Magnetic resonance imaging and/or spectroscopy contrast agents and methods of use thereof

Abstract

The presently disclosed subject matter demonstrates that a spin state which has zero magnetic resonance signal, but an extremely long lifetime, can be used to store magnetization, which can then be recovered into an observable transition. Coupled with hyperpolarization techniques, this permits the preparation of a wide range of contrast agent molecules for use in magnetic resonance imaging (MRI) techniques that have long effective relaxation time.

1 - 42 . (canceled) 
     
     
         43 . A contrast agent comprising a contrast agent molecule prepared by (a) providing a precursor molecule comprising two J-coupled, non-zero-spin, non-equivalent nuclei, wherein said precursor molecule is chemically convertible to a contrast agent molecule wherein the two J-coupled, non-zero-spin, non-equivalent nuclei are converted to equivalent nuclei; (b) hyperpolarizing the precursor molecule to provide a hyperpolarized precursor molecule; (c) applying one or more radiofrequency pulse(s) to the hyperpolarized precursor molecule to create one or both of a non-equilibrium αβ nuclear spin state population and a non-equilibrium βα nuclear spin state population; and (d) chemically converting the hyperpolarized precursor molecule into a contrast agent molecule by converting the two J-coupled, non-zero-spin, non-equivalent nuclei to two J-coupled, non-zero-spin, equivalent nuclei, wherein the contrast agent molecule comprises a non-equilibrium nuclear singlet spin state population and is chemically convertible to a detection molecule wherein said equivalent nuclei are converted to non-equivalent nuclei; 
       wherein said contrast agent can be used to enhance a signal in one of magnetic resonance imaging or magnetic resonance spectroscopy. 
     
     
         44 . The contrast agent of  claim 43 , wherein the contrast agent molecule is encapsulated in a biodegradable drug delivery format that prevents water contact with the contrast agent molecule. 
     
     
         45 . The contrast agent of  claim 43 , wherein the contrast agent molecule is selected from the group consisting of diacetyl, oxolin, alendronate, amitryptyline, nortriptyline, succinate, fumarate, maleimide, catechol, naphthalene, naphthoquinone, phenylbutazone, pyridazine, phthalazine, dopamine, L-dihydroxyphenylalanine (L-DOPA) and derivatives thereof. 
     
     
         46 . The contrast agent of  claim 43 , wherein the contrast agent molecule is encapsulated in a liposome or in a delivery agent that swells in water. 
     
     
         47 . The contrast agent of  claim 43 , wherein the contrast agent molecule is encapsulated in a delivery agent that comprises targeting groups for directing the contrast agent to a tissue, organ or cell. 
     
     
         48 . The contrast agent of  claim 43 , wherein the contrast agent molecule is incorporated in a pharmaceutically acceptable carrier. 
     
     
         49 . The contrast agent of  claim 43 , wherein the contrast agent molecule is convertible to the detection molecule under physiological conditions. 
     
     
         50 . The contrast agent of  claim 43 , wherein the contrast agent molecule is convertible to the detection molecule via contact with water or via an enzymatic reaction. 
     
     
         51 . The contrast agent of  claim 43 , wherein the contrast agent molecule is in chemical equilibrium with the precursor molecule or the detection molecule. 
     
     
         52 . The contrast agent of  claim 43 , wherein the precursor molecule and the detection molecule have the same molecular structure. 
     
     
         53 . The contrast agent of  claim 43 , wherein the two J-coupled, non-zero-spin non-equivalent nuclei of the precursor molecule are selected from the group consisting of  1 H,  13 C,  15 N, and  31 P. 
     
     
         54 . The contrast agent of  claim 43 , wherein the hyperpolarizing is performed by dynamic nuclear polarization (DNP). 
     
     
         55 . The contrast agent of  claim 43 , wherein chemically converting the hyperpolarized precursor molecule into the contrast agent molecule comprises dehydrating the hyperpolarized precursor molecule. 
     
     
         56 . The contrast agent of  claim 43 , wherein one or both of the precursor molecule and the detection molecule is the monohydrate of diacetyl. 
     
     
         57 . The contrast agent of  claim 43 , wherein the two J-coupled, non-zero-spin, equivalent nuclei of the contrast agent molecule are free of directly bonded hydrogen atoms. 
     
     
         58 . The contrast agent of  claim 43 , wherein the two J-coupled, non-zero-spin, equivalent nuclei of the contrast agent molecule are directly bonded to hydrogen atoms and are J-coupled to two other, additional equivalent nuclei, wherein the two other, additional equivalent nuclei are free of directly bonded hydrogen atoms, and whereby application of one or more radiofrequency pulse(s) can transfer a spin state population between the two J-coupled, non-zero-spin, equivalent nuclei and the two other, additional equivalent nuclei. 
     
     
         59 . The contrast agent of  claim 43 , wherein the non-equilibrium nuclear singlet spin state population can persist for a time that is substantially greater than T 1 . 
     
     
         60 . The contrast agent of  claim 59 , wherein the non-equilibrium nuclear singlet spin state population can persist for a time that is greater than 3 times T 1 . 
     
     
         61 . The contrast agent of  claim 60 , wherein the non-equilibrium nuclear singlet spin state population can persist for a time that is greater than 10 times T 1 . 
     
     
         62 . The contrast agent of  claim 59 , wherein the non-equilibrium nuclear singlet spin state population can persist for a time that is between about 3 times T 1  and about 10 times T 1 .