Syntheses and relaxation properties of mixed gadolinium hydroxypyridinonate MRI contrast agents.
The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2- didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 degrees C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5-4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (< 100 ns), higher molecular weights (> 700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1: Z = 4, a = 15.6963(2) A, b = 16.9978(1) A, c = 17.1578(2) A, alpha = 61.981(1) degrees, beta = 75.680(1) degrees, gamma = 71.600(1) degrees), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.
Cohen
S M
SM
Department of Chemistry, University of California, Berkeley, California 94720, USA.
Xu
J
J
Radkov
E
E
Raymond
K N
KN
Botta
M
M
Barge
A
A
Aime
S
S
D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005682:Gadolinium; D007202:Indicators and Reagents; D007502:Iron Chelating Agents / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
D003287:Contrast Media; D007202:Indicators and Reagents; D007502:Iron Chelating Agents; D011728:Pyridones; C409502:tris((3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl)amine; D005682:Gadolinium