发现一种有前景的氟-18 正电子发射断层扫描放射性示踪剂，用于脑内鞘氨醇-1-磷酸受体 1 的成像。
Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain.
机构信息
Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri 63110, United States.
Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, Saint Louis, Missouri 63110, United States.
出版信息
J Med Chem. 2023 Apr 13;66(7):4671-4688. doi: 10.1021/acs.jmedchem.2c01752. Epub 2023 Mar 16.
Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [C] into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound is potent (IC = 8.7 nM) and selective for S1PR1. [F] exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [F] . Radiometabolite analysis confirmed no radiometabolite of [F] entered into the brain to confound the PET measurement. In summary, [F] is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.
鞘氨醇-1-磷酸受体 1（S1PR1）被认为是神经紊乱的一种新的治疗和诊断靶点。我们最近将 S1PR1 放射性配体 [C] 转化为多发性硬化症的临床研究。在此，我们报告了新型 F-18 S1PR1 放射性配体的设计、合成和评估。我们结合了两种 S1PR1 放射性配体的结构优势，合成了 14 种新型 S1PR1 化合物，然后对最有前途的化合物进行了 F-18 放射化学研究。化合物 对 S1PR1 具有强大的亲和力（IC = 8.7 nM）和选择性。[F]在灵长类动物大脑中具有高摄取率（SUV > 3.0），并在正电子发射断层扫描（PET）研究中表现出良好的脑洗脱药代动力学。PET 阻断和置换研究证实了 [F] 的特异性。放射性代谢产物分析证实，没有 [F] 的放射性代谢产物进入大脑干扰 PET 测量。综上所述，[F] 是一种很有前途的 S1PR1 成像放射性配体，值得对大脑紊乱的人类进行转化临床研究。
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