Single Amino Acid Replacement in G‐7039 Leads to a 70‐fold Increase in Binding toward GHS‐R1a

Abstract

The growth hormone secretagogue receptor type 1a (GHS‐R1a) is a class A rhodopsin‐like G protein coupled receptor (GPCR) that is expressed in a variety of human tissues and is differentially expressed in benign and malignant prostate cancer. Previously, the peptidomimetic [1‐Nal4,Lys5(4‐fluorobenzoyl)]G‐7039 was designed as a molecular imaging tool for positron emission tomography (PET). However, this candidate was a poor binder (IC50=69 nm), required a lengthy four‐step radiosynthesis, and had a cLogP above 8. To address these challenges, we now report on changes targeted at the 4th position of G‐7039. A 2‐fluoropropionic acid (2‐FPA) group was added on to Lys5 to determine the potential binding affinity of the [18F]‐2‐FP radiolabeled analogue, which could be prepared by simplified radiochemistry. Lead candidate [Tyr4,Lys5(2‐fluoropropionyl)]G‐7039 exhibited an IC50 of 0.28 nm and low picomolar activity toward GHS‐R1a. Molecular docking revealed a molecular basis for this picomolar affinity.