Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

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• 作者：Lucia Tamborini ; Ying Chen ; Catherine A. Foss ; Andrea Pinto ; Andrew G. Horti ; Stephen F. Traynelis ; Carlo De Micheli ; Ronnie C. Mease ; Kasper B. Hansen ; Paola ContiMartin G. Pomper
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：11110-11119
• 全文大小：484K
• ISSN：1520-4804

文摘

Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer’s disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a–c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [^124/125I]4d and [¹¹C]4e (i.e., [^124/125I]11d and [¹¹C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [¹²⁵I]11d and [¹¹C]11e through autoradiography and biodistribution studies, imaging of neither [¹²⁴I]11d nor [¹¹C]11e could demonstrate brain penetration sufficient for detection by PET.