinetics, respectively. All compounds were tested for receptor binding, potency and efficacy in vitro, for biodistribution and -kinetics in rats and in preclinical prostate cancer models on mice. Radiolabeling with Cu-64 and Ga-68 was successfully achieved. The Cu-64- or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiotracer were specifically accumulated by the GHS-R1a in xenotransplanted human prostate tumor models (PC-3, DU-145) in mice. The tumors were clearly delineated by PET. The radiotracer uptake was also partially blocked by K-(D-1-Nal)-FwLL-NH2 in stomach and thyroid. The presence of the GHS-R1a was also confirmed by immunohistology. In the arterial rat blood plasma, only the original compounds were found. The Cu-64 or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiolabeled inverse agonists turned out to be potent and safe. Due to their easy synthesis, high affinity, medium potency, metabolic stability, and the suitable pharmacokinetic profiles, they are excellent tools for imaging and quantitation of GHS-R1a expression in normal and cancer tissues by PET. These compounds can be used as novel biomarkers of the Ghrelin system in precision medicine.

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