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Comparison of 18F-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression

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Molecular Imaging and Biology Aims and scope Submit manuscript

An Erratum to this article was published on 21 May 2013

Abstract

Purpose

CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation.

Procedures

Two new 18F-labeled radiotracers based on an Ac-TC14012 peptide, [18F]FP-Ac-TC14012 and [18F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [125I]CXCL12 radioligand. The cell uptake and retention of [18F]FP-labeled and [18F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies.

Results

The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [18F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [18F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [18F]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 μg), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake.

Conclusion

These results demonstrate that the [18F]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [18F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression.

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Acknowledgments

We want to thank the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) for the funding support. This work was performed while X-X Zhang held a National Research Council Research Associateship Award at NIH/NIBIB.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD, 20892, USA

    Xiao-Xiang Zhang, Jinxia Guo, Zhe Wang, Chenxi Wu, Gang Niu, Ying Ma, Dale O. Kiesewetter & Xiaoyuan Chen

  2. Department of Cardiology and Molecular Imaging Program, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Zhongchan Sun

  3. Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361005, China

    Jinxia Guo & Zhe Wang

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  1. Xiao-Xiang Zhang
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Corresponding authors

Correspondence to Dale O. Kiesewetter or Xiaoyuan Chen.

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Zhang, XX., Sun, Z., Guo, J. et al. Comparison of 18F-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression. Mol Imaging Biol 15, 758–767 (2013). https://doi.org/10.1007/s11307-013-0640-0

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