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Comparison of Al18F- and 68Ga-labeled NOTA-PEG4-LLP2A for PET imaging of very late antigen-4 in melanoma

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Abstract

Malignant melanoma is an aggressive cancer with poor prognosis. Very late antigen-4 (VLA-4) is overexpressed in melanoma and many other tumors, making it an attractive target for developing molecular diagnostic and therapeutic agents. We compared Al18F- and 68Ga-labeled LLP2A peptides for PET imaging of VLA-4 expression in melanoma. The peptidomimetic ligand LLP2A was modified with chelator 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and the resulting NOTA-PEG4-LLP2A peptide was then radiolabeled with Al18F or 68Ga. The two labeled peptides were assayed for in vitro and in vivo VLA-4 targeting efficiency. Good Al18F and 68Ga radiolabeling yields were achieved, and the resulting PET tracers showed good serum stability. In the in vivo evaluation of the B16F10 xenograft mouse model, both tracers exhibited high accumulation with good contrast in static PET images. Compared with 68Ga-NOTA-PEG4-LLP2A, Al18F-NOTA-PEG4-LLP2A resulted in relatively higher background, including higher liver uptake (1 h: 20.1 ± 2.6 vs. 15.3 ± 1.7%ID/g, P < 0.05; 2 h: 11.0 ± 1.2 vs. 8.0 ± 0.8%ID/g, P < 0.05) and lower tumor-to-blood ratios (2.5 ± 0.4 vs. 3.3 ± 0.5 at 1 h, P < 0.05; 5.1 ± 0.9 vs. 7.3 ± 0.6 at 2 h, P < 0.01) at some time points. The results obtained from the mice blocked with unlabeled peptides and VLA-4-negative A375 xenografts groups confirmed the high specificity of the developed tracers. Despite the relatively high liver uptake, both Al18F-NOTA-PEG4-LLP2A and 68Ga-NOTA-PEG4-LLP2A exhibited high VLA-4 targeting efficacy with comparable in vivo performance, rendering them promising candidates for imaging tumors that overexpress VLA-4.

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Acknowledgements

This work was supported, in part, by the National Natural Science Foundation of China (Nos. 81801738 and 81630049), the Fundamental Research Fund for the Chinese Central Universities of Huazhong University of Science and Technology (2017KFYXJJ235), opening foundation of Hubei key laboratory of molecular imaging (02.03.2017-187) and research foundation of Wuhan Union Hospital (02.03.2017-12). We also acknowledge the support from the National Institute of Biomedical Imaging and Bioengineering grant R21-EB020737, and the American Cancer Society Research Scholar ACS-RSG-17-004-01-CCE.

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  1. Yongkang Gai and Lujie Yuan contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yongkang Gai, Lujie Yuan, Huiling Li, Mengting Li, Hanyi Fang, Bouhari Altine, Qingyao Liu, Yongxue Zhang & Xiaoli Lan

  2. Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China

    Yongkang Gai, Lujie Yuan, Huiling Li, Mengting Li, Hanyi Fang, Bouhari Altine, Qingyao Liu, Yongxue Zhang & Xiaoli Lan

  3. Center for Radiochemistry Research, Department of Diagnostic Radiology, Oregon Health and Science University, Portland, OR, 97239, USA

    Lingyi Sun & Dexing Zeng

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  1. Yongkang Gai
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Gai, Y., Yuan, L., Sun, L. et al. Comparison of Al18F- and 68Ga-labeled NOTA-PEG4-LLP2A for PET imaging of very late antigen-4 in melanoma. J Biol Inorg Chem 25, 99–108 (2020). https://doi.org/10.1007/s00775-019-01742-6

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