| Autor: |
Hu E; Department of Small Molecule Chemistry, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. ehu@amgen.com, Ma J, Biorn C, Lester-Zeiner D, Cho R, Rumfelt S, Kunz RK, Nixey T, Michelsen K, Miller S, Shi J, Wong J, Hill Della Puppa G, Able J, Talreja S, Hwang DR, Hitchcock SA, Porter A, Immke D, Allen JR, Treanor J, Chen H |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2012 May 24; Vol. 55 (10), pp. 4776-87. Date of Electronic Publication: 2012 May 11. |
| DOI: |
10.1021/jm3002372 |
| Abstrakt: |
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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