Development of Radiopharmaceuticals for Diagnosis and Therapy of Metastatic Bone Cancer

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  • Ogawa Kazuma
    Graduate School of Medical, Pharmaceutical and Health Sciences, Kanazawa University

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  • 転移性骨腫瘍の核医学診断・治療を目的とした薬剤の開発研究
  • テンイセイコツ シュヨウ ノ カク イガク シンダン ・ チリョウ オ モクテキ ト シタ ヤクザイ ノ カイハツ ケンキュウ

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Abstract

  Rhemium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. However, delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of 186Re-HEDP. We designed, synthesized and evaluated a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl] carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) (186Re-MAG3-HBP). The stability of 186Re-MAG3-HBP and 186Re-HEDP in phosphate buffer were compared. No measurable decomposition of 186Re-MAG3-HBP occurred, while only approximately 30% of 186Re-HEDP remained intact 24 hours post-incubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of 186Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower. To evaluate the therapeutic effects of 186Re-MAG3-HBP, an animal model of bone metastasis was prepared. In the rats treated with 186Re-HEDP, tumor growth was comparable to that in untreated rats. In contrast, when 186Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Bone pain was attenuated by treatment with 186Re-MAG3-HBP or 186Re-HEDP, but 186Re-MAG3-HBP tended to be more effective. These results indicate that 186Re-MAG3-HBP could be useful as a therapeutic agent of metastatic bone pain. Moreover, based on the similar concept, we designed, synthesized, and evaluated a 99mTc-6-hydrazinopyridine-3-carboxylic acid-conjugated bisphosphonate (99mTc-HYNIC-HBP) as a bone scintigraphic agent. 99mTc-HYNIC-HBP gave higher levels of radioactivity in bone than 99mTc-HMDP. There was no significant difference in clearance from blood between 99mTc-HYNIC-HBP and 99mTc-HMDP. Consequently, 99mTc-HYNIC-HBP showed a higher bone-to-blood ratio than 99mTc-HMDP. The findings indicate that 99mTc-HYNIC-HBP holds great potential for bone scintigraphy.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 132 (10), 1151-1157, 2012-10-01

    The Pharmaceutical Society of Japan

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