We have designed and synthesized novel piperazine compounds with low lipophilicity as σ₁ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ₁ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ₂ receptors (52-fold), and adenosine A_2A, adrenergic α₂, cannabinoid CB₁, dopamine D₁, D_2L, γ-aminobutyric acid A (GABA_A), NMDA, melatonin MT₁, MT₂, and serotonin 5-HT₁ receptors. The corresponding radiotracer [¹⁸F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ₁ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [¹⁸F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [¹⁸F]10 to σ₁ receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [¹⁸F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ₁ receptors in Alzheimer’s disease.

中文翻译：

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1-（4- [ ¹⁸ F]氟苄基）-4 - [（四氢呋喃-2-基）甲基]哌嗪：一种新型具有低亲脂性的合适的放射性配体用于成像σ _1个在脑受体

我们设计并合成的新的哌嗪化合物具有低亲脂性为σ ₁受体配体。1-（4-氟苄基）-4 - [（四氢呋喃-2-基）甲基]哌嗪（10）具有的低纳摩尔σ _1个受体亲和力和朝向囊泡乙酰胆碱转运（> 2000倍）的高选择性，σ ₂受体（52倍），和腺苷A _2A，肾上腺素能α ₂，大麻素CB ₁，多巴胺d ₁，d _2L，γ氨基丁酸A（GABA_甲），NMDA，褪黑激素MT ₁，MT ₂和血清素5- HT ₁受体。相应的放射性示踪剂[ ¹⁸ F] 10在小鼠的生物分布研究中显示出高脑摄取和极高的脑血比。预处理与选择性σ ₁受体激动剂SA4503显著降低了在大脑中的放射性示踪剂的积累水平。没有观察到[ ¹⁸ F] 10的放射性代谢物进入大脑。正电子发射断层扫描和磁共振成像证实合适的动力学和高比的[结合¹⁸ F] 10至σ _1种受体在大鼠脑中。体外放射自显影显示[ ¹⁸ F]的结合水平降低10在皮质和衰老加速容易发生（SAMP8）海马相比，在衰老加速抗性（SAMR1）小鼠，表明σ的潜在功能障碍₁受体在阿尔茨海默氏病。