Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer

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• 作者：Adam J. Rosenberg ; Hui Liu ; Hongjun Jin ; Xuyi Yue ; Sean Riley ; Steven J. Brown ; Zhude Tu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6201-6220
• 全文大小：782K
• 年卷期：0
• ISSN：1520-4804

文摘

Sphingosine 1-phosphate receptor 1 (S1P₁) plays a pivotal signaling role in inflammatory response; because S1P₁ modulation has been identified as a therapeutic target for various diseases, a PET tracer for S1P₁ would be a useful tool. Fourteen fluorine-containing analogues of S1P ligands were synthesized and their in vitro binding potency measured; four had high potency and selectivity for S1P₁ (S1P₁ IC₅₀ < 10 nM, >100-fold selectivity for S1P₁ over S1P₂ and S1P₃). The most potent ligand, 28c (IC₅₀ = 2.63 nM for S1P₁) was ¹⁸F-labeled and evaluated in a mouse model of LPS-induced acute liver injury to determine its S1P₁-binding specificity. The results from biodistribution, autoradiography, and microPET imaging showed higher [¹⁸F]28c accumulation in the liver of LPS-treated mice than controls. Increased expression of S1P₁ in the LPS model was confirmed by immunohistochemical analysis (IHC). These data suggest that [¹⁸F]28c is a S1P₁ PET tracer with high potential for imaging S1P₁ in vivo.