Tuning the Coordination Number of Hydroxypyridonate-Based Gadolinium Complexes:  Implications for MRI Contrast Agents

Abstract

Eight-coordinate hydroxypyridinone/terephthalamide Gd(III) complexes display high relaxivities due to their two inner sphere water molecules. This relaxivity can be further increased by functionalizing the terephthalamide moiety with an amine. A significant hydrogen bonding interaction between the amine and another water molecule close to the Gd III apparently facilitates its coordination on the open site of the metal. The resulting nine-coordinate complex has 3 inner sphere water molecules, while maintaining high stability and fast ligand exchange rates.With seven unpaired electrons and a long electronic relaxation time, Gd III is ideal for use as a relaxation agent in Magnetic Resonance Imaging (MRI). Its high toxicity, however, requires that it be complexed by a strong chelator for in vivo applications. Current commercial poly-(amino carboxylate) based chelates have only one water molecule coordinated, which exchanges too slowly with the bulk solvent such that it limits the image enhancing capability (relaxivity, r 1p ) of macromolecular derivatives. 2 The development of second generation agents, for example site-specific, requires much higher relaxivity. As predicted by the Solomon-Bloembergen-Morgan theory, this can be achieved by increasing the number of water molecules coordinated to the Gd III without destabilizing the complex. 2 We have previously reported hydroxypyridonate (HOPO) based Gd III chelates which display high relaxivity while maintaining high stability. 3 In these complexes, the Gd III centers are eight-coordinate with a bicapped trigonal prism geometry. 4 Since the ligands are hexadentate, water molecules occupy two of the coordination sites of Gd III , resulting in a relaxivity double that of commercial agents. These complexes exchange water rapidly (k ex 1 0 8 s -1 ) through an associative interchange mechanism, suggesting that the eight and nine coordination states are close in energy. 5 This is supported by the structure of the La III analogue of TREN-1-Me-3,2-HOPO which crystallized as a dimer, with one La being eightcoordinate and the other nine. 6 The crystal structure of Gd-TREN-1-Me-3,2-HOPO indicates that filling the open coordination site of Gd III with a third water molecule would Correspondence to: Kenneth N. Raymond.raymond@socrates.berkeley.edu . Supporting Information Available: Detailed experimental procedures and characterization data for the synthesis of Gd-N1, Gd-N2 and Gd-N3; spectrophotometric titration data, pH-dependence of the hydrogen-bonding network of Gd-N3, temperature dependence of the paramagnetic contribution to the water 17 O NMR transverse relaxation rate (R 2p ) for Gd-N2, Gd-N1 and Gd-N3. This information is available free of charge via the internet at http://pubs.acs.org. 4 This indicates that it would be possible to stabilize the nine coordination state to achieve q=3 complexes which would still maintain high stability. One possibility to achieve this is to graft a hydrogen-bond acceptor, such as an amine on the terephthalamide moiety. A signif...

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…The energy difference between the 8-coordinate ground state and a 9-coordinate intermediate is small, leading to fast water exchange and subsequent high relaxivity (Figure 9). [62,70] This rapid exchange rate was initially supported by temperature-dependent relaxivity studies and the X-ray crystal structure of the La-TREN-1-Me-3,2-HOPO complex. In this structure both an 8-and a 9-coordinate metal center are observed.…”

Stability and Toxicity of Contrast Agents

“…These chelates usually have two inner-sphere water molecules and tend not to form ternary complexes with monodentate ligands. Unfortunately, the kinetic inertness of these complexes is expected to be considerably lower than Gd(DOTA) − and Gd(DO3A) [66,75,153]. Another interesting ligand, the pyridine-containing 12-membered macrocyclic chelate, PCTA, also forms thermodynamically stable, kinetically highly inert Gd 3+ chelate.…”

“…The superior kinetic inertness of macrocyclic Gd 3+ -based contrast agents has been demonstrated in in vitro experiments many times [275]. As early as 1988, it was noted that 153 Gd(DTPA) 2− deposited higher levels of 153 Gd in bone than 153 Gd(DOTA) − [276]. The first experimental evidence to support the idea that the in vitro acid catalyzed dissociation rates accurately predict the fate of a complex in vivo was reported in 1992 [219].…”

Highly Soluble Tris-hydroxypyridonate Gd(III) Complexes with Increased Hydration Number, Fast Water Exchange, Slow Electronic Relaxation, and High Relaxivity

“…For example, stabilization of the nine-coordinate, q = 3 ground state was recently reported in the TREN-bis-HOPO-TAM system by incorporating substituents on the terephthalamide (TAM) chelator capable of hydrogen bonding interactions with a third inner-sphere water as suggested by relaxivity and NMRD refinements. 9 While such an approach shows the potential for q = 3 complexes of higher relaxivity, the synthesis of the asymmetric bis-HOPOTAM compounds is arduous, requiring high-dilution, slow-addition reaction conditions for practical yields. It would be advantageous to generate soluble q = 3 complexes without the need for such a design to produce high-relaxivity agents which optimize not only q, but the other relevant parameters such as water exchange and electronic relaxation in a more straightforward manner.…”