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

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.MethodsWe 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 Kd 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, BPND 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.ConclusionWe demonstrated that including (Z)-[11C]ABP688 in the [11C]ABP688 injection can decrease BPND 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.