Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands.
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.
Tsang
B W
BW
Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907-1333.
Mathias
C J
CJ
Fanwick
P E
PE
Green
M A
MA
D000818:Animals; D002412:Cations; D018360:Crystallography, X-Ray; D005029:Ethylenediamines / Q000737:chemistry* / Q000493:pharmacokinetics; D005710:Gallium Radioisotopes / Q000737:chemistry*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D002412:Cations; D005029:Ethylenediamines; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; C081867:gallium bis(4,6-dimethoxy)salicylaldimine N,N'-bis(3-aminopropyl)ethylenediamine