Development of 2-(2-(3-(4-([F-18]Fluoromethoxy-d(2))phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione for Positron-Emission-Tomography Imaging of Phosphodiesterase 10A in the Brain

摘要

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central nervous system disorders. 2-(2-(3-(4-([F-18]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([F-18]MNI-659, [F-18]5) is a useful positron emission tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [F-18]5 can accumulate in the brain. In this study, using [F-18]5 as a lead compound, we designed four new F-18-labeled ligands ([F-18]6-9) to find one more suitable than [F-18]5. Of these, 2-(2-(3-(4-([F-18]fluoromethoxy-d(2))phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([F-18]9) exhibited high in vitro binding affinity (K-i = 2.9 nM) to PDE10A and suitable lipophilicity (LogD = 2.2). In PET studies, the binding potential (BPND) of [F-18]9 (5.8) to PDE10A in rat brains was significantly higher than that of [F-18]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites of [18F]9 in the brain than those of [F-18]5. In conclusion, [F-18]9 is a useful PET ligand for PDE10A imaging in brain.