Al(18)F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging.
Al(18)F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging.
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DOI：
10.7150/thno.20094
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Bormans G
中科院分区：
文献类型：
--
作者：
Cleeren F;Lecina J;Ahamed M;Raes G;Devoogdt N;Caveliers V;McQuade P;Rubins DJ;Li W;Verbruggen A;Xavier C;Bormans G
利用放射性标记生物分子的正电子发射断层扫描(PET)是一种翻译分子成像技术，越来越多地被用于支持药物开发。目前用氟-18标记生物分子的方法费时费力，而且需要多步程序，标记产量适中。Al18F-标记策略包括在单一[18F]氟化铝({Al18F}2+)的水介质中通过与生物分子偶联的合适的螯合剂进行螯合。然而，络合反应所需的高温(100-120℃)限制了它的广泛使用。因此，我们设计了一种新的抑制络合剂(RECA)，用于在室温下应用ALF策略。方法：研究方法。将新的螯合剂Resca连接到三种相关的生物制剂上，并用{Al18F}2+标记构建物，以评估一步Al18F-Resca方法的通用适用性。结果。我们成功地在不到30分钟的时间内以优异的放射化学产率标记了人血清白蛋白，并证实了Al18F标记蛋白在大鼠体内的稳定性。此外，我们有效地标记了针对Kupffer细胞标记Crig的纳米体，并在健康和Crig缺陷小鼠身上进行了µPET研究，以证明所提出的放射性标记方法不会影响蛋白质的功能完整性。最后，对靶向HER2的亲和体(PEP04314)进行了定点标记，并用全身PET/CT方法比较了(±)-[18F]Alf(ResCA)-PEP04314和[18F]Alf(NOTA)-PEP04314在恒河猴体内的分布。结论。这种通用的放射性标记方法有可能成为一种基于试剂盒的氟-18标记策略，并可能对PET放射化学领域产生重大影响，可能使许多新的氟-18标记蛋白质放射性示踪剂的开发成为可能。
Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al18F-labeling strategy involves chelation in aqueous medium of aluminum mono[18F]fluoride ({Al18F}2+) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature. Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al18F}2+ to evaluate the generic applicability of the one-step Al18F-RESCA-method. Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al18F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[18F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [18F]AlF(NOTA)-PEP04314 using whole-body PET/CT. Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers.