Oncotarget: A ghrelin receptor inverse agonist for positron emission tomography

Oncotarget published "Development of a ghrelin receptor inverse agonist for positron emission tomograph" which reported that 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 with nanomolar activity.

The authors developed novel compounds, derived from the potent inverse agonist K- -FwLL-NH2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid, palmitic acid and/or diethylene glycol 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.

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.

Dr. Ralf Bergmann from The Institute of Radiopharmaceutical Cancer Research as well as The Semmelweis University said, "The growth hormone secretagogue receptor type 1a (GHS-R1a) is the known biological relevant receptor of the endogenous ligand and pleiotropic hormone Ghrelin (acronym growth hormone release inducing), which mediates a broad range of complex biological functions [1], such as regulation of the body weight, body composition and energy expenditure."

"The growth hormone secretagogue receptor type 1a (GHS-R1a) is the known biological relevant receptor of the endogenous ligand and pleiotropic hormone Ghrelin (acronym growth hormone release inducing), which mediates a broad range of complex biological functions [1], such as regulation of the body weight, body composition and energy expenditure."

The occurrence of Ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of Ghrelin and further implicates acylated Ghrelin in pancreatic function.

Although widely studied as a promising drug target, the knowledge about Ghrelin signaling, behavior, dynamic interactions with its receptor and functional receptor expression in vivo is still limited and basic bioscientific research is warranted to further evaluate the safety and benefits of Ghrelin drug treatment in patients with cancer.

In order to develop imaging probes targeting the Ghrelin receptor, the inverse agonist radiotracer 68Ga-NODAGA-KwFwLL-NH2 1 was previously designed for PET imaging.

The focus of the present study was to develop potent inverse agonist radiotracers targeting the Ghrelin receptor as potential imaging and therapeutic agent.

Furthermore, they demonstrated specific binding to GHS-R1a and imaging of tumors and normal tissues expressing the Ghrelin receptor with 64Cu2 - and 68Ga3 -radiolabeled inverse agonist NODAGA-KK- -FwLL-NH2 in xenografted prostate tumor models in mice.

Figure 13: Immunoblots of GHS-R1a in lysates of DU-145 and PC-3 cell cultures, xenografts and Control. Type-A samples were heated to 100°C for 10 min and GHS-R1a was detected using the primary antibody ab170690; type-B samples were incubated at 37°C for 10 min and GHS-R1a was detected using the primary antibody ARG-031; mouse stomach served as positive control. (GAPDH) glyceraldehyde 3-phosphate dehydrogenase served as loading control.

The Bergmann Research Team concluded in their Oncotarget Research Output that the data support that the studied radiometal Ghrelin inverse agonists could be used for the imaging of functional expression of Ghrelin receptors in vivo that these radiotracers have the potential to gain a deeper understanding on Ghrelin and its receptors in vivo in health and disease, in particular, in cancer.

The Ghrelin binding, constitutively active growth hormone secretagogue receptor type 1a has been imaged and quantified by the developed novel compounds, structurally based on the potent inverse agonist KK- -FwLL-NH2 that were evaluated for receptor binding and efficacy in vitro.

In the biodistribution experiments the 10c reached at two hours a 2.68 ± 1.11 SUV in the tumor and could be blocked by Ghrelin and KKD to 1.28 ± 0.22 SUV and 1.26 ± 0.34 SUV, respectively.

In addition, the biodistribution 10c in rats and mice showed specific accumulation of the radiotracers in GHS-R1a expressing tissues, like stomach and thyroid in which the radiotracer uptake has been partially blocked by KKD.

The Cu- or Ga-NODAGA-NH-K-K- -F-w-L-L-NH2 radiolabeled inverse agonists with respect to its relative simple synthesis, high affinity and medium efficacy, high metabolic stability, and the suitable pharmacokinetic profiles, seem to be potent, and safe leads of future imaging agents for visualization and quantitation of GHS-R1a expression in normal and cancer tissues by PET. The GHS-R1a in vivo imaging and quantitation has the potential to serve as biomarkers of the Ghrelin system in precision medicine.

DOI - https://doi.org/10.18632/oncotarget.27895

Full text - https://www.oncotarget.com/article/27895/text/

Correspondence to - Ralf Bergmann - r.bergmann@hzdr.de

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

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