3 years ago

Structure–Activity Study of Ghrelin(1–8) Resulting in High Affinity Fluorine-Bearing Ligands for the Ghrelin Receptor

Structure–Activity Study of Ghrelin(1–8) Resulting in High Affinity Fluorine-Bearing Ligands for the Ghrelin Receptor
Savita Dhanvantari, Mark S. McFarland, Leonard G. Luyt, Carlie L. Charron, Michael S. Kovacs, Jinqiang Hou
The ghrelin receptor, also known as the growth hormone secretagogue receptor 1a (GHS-R1a), is a G-protein-coupled receptor that is differentially expressed in healthy tissue and several cancers, including prostate, testicular, and ovarian. Selectively targeting the ghrelin receptor using fluorine-18 tagged entities would allow localization and visualization of ghrelin receptor expressing carcinomas using PET imaging. The endogenous ligand ghrelin, a 28 amino acid peptide with 3.1 nM affinity, has poor in vivo stability. Here we report on ghrelin(1–8) analogues bearing modifications at residues 1, 3, 4, and 8. The lead analogue, [Inp1,Dpr3(6-fluoro-2-naphthoate),1-Nal4,Thr8]ghrelin(1–8), possessed an IC50 value of 0.11 nM that is a 28-fold improvement compared to the natural ligand. A novel 6-fluoro-2-pentafluorophenyl naphthoate (PFPN) prosthetic group was synthesized to incorporate fluorine-18 for PET imaging. This is not only the highest affinity ghrelin analogue reported but also the shortest ghrelin analogue capable of binding GHS-R1a with better affinity than ghrelin(1–28).

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00164

DOI: 10.1021/acs.jmedchem.7b00164

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