Macrocyclic diamide ligand systems: potential chelators for 64Cu- and 68Ga-based positron emission tomography imaging agents

Inorg Chem. 2009 Aug 3;48(15):7117-26. doi: 10.1021/ic900307f.

Abstract

The N(4)-macrocyclic ligand 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene H(2)L has been synthesized by the [1 + 1] condensation reaction between N,N'-bis(chloroacetyl)-1,2-phenylenediamine and 1,3-propylenediamine. The coordination chemistry of this ligand has been investigated with the metal ions Cu(II), Ni(II), Zn(II), and Ga(III) (complexes 1, 2, 3 and 4, respectively). H(2)L and its metal complexes have been fully characterized by the use of NMR, UV/vis, electron paramagnetic resonance, and elemental analysis where appropriate. The four metal complexes 1-4 have been structurally characterized by X-ray crystallography which confirmed that in all cases the amide nitrogen atoms are deprotonated and coordinated to the metal center. Complexes 3 and 4 are five-coordinate with a water molecule and chloride ion occupying the apical site, respectively. Cyclic voltammetric measurements on complex 1 show that this complex is oxidized reversibly with a half-wave potential, E(1/2) = 0.47 V, and reduced irreversibly at E(P) = -1.84 V. Density functional theory calculations reproduce the geometries of the four complexes. The one-electron reduction and oxidation potentials for 1 were calculated by using two solvent models, DMF and H(2)O. The calculations indicated that the one electron oxidation of 1 may involve removal of an electron from the ligand as opposed to the metal center, producing a diradical. The diamide macrocyle is of interest for the development of new positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents, and a radiolabeled complex has been synthesized with the positron emitting isotope (64)Cu. In vivo biodistribution studies for the (64)Cu labeled complex, (64)Cu-1, in male Lewis rats, showed that the activity is cleared rapidly from the blood within 1-2 h post-administration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Chelating Agents / chemistry*
  • Copper Radioisotopes / chemistry
  • Crystallography, X-Ray
  • Electrochemical Techniques
  • Gallium Radioisotopes / chemistry
  • Ligands
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Models, Molecular
  • Molecular Structure
  • Positron-Emission Tomography
  • Rats
  • Rats, Inbred Lew

Substances

  • 2,10-dioxo-1,4,8,11-tetraazabicyclo(11.4.0)1,12-heptadeca-1(12),14,16-triene
  • Bridged Bicyclo Compounds, Heterocyclic
  • Chelating Agents
  • Copper Radioisotopes
  • Gallium Radioisotopes
  • Ligands
  • Macrocyclic Compounds