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

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 4^th position of G-7039. A 2-fluoropropionic acid (2-FPA) group was added on to Lys⁵ to determine the potential binding affinity of the [¹⁸ F]-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.