Synthesis and evaluation of lanthanide ion DOTA-tetraamide complexes bearing peripheral hydroxyl groups.
The use of lanthanide-based contrast agents for magnetic resonance imaging has become an integral component of this important diagnostic modality. These inert chelates typically possess high thermodynamic stability constants that serve as a predictor for in vivo stability and low toxicity. Recently, a new class of contrast agents was reported having a significantly lower degree of thermodynamic stability while exhibiting biodistribution profiles indicative of high stability under biological conditions. These observations are suggestive that the nature of contrast agent stability is also dependent upon the kinetics of complex dissociation, a feature of potential importance when contemplating the design of new chelates for in vivo use. We present a study of the kinetics of acid-catalyzed dissociation, thermodynamic stability, serum stability, and biodistribution of a series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-tetraamide complexes that have been substituted with peripheral hydroxyl groups. The data indicate that these nontraditional contrast agents exhibit in vivo stability comparable to that of agents with much higher log K (ML) values, demonstrating the important contribution of kinetic inertness.
Pasha
Azhar
A
Department of Chemistry, University of Texas at Dallas, P.O. Box 803066, Richardson, TX 75083, USA.
Lin
Mai
M
Tircsó
Gyula
G
Rostollan
Cynthia L
CL
Woods
Mark
M
Kiefer
Garry E
GE
Sherry
A Dean
AD
Sun
Xiankai
X
D000577:Amides / Q000737:chemistry*; D000818:Animals; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D017665:Hydroxyl Radical / Q000097:blood / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D007700:Kinetics; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011199:Potentiometry; D011522:Protons; D051381:Rats; D013237:Stereoisomerism; D013816:Thermodynamics; D014018:Tissue Distribution
D000577:Amides; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D007477:Ions; D028581:Lanthanoid Series Elements; D008024:Ligands; D009942:Organometallic Compounds; D011522:Protons; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D017665:Hydroxyl Radical