Sigma (σ) receptor subtypes, σ₁ and σ₂, are targets of wide pharmaceutical interest. The σ₂ receptor holds promise for the development of diagnostics and therapeutics against cancer and Alzheimer’s disease. Nevertheless, little is known about the mechanisms activated by the σ₂ receptor. To contribute to the exploitation of its therapeutic potential, we developed novel specific fluorescent ligands. Indole derivatives bearing the N-butyl-3H-spiro[isobenzofuran-1,4′-piperidine] portion were functionalized with fluorescent tags. Nanomolar-affinity fluorescent σ ligands, spanning from green to red to near-infrared emission, were obtained. Compounds 19 (σ pan affinity) and 29 (σ₂ selective), which displayed the best compromise between pharmacodynamic and photophysical properties, were investigated in flow cytometry, confocal, and live cell microscopy, demonstrating their specificity for the σ₂ receptor. To the best of our knowledge, these are the first red-emitting fluorescent σ₂ ligands, validated as powerful tools for the study of σ₂ receptors via fluorescence-based techniques.

中文翻译：

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开发荧光 4-[4-(3H-Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)butyl]indolyl 衍生物作为高亲和力探针，通过基于荧光的技术研究 σ 受体

Sigma (σ) 受体亚型 σ ₁和 σ ₂是具有广泛药学意义的靶点。σ ₂受体有望用于开发针对癌症和阿尔茨海默病的诊断和治疗方法。_{然而，人们对 σ 2}受体激活的机制知之甚少。为了有助于开发其治疗潜力，我们开发了新型特异性荧光配体。带有N- butyl-3 H -spiro[isobenzofuran-1,4'-piperidine] 部分的吲哚衍生物用荧光标签进行功能化。获得了从绿色到红色再到近红外发射的纳摩尔亲和荧光 σ 配体。化合物19(σ pan affinity) 和29 (σ ₂ selective) 显示出药效学和光物理性质之间的最佳折衷，在流式细胞术、共聚焦和活细胞显微镜中进行了研究，证明了它们对 σ 2 受体的_特异性。据我们所知，这些是第一个发出红色荧光的 σ ₂配体，经验证可作为通过基于荧光的技术研究 σ _{2受体的强大工具。}