Effects of targeting moiety, linker, bifunctional chelator, and molecular charge on biological properties of 64Cu-labeled triphenylphosphonium cations

J Med Chem. 2008 May 22;51(10):2971-84. doi: 10.1021/jm7015045. Epub 2008 Apr 18.


In this report, we present the synthesis and evaluation of six new 64Cu-labeled triphenylphosphonium (TPP) cations. Biodistribution studies were performed using the athymic nude mice bearing U87MG human glioma xenografts to explore the impact of TPP moieties, linkers, bifunctional chelators (BFCs), and molecular charge on biological properties of 64Cu radiotracers. On the basis of the results from this study, it is concluded that (1) mTPP (tris(4-methoxyphenyl)phosphonium) is a better mitochondrion-targeting molecule than TPP and 3mTPP (tris(2,4,6-trimethoxyphenyl)phosphonium); (2) DO3A (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid) and DO2A (1,4,7,10-tetraazacyclododecane-4,7-diacetic acid) are suitable BFCs for the 64Cu-labeling of TPP cations; (3) NOTA-Bn ( S-2-(4-thioureidobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid) has a significant adverse effect on the radiotracer tumor uptake and tumor-to-background ratios; and (4) monoanionic BFCs should be avoided to ensure that 64Cu chelate has a neutral or negative charge. Considering the tumor uptake and tumor/liver ratios, 64Cu(DO2A-xy-TPP)+ is the best candidate for more extensive evaluations in different tumor-bearing animal models.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cations
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacokinetics
  • Copper Radioisotopes*
  • Electricity
  • Humans
  • Liver / metabolism
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Nude
  • Mitochondria / physiology
  • Neoplasms, Experimental / diagnostic imaging
  • Neoplasms, Experimental / metabolism
  • Onium Compounds / chemical synthesis*
  • Onium Compounds / chemistry
  • Onium Compounds / pharmacokinetics
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacokinetics
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Structure-Activity Relationship
  • Technetium Tc 99m Sestamibi / pharmacokinetics
  • Tissue Distribution
  • Transplantation, Heterologous


  • Cations
  • Chelating Agents
  • Copper Radioisotopes
  • Onium Compounds
  • Organophosphorus Compounds
  • Radiopharmaceuticals
  • triphenylphosphine
  • Technetium Tc 99m Sestamibi