Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

Ogawa, Kazuma; Kawashima, Hidekazu; Shiba, Kazuhiro; Washiyama, Kohshin; Yoshimoto, Mitsuyoshi; Kiyono, Yasushi; Ueda, Masashi; Mori, Hirofumi; Saji, Hideo

doi:10.1016/j.nucmedbio.2008.11.007

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 2 , Pages 129-135, February 2009

Development of [⁹⁰Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

Kazuma Ogawa
- Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan
- Corresponding author. Tel.: +81 76 265 2476; fax: +81 76 234 4245.
Hidekazu Kawashima
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
- Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Kazuhiro Shiba
- Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan
Kohshin Washiyama
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0942, Japan
Mitsuyoshi Yoshimoto
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0942, Japan
Yasushi Kiyono
- Biomedical Imaging Research Center, University of Fukui, Yoshida-gun 910-1193, Japan
- Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
Masashi Ueda
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
- Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
Hirofumi Mori
- Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan
Hideo Saji
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan

Received 19 December 2007; received in revised form 23 September 2008; accepted 19 November 2008.

Abstract

Introduction

Based on the concept of bifunctional radiopharmaceuticals, we have previously developed ¹⁸⁶Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed ⁹⁰Y-labeled radiopharmaceutical could be developed.

Methods

In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [⁹⁰Y]DOTA-complex-conjugated bisphosphonate ([⁹⁰Y]DOTA-HBP) was prepared by coordination with ⁹⁰Y, and its biodistribution was studied in comparison to [⁹⁰Y]citrate.

Results

In biodistribution experiments, [⁹⁰Y]DOTA-HBP and [⁹⁰Y]citrate rapidly accumulated and resided in the bone. Although [⁹⁰Y]citrate showed a higher level of accumulation in the bone than [⁹⁰Y]DOTA-HBP, the clearances of [⁹⁰Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [⁹⁰Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [⁹⁰Y]DOTA-HBP were lower than those of [⁹⁰Y]citrate.

Conclusions

[⁹⁰Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [⁹⁰Y]citrate. Since the DOTA ligand forms a stable complex not only with ⁹⁰Y but also with lutetium (¹⁷⁷Lu), indium (¹¹¹In), gallium (^67/68Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.

Keywords: Yttrium-90, DOTA, Bisphosphonate, Bone, Palliation, Radiation dose