Synthesis and biological evaluation of newly designed phosphonate based bone-seeking agent

Eur J Med Chem. 2013 Jul:65:12-20. doi: 10.1016/j.ejmech.2013.03.036. Epub 2013 Apr 17.

Abstract

A cyclic tetraaza based bifunctional triphosphonate ligand 10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3MP-EA) was synthesized as bone-seeking theranostic agent. The compound was characterized by spectroscopic techniques and labelled with (99m)Tc with more than 97% purity. Blood clearance of 99mTc labelled compound a quick wash out from the circulation. The compound was excreted mainly via kidneys and accumulation of (99m)Tc-DO3MP-EA in bone was 9.53 ± 1.06% of injected dose per gram of bone at 1 h. The preliminary CADD analysis confirms the efficacy of DO3MP-EA (G Score -7.005) as better binding agent for osteocalcin (pdb 1Q8H) rather than other known clinical agents. Subsequently stability constant of chelate with Ga(III) was found to be 18.6 which confirms its efficacy as (68)Ga labelled PET radiopharmaceutical for bone.

Keywords: DOTMP; Diagnostic agent; Ga; PET; Phosphonate; SPECT; Tc.

MeSH terms

  • Animals
  • Bone and Bones / diagnostic imaging*
  • Bone and Bones / metabolism
  • Chelating Agents / chemical synthesis
  • Chelating Agents / pharmacokinetics*
  • Drug Design*
  • Gallium Radioisotopes
  • Heterocyclic Compounds, 1-Ring / chemical synthesis
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics*
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Organ Specificity
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / pharmacokinetics*
  • Organotechnetium Compounds / chemical synthesis
  • Organotechnetium Compounds / pharmacokinetics*
  • Rabbits
  • Radionuclide Imaging
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics*
  • Tissue Distribution

Substances

  • 10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid)
  • Chelating Agents
  • Gallium Radioisotopes
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Organophosphorus Compounds
  • Organotechnetium Compounds
  • Radiopharmaceuticals