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 [Lys5(4-fluorobenzoyl-4-FB)]G7039 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 has a cLogP above 5. To address these challenges, we now report on changes targeted to the 4th position of G7039. A 2-fluoropropionic acid (2-FPA) group was added on to Lys5 to determine the binding affinity of the [18F]-2-FP radiolabelled analogue, which could be prepared by simplified radiochemistry. Lead candidate [Tyr4, Lys5(2-fluoropropionyl-2-FP)]G7039 exhibited an IC50 of 0.28 nM and low picomolar activity towards GHS-R1a. Molecular docking revealed a molecular basis for the picomolar affinity.

ChemMedChem. 2019 Aug 30 [Epub ahead of print]

Tyler Lalonde, Jinqiang Hou, Pierre E Thibeault, Mark Milne, Savita Dhanvantari, Rithwik Ramachandran, Leonard G Luyt

CANADA., The University of Western Ontario, London Regional Cancer Program, 790 Commissioners Rd. E., A4-817, N6A 4L6, London, CANADA.