The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific ¹⁸F-labelled tracer ¹⁸F-IAM6067 in two animal models and in human brain tissue./nMethods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT_2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by ¹⁸F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages)./nResults: We demonstrate that despite rapid peripheral metabolism of ¹⁸F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of ¹⁸F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT_2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of ¹⁸F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in ¹⁸F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls./nConclusion: This work shows that ¹⁸F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

中文翻译：

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评估 18F-IAM6067 作为 sigma-1 受体 PET 示踪剂对啮齿动物和人体组织体内神经变性的影响。


西格玛1受体（S1R）广泛表达于中枢神经系统中，主要位于内质网上。 S1R 参与许多神经传递系统的调节，并间接参与神经退行性疾病。因此，S1R 可能代表帕金森病 (PD) 或阿尔茨海默病 (AD) 等神经退行性疾病中一种有趣的神经元生物标志物。在这里，我们介绍了两种动物模型和人类脑组织中 S1R 特异性¹⁸ F 标记示踪剂¹⁸ F-IAM6067 的表征。/n方法：使用 Wistar 大鼠进行 PET-CT 成像（60 分钟动态采集）和代谢物分析（注射后 1、2、5、10、20、60 分钟）。为了验证体内选择性，给予氟哌啶醇、BD1047（S1R配体）、CM398（S2R配体）和SB206553（5HT _2B/C拮抗剂）进行预饱和研究。纹状体内注射 AMPA 诱导的兴奋性毒性损伤也通过¹⁸ F-IAM6067 PET-CT 进行成像，以测试该方法在完善的神经元损失模型中的敏感性。示踪剂脑摄取也通过大鼠和 PD 小鼠模型（纹状体内 6-羟基多巴胺 (6-OHDA) 单侧病变）的放射自显影得到验证。最后，通过放射自显影对三组受试者（Braak ≤2 的对照受试者，以及 Braak >2 & ≤4 和 Braak >4 阶段的 AD 患者）进行了人类皮质结合研究。/n结果：我们证明，尽管外周代谢快速¹⁸ F-IAM6067 中，在脑样本中几乎检测不到放射性标记的代谢物。 大脑对¹⁸ F-IAM6067 的摄取显示出 S1R 解剖分布的差异，即从高到低摄取：脑桥、丘脑背中、黑质、下丘脑、小脑、皮质区和纹状体。预饱和研究显示，除 5HT _2B/C拮抗剂 SB206553 和 S2R 配体 CM398 外，上述脑部所有区域的结合均被阻断 79-90%，而 S2R 配体 CM398 未诱导显着阻断，表明¹⁸ F-IAM6067 对 S1R 具有良好的特异性。在 PD 小鼠模型中，未检测到大脑同侧和对侧之间存在差异。 AMPA 损伤导致苍白球中¹⁸ F-IAM6067 的摄取显着减少 69%，与 NeuN 测量的神经元损失相匹配，但尾壳核中的 18 F-IAM6067 摄取仅呈减少趋势 (-16%)，尽管神经元损失显着减少 91%数数。此外，AD 组和对照组之间的人类皮质结合没有显示出差异。/n结论：这项工作表明¹⁸ F-IAM6067 是一种特异性和选择性的 S1R 放射性示踪剂。在动物模型和人体组织中检测到的 S1R 缺失或微小变化值得进一步研究，并表明 S1R 可能不是 AD 和 PD 等神经退行性疾病中神经元损失的预期理想生物标志物。