期刊
BIOCONJUGATE CHEMISTRY
卷 29, 期 10, 页码 3483-3494出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.8b00642
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资金
- National Institute of Biomedical Imaging and Bioengineering [R21-EB020737]
- National Natural Science Foundation of China [81801738]
- Fundamental Research Fund for the Chinese Central Universities of Huazhong University of Science and Technology (HUST) [2017KFYXJJ235, 2016YXMS140, 2016YXMS147, 2016JCTD109, 2014TS090]
- opening foundation of Hubei key laboratory of molecular imaging [02.03.2017-187]
- research foundation of Wuhan Union Hospital [02.03.2017-12]
- Natural Science Foundation of Hubei Province, China [2016CFB379]
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R21EB020737] Funding Source: NIH RePORTER
Due to the increasing use of generator-produced radiometal Gallium-68 (Ga-68) in positron-emission tomography/computed tomography (PET/CT), reliable bifunctional chelators that can efficiently incorporate Ga-68(3+) into biomolecules are highly desirable. In this study, we synthesized two new bifunctional chelators bearing one or two phosphonic acid functional groups, named p-SCN-PhPr-NE2A1P and p-SCN-PhPr-NE2P1A, with the aim of enabling facile production of Ga-68-based radiopharmaceuticals. Both chelators were successfully conjugated to LLP2A-PEG(4), a very late antigen-4 (VLA-4) targeting peptidomimetic ligand, to evaluate their application in Ga-68-based PET imaging. NE2P1A-PEG(4)-LLP2A exhibited the highest Ga-68(3+) binding ability with molar activity of 37 MBq/nmol under mild temperature and neutral pH. Excellent serum stability of Ga-68-NE2P1A-PEG(4)-LLP2A was observed, which was consistent with the result obtained from density functional theory calculation. The in vitro cell study showed that Ga-68-NE2P1A-PEG(4)-LLP2A had significantly longer retention in B16F10 cells comparing to the reported retention of Cu-64-NE3TA-PEG(4)-LLP2A, although the uptake was relatively lower. In the biodistribution and micro-PET/CT imaging studies, high tumor uptake and low background were observed after Ga-68-NE2P1A-PEG(4)-LLP2A was injected into mice bearing B16F10 tumor xenografts, making it a highly promising radiotracer for noninvasive imaging of VLA-4 receptors overexpressed in melanoma.
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