In Vivo Veritas: 18F-Radiolabeled Glycomimetics Allow Insights into the Pharmacological Fate of Galectin-3 Inhibitors
In Vivo Veritas: 18F-Radiolabeled Glycomimetics Allow Insights into the Pharmacological Fate of Galectin-3 Inhibitors
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DOI：
10.1021/acs.jmedchem.9b01692
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发表时间：
2020-01-23
影响因子：
7.3
通讯作者：
Erlandsson, Maria
中科院分区：
文献类型：
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作者：
Bratteby, Klas;Torkelsson, Edvard;Erlandsson, Maria
拟糖药物作为内源性生物分子的独特靶向载体或替代物，已引起人们越来越多的兴趣。然而，通常很难确定这些化合物的体内药代动力学特征。在这项工作中，两个Galectin-3抑制剂被氟-18标记，并被用作TD139和GB1107的替代PET示踪剂。这两种化合物都有很好的临床应用前景。体内评估显示，这两种代谢物在其生物分布特征方面存在很大差异。二糖(TD139替代物)从血液中迅速排出，而单糖(GB1107替代物)没有排泄迹象。获得的数据使我们能够推断TD139和GB1107在体内的不同命运，并合理地说明不同的给药途径如何提高疗效。TD139替代物的快速排泄表明不利于双糖的全身应用，而GB1107替代物延长的生物半衰期表明单糖的全身给药是可能的。
Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it is generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed with respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.