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Development of radioiodinated pyrimidinopyridone derivatives as targeted imaging probes of activated p38α for single photon emission computed tomography

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Abstract

Objective

p38α, a member of the mitogen-activated protein kinase superfamily, is ubiquitously expressed in a variety of mammalian cells. Activated p38α induces inflammatory responses to external stimuli, suggesting that non-invasive detection of activated p38α would be valuable for diagnosing inflammatory diseases. For this purpose, we designed radiolabeled compounds [123I]2-IR and [123I]4-IR based on a potent p38α selective inhibitor R1487 for use with single photon emission computed tomography (SPECT). In this study, we used 125I instead of 123I due to its more usable radiochemical properties, synthesized [125I]2-IR and [125I]4-IR, and evaluated their effectiveness as activated p38α imaging probes.

Methods

[123I]2-IR and [123I]4-IR were designed by introduction of a 123I atom at the 2- or 4-ositions of the phenoxy ring, preserving the pyrimidinopyridone structure of R1487. We synthesized 2-IR and 4-IR via a 7-step process. The inhibitory potencies of 2-IR, 4-IR, and p38α inhibitors were measured using an ADP-Glo™ kinase assay system. Radioiodination of 2-IR and 4-IR was performed via an organotin-radioiodine exchange reaction using the corresponding tributyltin precursors. Biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous administration of [125I]2-IR and [125I]4-IR in normal ddY mice and turpentine oil-induced inflammation model mice. In vivo inhibition study was also performed in inflammation model mice after intravenous administration of [125I]4-IR with pretreatment of p38α inhibitors.

Results

We synthesized 2-IR and 4-IR at total yields of 17.5% and 19.2%, respectively. 4-IR had higher p38α inhibitory potency than 2-IR; both compounds were significantly less potent than R1487. [125I]2-IR and [125I]4-IR were successfully obtained from tributyltin precursors with high radiochemical yield (> 65%), purity (> 97%), and molar activity (~ 81 GBq/µmol). [125I]4-IR showed high radioactivity accumulation in the inflamed tissue (7.0 ± 1.2%D/g), rapid delivery throughout the body, and rapid blood clearance, resulting in a high inflammation-to-blood ratio (6.2 ± 0.4) and a high inflammation-to-muscle ratio (5.2 ± 1.3) at 30 min, while [125I]2-IR showed low radioactivity accumulation in inflamed tissue over the experimental period. Further, radioactivity accumulation in inflamed tissue after [125I]4-IR administration was significantly decreased by pretreatment with selective inhibitors.

Conclusions

[123I]4-IR would be a promising imaging agent for detection of activated p38α.

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Acknowledgements

We are grateful for the technical assistance of Ms. Atsuko Takeguchi, Ms. Kaede Hanazono, Mr. Ryuji Kakisaka, Mr. Naofumi Yoshida, and Ms. Nami Nakai.

Funding

This work was supported in part by JSPS KAKENHI (19H03606).

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Authors and Affiliations

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

    Tomoyuki Hashimoto, Naoya Kondo, Masahiko Hirata & Takashi Temma

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  1. Tomoyuki Hashimoto
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  2. Naoya Kondo
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  3. Masahiko Hirata
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  4. Takashi Temma
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Contributions

TH, MH, and TT conceptualized and designed the study. TH, NK, and MH performed the experiments and collected the data. TH, NK, MH, and TT interpreted the data. TH drafted the initial manuscript, which was critically reviewed by NK and TT. All authors approved the final manuscript and are accountable for all of the work.

Corresponding author

Correspondence to Takashi Temma.

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All authors declare no conflicts of interests. The funding bodies had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

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Hashimoto, T., Kondo, N., Hirata, M. et al. Development of radioiodinated pyrimidinopyridone derivatives as targeted imaging probes of activated p38α for single photon emission computed tomography. Ann Nucl Med 35, 1293–1304 (2021). https://doi.org/10.1007/s12149-021-01669-6

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  • DOI: https://doi.org/10.1007/s12149-021-01669-6

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