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

Area of Science:

• Medicinal Chemistry
• Molecular Imaging
• Oncology

Background:

• The ghrelin receptor (GHS-R1a) is a G-protein-coupled receptor found in healthy tissues and various cancers, including prostate, testicular, and ovarian.
• Targeting GHS-R1a with fluorine-18 labeled compounds could enable Positron Emission Tomography (PET) imaging for cancer detection.
• The natural ligand, ghrelin, has poor in vivo stability, limiting its use in imaging applications.

Purpose of the Study:

• To design and synthesize novel, stable ghrelin analogues with high affinity for the GHS-R1a.
• To develop a fluorine-18 labeled ghrelin analogue for PET imaging of GHS-R1a expressing carcinomas.
• To identify the shortest ghrelin analogue capable of high-affinity binding to GHS-R1a.

Main Methods:

• Chemical synthesis of modified ghrelin(1-8) analogues with alterations at specific residues.
• Synthesis of a novel 6-fluoro-2-pentafluorophenyl naphthoate (PFPN) prosthetic group for fluorine-18 incorporation.
• In vitro binding assays to determine the affinity (IC50) of the synthesized analogues for GHS-R1a.

Main Results:

• The lead analogue, [Inp¹,Dpr³(6-fluoro-2-naphthoate),1-Nal⁴,Thr⁸]ghrelin(1-8), demonstrated a high affinity with an IC50 of 0.11 nM, representing a 28-fold improvement over natural ghrelin.
• This analogue is the shortest ghrelin analogue reported to date that binds GHS-R1a with higher affinity than full-length ghrelin.
• A novel PFPN prosthetic group suitable for fluorine-18 radiolabeling was successfully synthesized.

Conclusions:

• Novel ghrelin analogues, particularly the lead compound, exhibit significantly enhanced affinity and stability for the GHS-R1a.
• The developed fluorine-18 labeled ghrelin analogue holds promise for sensitive and specific PET imaging of GHS-R1a-expressing cancers.
• This research provides a foundation for developing advanced molecular imaging agents for cancer diagnostics.