Binding potential of (E)-[¹¹C]ABP688 to metabotropic glutamate receptor subtype 5 is decreased by the inclusion of its ¹¹C-labelled Z-isomer

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• 作者：Kazunori Kawamura ; Tomoteru Yamasaki ; Katsushi Kumata ; Kenji Furutsuka ; Makoto Takei ; Hidekatsu Wakizaka ; Masayuki Fujinaga ; Kaori Kariya ; Joji Yui ; Akiko Hatori ; Lin Xie ; Yoko Shimoda ; Hiroki Hashimoto ; Kazutaka Hayashi ; Ming-Rong Zhang
• 关键词：11C ; (E)-ABP688 ; (Z)-ABP688 ; Metabotropic glutamate receptor subtype 5 ; Positron emission tomography
• 刊名：Nuclear Medicine and Biology
• 出版年：January, 2014
• 年：2014
• 卷：41
• 期：1
• 页码：17-23
• 全文大小：989 K

文摘

Introduction

[¹¹C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [¹¹C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[¹¹C]ABP688 on the synthesis of [¹¹C]ABP688 to be used for binding (E)-[¹¹C]ABP688 in the brain.

Methods

We synthesized and separated (E)- and (Z)-[¹¹C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[¹¹C]ABP688.

Results

(E)- and (Z)-[¹¹C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the K_d value of (E)-[¹¹C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[¹¹C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[¹¹C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[¹¹C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BP_ND in the striatum and hippocampus was highly correlated (R² = 0.99) with the percentage of (E)-[¹¹C]ABP688 of the total radioactivity of (E)- and (Z)-[¹¹C]ABP688 in the injection.

Conclusion

We demonstrated that including (Z)-[¹¹C]ABP688 in the [¹¹C]ABP688 injection can decrease BP_ND in regions rich in mGlu5 receptors. Routine production of (E)-[¹¹C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies.