Department of Small Molecule Chemistry, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
J Med Chem. 2012 May 24;55(10):4776-87. doi: 10.1021/jm3002372. Epub 2012 May 11.
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.
用于脑内治疗靶点成像的放射性示踪剂是中枢神经系统药物发现中先导化合物优化和临床开发中剂量选择的有价值的工具。我们报告了使用 LC-MS/MS 技术快速鉴定新型磷酸二酯酶 10A（PDE10A）示踪剂候选物。这种结构独特的 PDE10A 示踪剂 AMG-7980（5）已被证明在纹状体（1.2% ID/g 组织）中有良好的摄取，具有高特异性（纹状体/丘脑比值为 10），并在体内具有可饱和的结合。使用 [(3)H]5 在大鼠纹状体匀浆中，测定 PDE10A 亲和力（K(D)）和 PDE10A 靶密度（B(max)）分别为 0.94 nM 和 2.3 pmol/mg 蛋白。大鼠脑切片的放射自显影表明，示踪剂信号与已知的 PDE10A 表达模式一致。[(3)H]5 与大鼠脑的特异性结合被另一种结构独特的已发表的 PDE10A 抑制剂 MP-10 阻断。最后，我们的示踪剂被用于使用 LC-MS/MS 技术测量大鼠体内 PDE10A 抑制剂的 PDE10A 靶标占有率。
