Kreimerman Ingrid, Reyes Ana Laura, Paolino Andrea, Pardo Tania, Porcal Williams, Ibarra Manuel, Oliver Patricia, Savio Eduardo, Engler Henry
Radiopharmacy Department, Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay.
Department of Organic Chemistry, Faculty of Chemistry, University of the Republic (UdelaR), Montevideo, Uruguay.
Front Neurosci. 2019 Jul 16;13:734. doi: 10.3389/fnins.2019.00734. eCollection 2019.
Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [C]Deuterodeprenyl ([C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer's disease, Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with F, namely SR101 -(3-[F]Fluoropropyl) sulfonamide ([F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [C]DED were also done to compare with [F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [F]2B-SRF101 and [C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [F]2B-SRF101 was not found in the case of [C]DED. The comparative studies between [F]2B-SRF101 and [C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.
神经退行性疾病主要与神经元死亡有关。最近的研究表明，星形胶质细胞可能在疾病的早期和晚期调节神经炎症。[C]去铁胺（[C]DED）是一种示踪剂，已用于在阿尔茨海默病、克雅氏病和肌萎缩侧索硬化症等疾病中检测反应性星形胶质细胞，但存在一些局限性。为了开发一种用于检测星形细胞增生并克服相关困难的新型放射性示踪剂，我们最近报道了一种用氟标记的磺基罗丹明101（SR101）的磺酰胺衍生物的合成，即SR101 -（3-[F]氟丙基）磺酰胺（[F]2B-SRF101）。红色荧光染料SR101已被用作啮齿动物新皮质中星形胶质细胞的特异性标记物。在本研究中，我们对新示踪剂进行了生物学特性分析，包括生物分布和微型正电子发射断层扫描/计算机断层扫描（CT）图像。还进行了用[C]DED的PET/CT研究，以便与[F]2B-SRF101进行比较，以评估其作为星形胶质细胞标记物的潜力。用[F]2B-SRF101在C57BL6J黑色小鼠和转基因（3xTg）小鼠中进行了生物分布研究。确定了肝肠代谢以及药代动力学特征，显示出适合成为PET诊断剂的特性。用[F]2B-SRF101和[C]DED进行了动态PET/CT研究，以评估两种示踪剂在脑中的分布。特别在皮质和海马中观察到[F]2B-SRF101摄取有显著差异，并且在3xTg小鼠中比对照组更高。这些结果表明，[F]2B-SRF101作为一种星形胶质细胞示踪剂有希望进行更广泛的评估。在[C]DED的情况下未发现[F]2B-SRF101所观察到的差异。[F]2B-SRF101和[C]DED之间的比较研究表明，在这个动物模型中，两种示踪剂作为星形细胞增生标记物具有不同的作用，并且可以同时提供不同的补充信息。通过这种方式，借助多示踪剂方法，可以获得用于疾病分期的有用信息。
