Contrast Agent Enhancement of Chemical Exchange Dependent Saturation Transfer (CEDST) MRI

Available for licensing is an MRI image improving system wherein at least one contrast agent is administered to a subject in amounts effective to perform chemical exchange dependent saturation transfer (CEDST) MRI analysis.

Examples of contrast agents suitable for administration as exogenous contrast agents include at least one functional group bearing a proton capable of chemical exchange. Examples of these functional groups include, without limitation, amides, amines, and carboxyl, hydroxyl, and sulfhydryl groups.

The contrast agent can be administered as a solid, as a dispersion or solution, such as an aqueous composition, as a mixture of two or more agents, etc. The contrast agent may also be in the form of a polymer.

One feature of the present invention involved identifying contrast agents, which contain the functional groups having the appropriate proton exchange and chemical shift properties at physiological pH and temperature to function effectively for performing CEDST MRI analyses in vivo. A number of different contrast agents can be used to practice the present method for performing CEDST MRI analyses in vivo can be selected from the group consisting of: sugars, including oligosaccharides and polysaccharides, such as dextran; amino acids, such as 5-hydroxy-tryptophan (which also includes an indole -NH) and including oligomers of amino acids and proteins; nitrogen-containing heterocycles generally; indoles, purines and pyrimidines; nucleosides; imidazole and derivatives thereof, such as 2-imidazolidone and 2-imidazoldinethione; imino acids, including azetidines, such as azetidine-2-carboxylic acid, pyrolidines, such as 4-trans-hydroxy-proline, and piperidines, such as pipecolinic acid; barbituric acid and analogs thereof, such as 2-thio-barbituric acid and 5,5-diethylbarbituric acid; miscellaneous materials, such as guanidine, hydantoin, parabanic acid, and biologically active salts thereof; and mixtures of these contrast agents.

Working embodiments of the invention used all of the above materials at a variety of concentration levels for in-vitro experiments and, using a 500 mM solution of barbituric acid, in an in-vivo rabbit model.

The method of the present invention is useful for enhancing the contrast of MRI images, including images produced in vivo, using CEDST.

A second feature of the present invention involved identifying contrast agents which contained the functional groups which could be used, either alone or in combination, to function effectively at performing pH measurement using CEDST in vivo.

Working embodiments of this feature of the invention used either dihydrouracil or a combination solution of 5-Hydroxytryptophan and 2-Imidazolidinethione as the contrast agent, which was provided as an aqueous composition having about 62.5 mM of each chemical in the solution. Other chemicals with more than one chemical exchange site or mixtures of other contrast agents may also be used to practice the second feature of the present invention. A standard pH curve is prepared by performing in vitro CEDST MRI analyses of the contrast agent, which is then used to evaluate the in vivo pH measurement results.

A third feature of the present invention involved identifying contrast agents which contained the functional groups which could be used to function effectively at performing temperature measurement using CEDST in vivo.

Working embodiments of this feature of the invention used barbituric acid as the contrast agent, which was provided as an aqueous composition having about 62.5 mM of chemical in the solution. Other chemicals may be used to practice the third feature of the present invention. A standardized temperature curve is prepared performing in vitro CEDST MRI analyses of the contrast agent, which is then used to evaluate the in vivo temperature results.

A fourth feature of the present invention involved identifying contrast agents which contained the function groups which could be used to function effectively at measuring a metabolite of interest using CEDST in vivo.

Working embodiments of this feature of the invention used dihydrouracil as the contrast agent, which was provided as an aqueous composition having about 62.5 mM with phosphate as the metabolite of interest. Other chemicals may be used to practice the third feature of the present invention. A standardized metabolite curve is prepared performing in vitro CEDST MRI analyses of the contrast agent, which is then used to evaluate the in vivo metabolite results.