A Highly Stable Gadolinium Complex with a Fast, Associative Mechanism of Water Exchange

Abstract

The prominence of magnetic resonance imaging (MRI) as a medical diagnostic technique has prompted intense interest in the development of contrast agents. The primary clinical contrast agents are nine-coordinate gadolinium (Gd III ) complexes based on a poly-(amino carboxylate) ligand and function by enhancing the relaxation rate of water protons. [1][2][3] The image enhancement capability (proton relaxivity, r 1p ) of current clinical contrast agents is only a few percent of that theoretically possible 2,4 due to the presence of only one inner sphere water molecule and a short rotational correlation time. When the rotational correlation time is optimized, the slow water exchange rate (k ex ≈ 10 6 s -1 ) becomes the limiting factor in attaining higher relaxivities. 1 Therefore, any rational design of a high-relaxivity contrast agent requires a thorough understanding of the mechanism of water exchange at the metal center.The Gd III complexes based on a hexadentate, hetero-tripodal hydroxypyridonate (HOPO) ligand, such as [Gd-TREN-bis(1-Me-HOPO)-(TAM-Me)(H 2 O) 2 ] (Gd-1) (Figure 1), are promising candidates for the development of second-generation MRI contrast agents. 5,6 In this series of complexes, the metal ion is eightcoordinate and possesses two inner sphere water molecules. 7 The generally high stability and fast water exchange of the complexes make them highly desirable as candidates for MRI. [Gd-TRENbis(6-Me-HOPO)-(TAM-TRI)(H 2 O) 2 ] (Gd-2) represents a new entry into this class of complexes and is based on a hetero-tripodal ligand design involving 6-Me-3,2-HOPO chelating units, as opposed to the 1-Me-3,2-HOPO isomer in the parent complex (Gd-1). A tri-(ethylene glycol) is conjugated to the terephthalamide (TAM) chelating unit to enhance the water solubility of the complex.The stability of a MRI contrast agent is critical, because the toxicity of the agent has been shown to be directly related to the concentration of free Gd III in vivo. 8 As contrast agent development is now oriented toward targeted imaging and longer in vivo residence times are sought, the thermodynamic stability of future agents will come under increased scrutiny. The stability of Gd-2 was assessed using both potentiometric and spectrophotometric titration techniques. The ligand protonation constants of TRENbis(6-Me-HOPO)-(TAM-TRI) (2) were determined by potentiometric titration. The experimental procedure, including instrumentation and solution preparations, is as described in detail in previous reports. 9-11 Ligand 2 is slightly more basic than 1, in keeping with the higher basicity of the 6-Me-HOPO moiety as compared to the 1-Me-HOPO isomer. 11 Gd III formation constants were determined by spectrophotometric titrations in the pH 3-9 range using procedures previously reported. [9][10][11] The chemical model employed in the fitting of the Gd III titration data closely resembles that applied in related ligand systems, 5,9-11 with the formation of a monomeric complex with stepwise addition of up to two protons before the complex dissoci...

Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules1

“…29 This model 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 eight-coordinate and the other nine. 14 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 result in minimal distortion of the complex.…”

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.…”

Tuning the Coordination Number of Hydroxypyridonate-Based Gadolinium Complexes: Implications for MRI Contrast 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 .…”