Abstract |
Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central-nervous-system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron-emission-tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [18F]5 can accumulate in the brain. In this study, using [18F]5 as a lead compound, we designed four new 18F-labeled ligands ([18F]6-9) to find one more suitable than [18F]5. Of these, 2-(2-(3-(4-([18F]fluoromethoxy- d2)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]9) exhibited high in vitro binding affinity ( Ki = 2.9 nM) to PDE10A and suitable lipophilicity (log D = 2.2). In PET studies, the binding potential (BPND) of [18F]9 (5.8) to PDE10A in the striatum of rat brains was significantly higher than that of [18F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites in the brains of rats given [18F]9 than in those given [18F]5. In conclusion, [18F]9 is a useful PET ligand for PDE10A imaging in brain.
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Authors | Wakana Mori, Tomoteru Yamasaki, Masayuki Fujinaga, Masanao Ogawa, Yiding Zhang, Akiko Hatori, Lin Xie, Katsushi Kumata, Hidekatsu Wakizaka, Yusuke Kurihara, Takayuki Ohkubo, Nobuki Nengaki, Ming-Rong Zhang |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 62
Issue 2
Pg. 688-698
(01 24 2019)
ISSN: 1520-4804 [Electronic] United States |
PMID | 30516998
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione
- Fluorine Radioisotopes
- Ligands
- Phthalimides
- Quinazolinones
- Radiopharmaceuticals
- PDE10A protein, rat
- Phosphoric Diester Hydrolases
- Fluorine-18
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Topics |
- Animals
- Brain
(diagnostic imaging, metabolism)
- Drug Evaluation, Preclinical
- Fluorine Radioisotopes
(chemistry)
- Isotope Labeling
- Ligands
- Male
- Mice
- Phosphoric Diester Hydrolases
(chemistry, metabolism)
- Phthalimides
(blood, chemistry, metabolism)
- Positron-Emission Tomography
- Protein Binding
- Quinazolinones
(blood, chemistry, metabolism)
- Radiopharmaceuticals
(chemistry, metabolism)
- Rats
- Rats, Sprague-Dawley
- Tissue Distribution
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