title: Synthesis and evaluation of a novel 68Ga-chelate-conjugated bisphosphonate as a bone-seeking agent for PET imaging.
abstract: BACKGROUND
  (68)Ga is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced (18)F, the isotope can be produced on-site utilizing a (68)Ge/(68)Ga generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the (68)Ga chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this (68)Ga bone-seeking radiopharmaceutical in the detection of bone metastases.
  
  
  METHODS
  4-Amino-1-hydroxybutylidene-1,1-bisphosphonate was conjugated with 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]pentanedioic acid, yielding 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]-5-[(4-hydroxy-4,4-diphosphonobutyl)amino]-5-oxopentanoic acid (NOTA-BP). (68)Ga-labeled NOTA-BP ([(68)Ga]NOTA-BP) was prepared by complexation of NOTA-BP with [(68)Ga] gallium chloride and evaluated in in vitro experiments, biodistribution experiments and micro-positron emission tomography (PET) imaging experiments.
  
  
  RESULTS
  The labeling of NOTA-BP with (68)Ga was completed by heating for 10 min. [(68)Ga]NOTA-BP was determined to have a radiochemical purity of over 95%, a high affinity for hydroxyapatite and a high stability in plasma. In in vivo biodistribution experiments, [(68)Ga]NOTA-BP demonstrated high bone uptake potential. Compared with (99m)Tc-labeled methylene diphosphonate ([(99m)Tc]MDP) and [(18)F]fluoride, [(68)Ga]NOTA-BP exhibited faster blood clearance and a higher bone-to-blood ratio. In addition, mouse model bone metastasis was detected by micro-PET imaging at 1 h postinjection of [(68)Ga]NOTA-BP.
  
  
  CONCLUSIONS
  We have developed a novel (68)Ga-radiolabeled bone-seeking agent. This [(68)Ga]NOTA-BP complex was found to have a high bone affinity and rapid blood clearance, and may thus prove to be useful as a bone-seeking agent for clinical PET.
authors: Research Department, Fujifilm RI Pharma Co., Ltd., Sammu-City, Chiba, 289-1592 Japan. skentarou@ffri.co.jp
authors: Kentaro
authors: K
authors: Suzuki
authors: Miho
authors: M
authors: Satake
authors: Jun
authors: J
authors: Suwada
authors: Shinobu
authors: S
authors: Oshikiri
authors: Hiroki
authors: H
authors: Ashino
authors: Hiroyuki
authors: H
authors: Dozono
authors: Akihiro
authors: A
authors: Hino
authors: Hiroyuki
authors: H
authors: Kasahara
authors: Takao
authors: T
authors: Minamizawa
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000556:secondary; D001842:Bone and Bones / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D017886:Durapatite / Q000378:metabolism; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008297:Male; D051379:Mice; D010014:Osteolysis / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000473:pathology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results
chemical_list: D002614:Chelating Agents; D004164:Diphosphonates; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D017886:Durapatite