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Fundamental study of radiogallium-labeled aspartic acid peptides introducing octreotate derivatives

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Abstract

Objective

Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To simultaneously detect not only primary cancer but also bone metastases, this study aimed to develop a positron emission tomography probe using generator-produced nuclide Gallium-68 (T1/2 = 68 min), in which a carrier for primary cancer, a carrier for bone metastases lesions, and a stable gallium complex are introduced into the one molecule. Based on this strategy, the somatostatin receptor-targeted peptide, [Tyr3]-octreotate (TATE), aspartic acid peptide (Dn) with high binding affinity for hydroxyapatite, and Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a stable gallium complex were selected. The novel complexes, Ga-DOTA-Dn-TATE (n = 0, 2, 5, 8, or 11), were designed, synthesized, and evaluated. The radiogallium complexes were prepared using the easy-to-handle radioisotope 67Ga due to relatively long half-life.

Methods

The radiogallium complex precursor DOTA-Dn-TATE was synthesized by the Fmoc-based solid-phase method and by the air oxidation method to form the disulfide bond. [67Ga]Ga-DOTA-Dn-TATE was synthesized by reacting DOTA-Dn-TATE and 67Ga. Hydroxyapatite binding assays, in vitro cellular uptake experiments in AR42J tumor cells, in biodistribution experiments in AR42J tumor-bearing mice, were performed using [67Ga]Ga-DOTA-Dn-TATE.

Results

The radiochemical purities of [67Ga]Ga-DOTA-Dn-TATE were > 96.0%. In in vitro and in vivo experiments, [67Ga]Ga-DOTA-D11-TATE had a high affinity for hydroxyapatite and highly accumulated in bone. However, the uptake of [67Ga]Ga-DOTA-D11-TATE into somatostatin receptor-positive AR42J cells was lower than that of [67Ga]Ga-DOTA-TATE, and the accumulation of [67Ga]Ga-DOTA-D11-TATE in tumor was significantly low.

Conclusion

Ga-DOTA-D11-TATE may not be recognized by somatostatin receptor by the introduction of D11, and the charge adjustment may be important for somatostatin receptor-positive cell uptake.

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Acknowledgements

This work was supported in part by Sagawa Foundation for Promotion of Cancer Research, Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI Grant Number 15K09948) from Japan Society for the Promotion of Science, Terumo Life Science Foundation, and Mochida Memorial Foundation for Medical and Pharmaceutical Research.

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Authors and Affiliations

  1. Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

    Atsushi Ishizaki, Seigo Kinuya, Akira Odani & Kazuma Ogawa

  2. Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Japan

    Kenji Mishiro & Kazuma Ogawa

  3. Advanced Science Research Center, Kanazawa University, Kanazawa, Japan

    Kazuhiro Shiba

  4. Department of Bioimaging Information Analysis, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Hirofumi Hanaoka

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  1. Atsushi Ishizaki
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Correspondence to Kazuma Ogawa.

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Ishizaki, A., Mishiro, K., Shiba, K. et al. Fundamental study of radiogallium-labeled aspartic acid peptides introducing octreotate derivatives. Ann Nucl Med 33, 244–251 (2019). https://doi.org/10.1007/s12149-018-01326-5

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  • DOI: https://doi.org/10.1007/s12149-018-01326-5

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