Development of Candidates for PET Imaging of Ghrelin Receptor in Disease: Design, Synthesis and Evaluation of Fluorine-bearing Quinazolinone Derivatives

Molecular imaging with PET (Positron Emission Tomography) is an attractive platform for non-invasive detection and assessment of disease. The development of a PET imaging agent targeting the ghrelin receptor (growth hormone secretagogue receptor type 1a or GHS-R1a) has the potential to lead to the detection and assessment of the higher than normal expression of GHS-R1a in diseases such as prostate, breast, and ovarian cancer. To enable the development of 18F radiopharmaceuticals, we have designed and synthesized three series of quinazolinone derivatives, resulting in the identification of two compound (5i, 17) with sub-nanomolar binding affinity and one fluorine-bearing compound (10b) with picomolar binding affinity (20 pM), representing the highest binding affinity for GHS-R1a reported to date. Two lead compounds were successfully 18F-radiolabeled with radiochemical purity of greater than 99%. Molecular modelling studies were performed to shed light on ligand-receptor interactions.

Journal of medicinal chemistry. 2018 Jan 12 [Epub ahead of print]

Jin-Qiang Hou, Michael S Kovacs, Savita Dhanvantari, Leonard G Luyt

email news signup