Giglio Benjamin C, Fei Haiyang, Wang Mengzhe, Wang Hui, He Liu, Feng Huijuan, Wu Zhanhong, Lu Hongjian, Li Zibo
Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
Theranostics. 2017 Apr 7;7(6):1524-1530. doi: 10.7150/thno.19371. eCollection 2017.
Indoleamine 2,3-dioxygenase (IDO1) plays a special role in the biology of various cancer types, because it breaks down the essential amino acid tryptophan for immune cell activation. Upregulation of IDO1 significantly correlates with the number of various T cell types in tumor tissues in melanoma and other cancers, suggesting that IDO expression is linked with effective and ineffective ('exhausted') immune response in cancer. Based on the reported IDO inhibitors (α-Methylated and indole--methylated tryptophan (Trp)), here we report the synthesis of potential IDO1 imaging agents through direct introduction of F into the tryptophan aromatic ring. Overall, the resulting PET agents could be obtained in high radiochemical purity (>97%) with labeling yield ranges from 4.2-14.9% decay corrected yield. Using Trp as the model compound, our results also demonstrate that F could be directly introduced to the Trp backbone at the 4, 5, 6, and 7 position. Moreover, our initial imaging study suggests that 5-[F]F-L-α-methyl tryptophan (5-[F]F-AMT) holds great potential for cancer imaging. The success of this approach will provide researchers easy access to a library of Trp/Trp-derivative based PET agents for biomedical research, including potential IDO1 targeted imaging.
吲哚胺2,3-双加氧酶（IDO1）在多种癌症类型的生物学过程中发挥着特殊作用，因为它会分解必需氨基酸色氨酸以激活免疫细胞。IDO1的上调与黑色素瘤和其他癌症肿瘤组织中各种T细胞类型的数量显著相关，这表明IDO的表达与癌症中有效和无效（“耗竭”）的免疫反应有关。基于已报道的IDO抑制剂（α-甲基化和吲哚-甲基化色氨酸（Trp）），在此我们报告通过将氟直接引入色氨酸芳香环来合成潜在的IDO1成像剂。总体而言，所得的PET试剂能够以高放射化学纯度（>97%）获得，标记产率范围为4.2 - 14.9%（衰变校正产率）。以Trp作为模型化合物，我们的结果还表明氟可以直接引入到Trp主链的4、5、6和7位。此外，我们的初步成像研究表明5-[F]F-L-α-甲基色氨酸（5-[F]F-AMT）在癌症成像方面具有巨大潜力。这种方法的成功将为研究人员提供便利，使其能够获取一系列基于Trp/Trp衍生物的PET试剂用于生物医学研究，包括潜在的IDO1靶向成像。
