Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands

J Med Chem. 1994 Dec 9;37(25):4400-6. doi: 10.1021/jm00051a018.

Abstract

A series of 10 cationic gallium(III) complexes with hexadentate bis(salicylaldimine) ligands were synthesized, characterized, radiolabeled with 67Ga, and screened in a rat model to assess their potential as 68Ga radiopharmaceuticals for imaging the heart with positron emission tomography. The tris(salicylaldimine) ligand precursors were synthesized by condensation of either bis(3-aminopropyl)ethylenediamine (BAPEN) or bis(2,2-dimethyl-3-aminopropyl)ethylenediamine (DM-BAPEN) with 3 equiv of a salicylaldehyde derivative containing alkyl, alkoxy, or alkylamino substituents in the 4, 5, or 6 position of the aromatic ring. The cationic six-coordinate gallium(III) bis(salicylaldimine) complexes were obtained by reaction of these tris(salicylaldimines) with tris(acetylacetonato)gallium(III). X-ray crystallographic confirmation of the molecular structure of Ga[(4,6-(MeO)2sal)2DM-BAPEN]+I- shows the Ga cation to adopt a pseudo-octahedral N4O2 coordination sphere with a trans configuration. All of the 67Ga complexes are lipophilic with measured octanol/water partition coefficients (P) varying from log P = 0.84 to 3.00. These 67Ga-labeled complexes are all found to exhibit significant myocardial uptake following intravenous administration to rats (ranging from 0.34 to 1.08% of the injected dose in myocardium at 1 min postinjection) combined with the desired myocardial retention of tracer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cations
  • Crystallography, X-Ray
  • Ethylenediamines / chemistry*
  • Ethylenediamines / pharmacokinetics
  • Gallium Radioisotopes / chemistry*
  • Kinetics
  • Liver / metabolism
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Myocardium / metabolism*
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tissue Distribution
  • Tomography, Emission-Computed*

Substances

  • Cations
  • Ethylenediamines
  • Gallium Radioisotopes
  • Organometallic Compounds
  • gallium bis(4,6-dimethoxy)salicylaldimine N,N'-bis(3-aminopropyl)ethylenediamine