Development of a ghrelin receptor inverse agonist for positron emission tomography

Abstract

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-NH 2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1glutaric 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-NH 2 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-NH 2 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-NH 2 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.

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“…Recent efforts have been devoted to the development of PET imaging agents targeting GHS-R1a, with the aim to image and target this receptor for diagnosis and treatment of different diseases, especially cancer and cardiovascular disorders, as well as for the study of the localization and functions of GHS-R1a in the body. Though several studies have been focused on ghrelin analogues and peptide derivatives, − as stated above, in this section we will only discuss radiopharmaceutical nonpeptide small molecules. In particular, fluorine-containing molecules with high GHS-R1a affinity have been identified to be radiolabeled with 18 F, one of the most common radioisotopes used for PET imaging …”