Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r1) and transverse (r2) relaxivity as a function of field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally. The field dependent relaxivity of a panel of gadolinium and manganese complexes with different molecular parameters: water exchange rates, rotational correlation times, hydration state, etc were measured to confirm that measured relaxivities were consistent with theory. The design tenets previously stressed for optimizing r1 at low fields (very slow rotational motion; chelate immobilized by protein binding; optimized water exchange rate) do not apply at higher fields. At 1.5T and higher fields, an intermediate rotational correlation time is desired (0.5 – 4 ns), while water exchange rate is not as critical to achieving a high r1. For targeted applications it is recommended to tether a multimer of metal chelates to a protein-targeting group via a long flexible linker to decouple the slow motion of the protein from the water(s) bound to the metal ions. Per ion relaxivities of 80, 45, and 18 mM−1s−1 at 1.5, 3, and 9.4T respectively are feasible for Gd3+ and Mn2+ complexes.

The water-soluble complexes of Ti(IV) with citrate are of interest in environmental, biological, and materials chemistry. The aqueous solution speciation is revealed by spectropotentiometric titration. From pH 3-8, given at least three equivalents of ligand, 3:1 citrate/titanium complexes predominate in solution with successive deprotonation of dangling carboxylates as the pH increases. In this range and under these conditions, hydroxo- or oxo-metal species are not supported by the data. At ligand/metal ratios between 1:1 and 3:1, the data are difficult to fit, and are consistent with the formation of such hydroxo- or oxo- species. Stability constants for observed species are tabulated, featuring log beta-values of 9.18 for the 1:1 complex [Ti(Hcit)](+), and 16.99, 20.41, 16.11, and 4.07 for the 3:1 complexes [Ti(H(2)cit)(3)](2-), [Ti(H(2)cit)(Hcit)(2)](4-), [Ti(Hcit)(2)(cit)](6-), and [Ti(cit)(3)](8-), respectively (citric acid = H(4)cit). Optical spectra for the species are reported. The complexes exhibit similar yet distinct spectra, featuring putative citrate-to-Ti(IV) charge-transfer absorptions (lambda(max) approximately 250-310 nm with epsilon approximately 5000-7000 M(-)(1) cm(-1)). The prevailing 3:1 citrate/titanium ratio in solution is supported by electrospray mass spectrometry data. The X-ray crystal structure of a fully deprotonated tris-citrate complex Na(8)[Ti(C(6)H(4)O(7))(3)].17H(2)O (1) (or Na(8)[Ti(cit)(3)].17H(2)O) that crystallizes from aqueous solution at pH 7-8 is reported. Compound 1 crystallizes in the triclinic space group P, with a = 11.634(2) Angstroms, b = 13.223(3) Angstroms, c = 13.291(3) Angstroms, V = 1982.9(7) Angstroms(3), and Z = 2.

Background & Aims Liver biopsy, the current clinical gold standard for assessment of fibrosis, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method for assessment of fibrosis. Methods Liver fibrosis was generated in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal wash-out characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results EP-3533 enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39±0.04, fibrotic = 0.55±0.03, p <0.01) and slower signal washout in fibrotic liver compared to controls (liver t1/2 = 51.3±3.6 vs 42.0±2.5 min, p <0.05 and 54.5±1.9 vs 44.1±2.9 min, p <0.01 for fibrotic vs controls in rat and mouse models, respectively). Gd-DTPA enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusion Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease.