Kim Ho Young, Lee Ji Youn, Hsieh Chia-Ju, Riad Aladdin, Izzo Nicholas J, Catalano Susan M, Graham Thomas J A, Mach Robert H
Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania 15203-5118, United States.
J Med Chem. 2022 Apr 28;65(8):6261-6272. doi: 10.1021/acs.jmedchem.2c00191. Epub 2022 Apr 11.
In this study, a panel of 46 compounds containing five different scaffolds known to have high σ receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-] ( for σ = 48.4 ± 7.7 nM, and for σ = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)- ( for σ = 108 ± 35 nM, and for σ = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ receptors. cell binding indicated that σ receptor binding of [C]-(±)- and [C]-(±)- was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [C]-(±)- (8.28 ± 2.52%ID/cc) was higher than that of [C]-(±)- (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 σ receptor binding affinities. The results suggest [C]-(±)- can be used as a PET radiotracer for imaging the function of σ receptors in central nervous system disorders.
在本研究中，对一组包含已知具有高σ受体亲和力的五种不同骨架的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[(±)-]（对于σ1 = 48.4±7.7 nM，对于σ2 = 0.59±0.02 nM）及其去甲基类似物(±)-（对于σ1 = 108±35 nM，对于σ2 = 4.92±0.59 nM）对σ受体显示出优异的结合亲和力和亚型选择性。细胞结合表明，[C]-(±)-和[C]-(±)-的σ受体结合依赖于TMEM97蛋白表达。在PET研究中，[C]-(±)-的脑摄取峰值（8.28±2.52%ID/cc）高于[C]-(±)-（4.25±0.97%ID/cc），并在皮质和下丘脑有特异性分布。脑摄取或组织结合被具有不同σ受体结合亲和力的配体选择性抑制。结果表明，[C]-(±)-可作为PET放射性示踪剂用于成像中枢神经系统疾病中σ受体的功能。
