The metabotropic glutamate receptor subtype 5 (mGluR5) is recognized to be involved in numerous brain disorders. In an effort to obtain a fluorine-18 labeled analogue of the mGluR5 PET tracer [¹¹C]ABP688, 13 novel ligands based on the core structure of ABP688 were synthesized. Molecules in which the methyl group at the oxime functionality of ABP688 was replaced by fluorobenzonitriles, fluoropyridines, and fluorinated oxygen containing alkyl side chains were investigated. Substituents at the oxime functionality are well tolerated and resulted in five candidates with K_i values below 10 nM. The most promising candidate, (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone-O-2-(2-fluoroethoxy)ethyloxime (38, K_i = 3.8 nM), was radiolabeled with fluorine-18. Scatchard analysis of [¹⁸F]38 which modeled best for two sites pointed to high binding affinity (K_D1 = 0.61 ± 0.19 nM and K_D2 = 13.73 ± 4.69 nM) too. These data strongly suggest the further evaluation of [¹⁸F]38 as a candidate for imaging the mGluR5.

中文翻译：

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氟化（E）-3-（（6-甲基吡啶-2--2-基）乙炔基）环己-2-烯酮-O-甲基肟（ABP688）衍生物的结构活性关系和高亲和力类似物作为潜在候选物的发现使用正电子发射断层扫描（PET）对5型代谢型谷氨酸受体（mGluR5）进行成像

代谢型谷氨酸受体亚型5（mGluR5）被认为与多种脑部疾病有关。为了获得mGluR5 PET示踪剂[ ¹¹ C] ABP688的氟18标记类似物，合成了13种基于ABP688核心结构的新型配体。研究了其中ABP688肟官能团上的甲基被氟苄腈，氟吡啶和含氟氧烷基侧链取代的分子。肟官能团的取代基具有良好的耐受性，并导致5个候选基团的K _i值低于10 nM。最有前途的候选物（E）-3-（吡啶-2-基乙炔基）环己基-2-烯酮-O -2-（2-氟乙氧基）乙基肟（38，K _i = 3.8 nM），用氟18进行放射性标记。最佳模拟两个位点的[ ¹⁸ F] 38的Scatchard分析也指出了高结合亲和力（K _D1 = 0.61±0.19 nM和K _D2 = 13.73±4.69 nM）。这些数据强烈建议进一步评估[ ¹⁸ F] 38作为对mGluR5成像的候选者。