Rapid Identification of a Novel Small Molecule Phosphodiesterase 10A (PDE10A) Tracer

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• 作者：Essa Hu ; Ji Ma ; Christopher Biorn ; Dianna Lester-Zeiner ; Robert Cho ; Shannon Rumfelt ; Roxanne K. Kunz ; Thomas Nixey ; Klaus Michelsen ; Silke Miller ; Jianxia Shi ; Jamie Wong ; Geraldine Hill Della Puppa ; Jessica Able ; Santosh Talreja ; Dah-Ren Hwang ; Stephen A. Hitchcock ; Amy Porter ; David Immke ; Jennifer R. Allen ; James Treanor ; Hang Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4776-4787
• 全文大小：504K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

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鈥揗S/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 [³H]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 [³H]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鈥揗S/MS technology.