title: Development of [(90)Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases.
abstract: BACKGROUND
  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.affiliation: Advanced Science Research Center, Kanazawa University, Kanazawa, Japan. kogawa@med.kanazawa-u.ac.jp
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kawashima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Kohshin
authors.initials: K
authors.lastname: Washiyama
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mori
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D004164:Diphosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004355:Drug Stability; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000627:therapeutic use; D007553:Isotope Labeling / Q000379:methods*; D008297:Male; D051379:Mice; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D004164:Diphosphonates; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid