Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C‑Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)­butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.本研究对包含5种已知具有高σ₂受体亲和力骨架的46种化合物进行了筛选。6,7-二甲氧基-2-[4-(4-甲氧基苯基)丁-2-基]-1,2,3,4-四氢异喹啉[(±)-7]（σ₁受体抑制常数Ki=48.4±7.7 nM，σ₂受体Ki=0.59±0.02 nM）及其去甲基类似物(±)-8（σ₁受体Ki=108±35 nM，σ₂受体Ki=4.92±0.59 nM）对σ₂受体展现出优异的结合亲和力与亚型选择性。体外细胞结合实验证实，[¹¹C]-(±)-7与[¹¹C]-(±)-8的σ₂受体结合作用依赖于跨膜蛋白97（TMEM97）的表达。在正电子发射断层扫描（PET）研究中，[¹¹C]-(±)-7的脑摄取峰值（8.28±2.52%ID/cc）高于[¹¹C]-(±)-8的脑摄取峰值（4.25±0.97%ID/cc），且二者在大脑皮层与下丘脑具有特异性分布。具有不同σ₂受体结合亲和力的配体可选择性抑制该类示踪剂的脑摄取与组织结合作用。研究结果表明，[¹¹C]-(±)-7可作为PET放射性示踪剂，用于中枢神经系统疾病中σ₂受体功能的成像检测。