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

Abstract

INTRODUCTION:

Based on the concept of bifunctional radiopharmaceuticals, we have previously developed (186)Re-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 (90)Y-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. [(90)Y]DOTA-complex-conjugated bisphosphonate ([(90)Y]DOTA-HBP) was prepared by coordination with (90)Y, and its biodistribution was studied in comparison to [(90)Y]citrate.

RESULTS:

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

CONCLUSIONS:

[(90)Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [(90)Y]citrate. Since the DOTA ligand forms a stable complex not only with (90)Y but also with lutetium ((177)Lu), indium ((111)In), gallium ((67/68)Ga), 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.

• Authors: Kazuma Ogawa, Hidekazu Kawashima, Kazuhiro Shiba, Kohshin Washiyama, Mitsuyoshi Yoshimoto, Yasushi Kiyono, Masashi Ueda, Hirofumi Mori, Hideo Saji
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 36 Issue 2 Pg. 129-35 (Feb 2009) ISSN: 0969-8051 [Print] United States
• PMID: 19217524 (Publication Type: Journal Article)

Chemical References

• Diphosphonates
• Heterocyclic Compounds, 1-Ring
• Radiopharmaceuticals
• Yttrium Radioisotopes
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

Topics

• Animals
• Bone Neoplasms (radiotherapy, secondary)
• Diphosphonates (chemistry, pharmacokinetics, therapeutic use)
• Drug Stability
• Heterocyclic Compounds, 1-Ring (chemistry, therapeutic use)
• Isotope Labeling (methods)
• Male
• Mice
• Radiopharmaceuticals (chemistry, pharmacokinetics, therapeutic use)
• Radiotherapy Dosage
• Tissue Distribution
• Yttrium Radioisotopes (chemistry, pharmacokinetics, therapeutic use)