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

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 18F 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 18F-radiolabeled with radiochemical purity of greater than
99%. Molecular modeling studies were performed to shed light on ligand–receptor
interactions.