背景:帕金森病(PD)是世界范围内普遍存在的神经退行性疾病,根据运动功能障碍和认知障碍等经典症状进行诊断。随着各种放射性配体的发展,已证明,正电子发射断层扫描(PET)成像与特定的放射性标记探针相结合可有效帮助临床PD诊断。在这些探测器中,2β-甲氧基-3β-(4-氯苯基)-8-(2-[18F]-氟乙基)去甲氨烷([18F]FECNT)已被用作PET示踪剂,以对纹状体突触前多巴胺能终末的多巴胺转运蛋白(DAT)完整性进行成像。然而,[18F]FECNT产生的脑穿透性放射性代谢物的存在可能会影响PET成像的准确性.在以前的研究中,我们开发了2β-碳甲氧基-3β-(4-氯苯基)-8-(2-[18F]-氟乙基-1,1,2,2-d4)去甲氨烷([18F]FECNT-d4),在血浆和纹状体中具有增强的稳定性的氘代衍生物,以及较慢的冲洗速度。在这项研究中,我们进一步研究了[18F]FECNT-d4检测帕金森病多巴胺能神经元变性的潜力。这涉及单侧损伤的PD模型大鼠的PET成像以及在死后脑切片上进行的体外放射自显影。
结果:PET图像显示立体定向注射6-羟基多巴胺盐酸盐(6-OHDA)的大鼠同侧纹状体的特异性摄取降低。与假手术组相比,同侧纹状体与对侧纹状体的标准化摄取值(SUV)的比率下降了13%,23%,63%的人在温和的情况下,中度,和严重病变的群体,分别。在PET成像中观察到的多巴胺能神经支配得到行为评估的进一步支持,免疫染色,和单胺浓度测试。此外,microPET结果与这些测量结果呈正相关,除了阿朴吗啡诱导的旋转行为试验,呈负相关。此外,与健康受试者相比,PD患者死后纹状体切片中的[18F]FECNT-d4摄取低约40%。此外,估计人体剂量测定(有效剂量当量:5.06E-03mSv/MBq),从大鼠生物分布数据推断,仍然低于当前的食品和药物管理局的辐射暴露限制。
结论:我们的发现表明,[18F]FECNT-d4准确估计6-OHDA诱导的PD大鼠模型中多巴胺能神经元变性的水平,并有效区分PD患者和健康个体。这种高度敏感和安全的PET探针在帕金森病的诊断和监测中具有很好的临床应用潜力。
BACKGROUND: Parkinson\'s disease (PD) is a prevalent neurodegenerative disorder worldwide, diagnosed based on classic symptoms like motor dysfunction and cognitive impairments. With the development of various radioactive ligands, positron emission tomography (PET) imaging combined with specific radiolabelling probes has proven to be effective in aiding clinical PD diagnosis. Among these probes, 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl) nortropane ([18F]FECNT) has been utilized as a PET tracer to image dopamine transporter (DAT) integrity in striatal presynaptic dopaminergic terminals. However, the presence of brain-penetrant radioactive metabolites produced by [18F]FECNT may impact the accuracy of PET imaging. In previous research, we developed 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl-1,1,2,2-d4) nortropane ([18F]FECNT-d4), a deuterated derivative with enhanced stability in plasma and the striatum, along with a slower washout rate. In this study, we further investigated the potential of [18F]FECNT-d4 to detect dopaminergic neuron degeneration in Parkinson\'s disease. This involved PET imaging in unilaterally-lesioned PD model rats and in vitro autoradiography conducted on postmortem brain sections.
RESULTS: PET images revealed reduced specific uptake in the ipsilateral striatum of rats stereotactically injected with 6-hydroxydopamine hydrochloride (6-OHDA). Compared to the sham group, the ratio of standardized uptake value (SUV) in the ipsilateral to contralateral striatum decreased by 13%, 23%, and 63% in the mild, moderate, and severe lesioned groups, respectively. Dopaminergic denervation observed in PET imaging was further supported by behavioral assessments, immunostaining, and monoamine concentration tests. Moreover, the microPET results exhibited positive correlations with these measurements, except for the apomorphine-induced rotational behavior test, which showed a negative correlation. Additionally, [18F]FECNT-d4 uptake was approximately 40% lower in the postmortem striatal sections of a PD patient compared to a healthy subject. Furthermore, estimated human dosimetry (effective dose equivalent: 5.06 E-03 mSv/MBq), extrapolated from rat biodistribution data, remained below the current Food and Drug Administration limit for radiation exposure.
CONCLUSIONS: Our findings demonstrate that [18F]FECNT-d4 accurately estimates levels of dopaminergic neuron degeneration in the 6-OHDA-induced PD rat model and effectively distinguishes between PD patients and healthy individuals. This highly sensitive and safe PET probe holds promising potential for clinical application in the diagnosis and monitoring of Parkinson\'s disease.