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Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for Improved in vivo Stability in Tracer Design
ChemMedChem ( IF 3.4 ) Pub Date : 2018-01-16 , DOI: 10.1002/cmdc.201700543
Alexander Axer 1, 2 , Sven Hermann 2, 3, 4 , Gerald Kehr 1 , David Clases 5 , Uwe Karst 2, 5 , Lena Fischer-Riepe 6 , Johannes Roth 2, 4, 6 , Manfred Fobker 7 , Michael Schäfers 2, 3, 4, 8 , Ryan Gilmour 1, 2 , Andreas Faust 2, 3, 4
Affiliation  

Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria‐specific metabolic pathways, such as the maltodextrin transport mechanism, may allow specific localization and imaging of small or hidden colonies. This requires that the intrabacterial tracer accumulation provided by the transporter is matched by high serum stability of the tracer molecule. Herein, radiolabeled maltodextrins of varying chain lengths and with free nonreducing/reducing ends are reported and their behavior against starch‐degrading enzymes in the blood, which compromise their serum stability, is evaluated. Successful single‐photon emission computed tomography (SPECT) imaging is shown in a footpad infection model in vivo by using the newly developed model tracer, [99mTc]MB1143, and the signal is compared with that of 18F‐fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET) as a nonbacterial specific marker for inflammation. Although the [99mTc]MB1143 imaging signal is highly specific, it is low, most probably due to insufficient serum stability of the tracer. A series of stability tests with different 18F‐labeled maltodextrins finally yielded clear structural guidelines regarding substitution patterns and chain lengths of maltodextrin‐based tracers for nuclear imaging of bacterial infections.

中文翻译:

利用麦芽糖糊精的靶向细菌成像运输机制:示踪剂设计中提高体内稳定性的结构要求。

细菌感染的诊断和定位仍然是一项重大的临床挑战。利用细菌特有的代谢途径,例如麦芽糖糊精的转运机制,可以对小的或隐藏的菌落进行特异性定位和成像。这要求由转运蛋白提供的细菌内示踪剂积累与示踪剂分子的高血清稳定性相匹配。在此,报道了具有不同链长且具有自由的非还原/还原末端的放射性标记的麦芽糖糊精,并评估了它们对抗血液中淀粉降解酶的行为,从而损害了它们的血清稳定性。使用新开发的模型示踪剂[ 99m Tc] ,成功的单光子发射计算机断层扫描(SPECT)成像显示在体内的脚掌感染模型中。MB1143,并将该信号与18 F-氟脱氧葡萄糖正电子发射断层扫描([ 18 F] FDG-PET)的信号作比较,以作为炎症的非细菌特异性标志物。尽管[ 99m Tc] MB1143成像信号具有很高的特异性,但它很低,很可能是由于示踪剂的血清稳定性不足所致。最终,使用18种F-标记的麦芽糖糊精进行了一系列稳定性测试,最终得出了清晰的结构指导,涉及基于麦芽糊精的示踪剂的取代模式和链长,用于细菌感染的核显像。
更新日期:2018-01-16
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