The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

中文翻译：

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[11C] MK-6884的发现：正电子发射断层扫描（PET）成像剂，用于研究神经退行性疾病中M4毒蕈碱受体阳性变构调节剂（PAM）。

使用正电子发射断层扫描（PET）来测量受体占有率（RO）在指导中枢神经系统定向疗法的发现和开发中发挥了重要作用。我们和其他人已经研究了毒蕈碱型乙酰胆碱受体4（M4）阳性变构调节剂（PAM），用于治疗与神经精神疾病有关的症状。在本文中，我们描述了一系列中央吡啶相关的M4 PAM的合成，体外和体内表征，可以方便地用碳11作为PET示踪剂对其进行放射性标记，用于体内成像的变构结合位点。 M4受体。我们首先通过绘制小鼠大脑中的受体分布图并证实铅分子1仅在正构激动剂卡巴胆碱的存在下选择性结合至受体，证明了其可行性。通过竞争性结合亲和力测定和许多理化性质过滤器，几种相关化合物被鉴定为体内评估的候选物。然后将这些候选物用11C进行放射性标记，并在恒河猴中进行体内研究。这项研究最终导致了临床放射性示踪剂候选物[11C] MK-6884的发现。