Development of Candidates for Positron Emission Tomography (PET) Imaging of Ghrelin Receptor in Disease: Design, Synthesis, and Evaluation of Fluorine-Bearing Quinazolinone Derivatives

作者：Hou Jinqiang; Kovacs Michael S; Dhanvantari Savita; Luyt Leonard G^*

来源：Journal of Medicinal Chemistry, 2018, 61(3): 1261-1275.

DOI：10.1021/acs.jmedchem.7b01754

Molecular imaging with positron emission tomography (PET) is an attractive platform for noninvasive 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 F-18 radiopharmaceuticals, we have designed and synthesized three series of quinazolinone derivatives, resulting in the identification of two compound (5i, 17) with subnanomolar 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 (5b, IC50 = 20.6 nM; 5e, IC50 = 9.3 nM) were successfully F-18-radiolabeled with radiochemical purity of greater than 99%. Molecular modeling studies were performed to shed light on ligand-receptor interactions.

• 出版日期2018-2-8