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Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT

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Abstract

Objective

p38 mitogen-activated protein (MAP) kinase (p38α) has drawn attention as a new target molecule for the treatment and diagnosis of cancer, and its overexpression and activation have been reported in various types of cancer. In this study, a single photon emission computed tomography (SPECT) imaging probe of p38α was developed to noninvasively image p38α activity for effective qualitative diagnosis of cancer.

Methods

Pyrrolepyridine derivatives, m-YTM and p-YTM, were designed and synthesized based on the structure of the p38α-selective inhibitor. Radioactive iodine-labeled m-YTM, [125I]m-YTM, was synthesized because m-YTM greatly inhibited the phosphorylation of p38α upon examining the inhibitory effects of the compounds. After investigating the binding affinity of [125I]m-YTM to the recombinant p38α, a saturation binding experiment using activated p38α and inactive p38α was performed to determine the binding site. Uptake of [125I]m-YTM into various cancer cell lines was investigated, and the pharmacokinetics was evaluated using tumor-bearing mice.

Results

The inhibitory activity of m-YTM was approximately 13 times higher than that of SB203580, a p38α-selective inhibitor. The binding site of [125I]m-YTM was estimated to be the p38α activating site, similar to that of SB203580, because the [125I]m-YTM bound strongly to both activated p38α and inactive p38α. Various different cancer cells incorporated [125I]m-YTM; however, its accumulation was significantly reduced by treatment with SB203580. Pharmacokinetics study of [125I]m-YTM in B-16 tumor-bearing mice was examined which revealed high accumulation of radioactivity in tumor tissues. The ratios of radioactivity in the B-16 tumor to that in blood were 3.1 and 50 after 1 and 24 h, respectively. The ratio of radioactivity in the tumor to that in blood in the tumor-bearing mice generated using other cancer cell lines was also ≥ 1 at 1 h after the administration of the probe.

Conclusions

This study suggests that [123I]m-YTM has potential as a p38α imaging probe effective for various cancer types.

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Funding

This work was partly supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 12770512). There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan

    Masahiko Hirata, Tatsuma Yao, Shigeaki Fujimura, Yasukazu Kanai, Mitsuyoshi Yoshimoto, Takaji Sato, Yoshiro Ohmomo & Takashi Temma

  2. Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Mitsuyoshi Yoshimoto

Authors
  1. Masahiko Hirata
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  2. Tatsuma Yao
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  3. Shigeaki Fujimura
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  4. Yasukazu Kanai
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  5. Mitsuyoshi Yoshimoto
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  6. Takaji Sato
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  7. Yoshiro Ohmomo
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  8. Takashi Temma
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Correspondence to Takashi Temma.

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Hirata, M., Yao, T., Fujimura, S. et al. Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT. Ann Nucl Med 33, 333–343 (2019). https://doi.org/10.1007/s12149-019-01341-0

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  • DOI: https://doi.org/10.1007/s12149-019-01341-0

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