Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, United States.
Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, United States.
ACS Chem Neurosci. 2021 Oct 6;12(19):3733-3744. doi: 10.1021/acschemneuro.1c00492. Epub 2021 Sep 13.
Sphingosine-1-phosphate receptor 1 (S1PR1) is ubiquitously expressed among all tissues and plays key roles in many physiological and cellular processes. In the central nervous system (CNS), S1PR1 is expressed in different types of cells including neurons, astrocytes, and oligodendrocyte precursor cells. S1PR1 has been recognized as a novel therapeutic target in multiple sclerosis and other diseases. We previously reported a promising S1PR1-specific radioligand, [C]CS1P1 (previously named [C]TZ3321), which is under clinical investigation for human use. In the current study, we performed a detailed characterization of [H]CS1P1 for its binding specificity to S1PR1 in CNS using autoradiography and immunohistochemistry in human and rat CNS tissues. Our data indicate that [H]CS1P1 binds to S1PR1 in human frontal cortex tissue with a of 3.98 nM and a of 172.5 nM. The distribution of [H]CS1P1 in human and rat CNS tissues is consistent with the distribution of S1PR1 detected by immunohistochemistry studies. Our microPET studies of [C]CS1P1 in a nonhuman primate (NHP) show a standardized uptake value of 2.4 in the NHP brain, with test-retest variability of 0.23% among six different NHPs. Radiometabolite analysis in the plasma samples of NHP and rat, as well as in rat brain samples, showed that [C]CS1P1 was stable . Kinetic modeling studies using a two-compartment tissue model showed that the positron emission tomography (PET) data fit the model well. Overall, our study provides a detailed characterization of [H]CS1P1 binding to S1PR1 in the CNS. Combined with our microPET studies in the NHP brain, our data suggest that [C]CS1P1 is a promising radioligand for PET imaging of S1PR1 in the CNS.
鞘氨醇-1-磷酸受体 1（S1PR1）在所有组织中广泛表达，在许多生理和细胞过程中发挥关键作用。在中枢神经系统（CNS）中，S1PR1 表达于包括神经元、星形胶质细胞和少突胶质细胞前体细胞在内的不同类型的细胞中。S1PR1 已被认为是多发性硬化症和其他疾病的新的治疗靶点。我们之前报道了一种有前途的 S1PR1 特异性放射性配体 [C]CS1P1（以前称为 [C]TZ3321），目前正在进行人体临床试验。在本研究中，我们使用放射自显影和免疫组织化学技术，在人源和大鼠 CNS 组织中对 [H]CS1P1 与 S1PR1 的结合特异性进行了详细表征。我们的数据表明，[H]CS1P1 与人前额皮质组织中的 S1PR1 结合的 为 3.98 nM， 为 172.5 nM。[H]CS1P1 在人源和大鼠 CNS 组织中的分布与免疫组织化学研究检测到的 S1PR1 分布一致。我们在非人类灵长类动物（NHP）中进行的 [C]CS1P1 的 microPET 研究显示，NHP 大脑中的标准化摄取值为 2.4，6 只不同 NHP 之间的测试-复测变异性为 0.23%。在 NHP 和大鼠的血浆样本以及大鼠脑组织样本中的放射性代谢产物分析表明，[C]CS1P1 稳定。使用双室组织模型进行的动力学建模研究表明，正电子发射断层扫描（PET）数据与模型拟合良好。总体而言，我们的研究提供了 [H]CS1P1 与 CNS 中 S1PR1 结合的详细特征。结合我们在 NHP 大脑中的 microPET 研究，我们的数据表明，[C]CS1P1 是一种很有前途的 S1PR1 在 CNS 中的 PET 成像放射性配体。
