No abstract

17O NMR and (1)H NMRD studies have been performed on a series of Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives as potential liver-specific magnetic resonance imaging (MRI) contrast agents. They bear aliphatic side chains which make them capable of micellar self-organization. The compounds differ in the length (C10-C18) and in the chemical nature (alkyl or monoamide-alkyl) of their lipophilic chain. We have established a convenient method to determine the critical micellar concentration (cmc) of paramagnetic surfactants by (1)H relaxivity measurements. This technique can be easily used over a large temperature range; thus, it can find wide application outside the field of MRI contrast agents. The knowledge of the cmc allowed us to determine the parameters governing the water proton relaxivity of the Gd(III) chelates in both nonaggregated and aggregated micellar forms. The relaxation data of the micellar complexes have been interpreted with the Lipari-Szabo approach. This model allows a local motion to be separated from the global tumbling of the whole micelle (modulated by a local, tau(l), and a global, tau(g), rotational correlation time, respectively). The aggregation substantially affects the rotational dynamics and thus increases the proton relaxivity of the Gd(III) chelates. The global rotational correlation times increase with increasing length of the side chain (500-2800 ps for C10-C18). Local motions are also influenced by the length and by the hydrophobicity of the side chain. The analysis of the relaxation data reveals considerable flexibility for these micellar aggregates. The rate of water exchange obtained for these chelates is identical to that for [Gd(DOTA)(H(2)O)](-) (k(ex)(298)= 4.8 x 10(6)s(-1))and is not sensitive either to micellization or to differences in the aliphatic chain. A relaxivity gain in such systems could be attained by simultaneously optimizing the water exchange by modifications of the chelate and increasing the micelle rigidity by using water-soluble surfactants with more hydrophobic side chains.

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...