Contrast agents based on long-lived nuclear singlet states and related methods

Abstract

Methods are described for preparing magnetic resonance imaging (MRI) and/or magnetic resonance spectroscopy contrast agents where the contrast agents are prepared from precursor molecules having at least four non-zero-spin nuclei that form two pairs of chemically equivalent or effectively equivalent nuclei, e.g., diphenylacetylene or diethyl oxalate. The precursor molecule is hyperpolarized and a sequence of one or more radiofrequency pulses is applied to transfer spin state population between the first and second pair of nuclei, thereby providing a non-equilibrium single state nuclear spin population. To detect the contrast agent, another sequence of one or more radiofrequency pulses is applied to transfer singlet order to polarization. No transformation of the molecular structure of the contrast agent is necessary for detection. Also described are methods of imaging targets using the contrast agents.

1 . A method of providing a contrast agent for magnetic resonance imaging (MRI) or magnetic resonance spectroscopy, the method comprising:
 providing a molecule comprising at least four non-zero-spin nuclei X, X′, Y, and Y′, wherein X and X′ are a first pair of chemically equivalent or effectively equivalent nuclei, and Y and Y′ are a second pair of chemically equivalent or effectively equivalent nuclei;   hyperpolarizing the molecule to provide a hyperpolarized molecule; and   applying a first sequence of one or more radiofrequency pulses to the hyperpolarized molecule to transfer a spin state population between the first and the second pair of chemically equivalent or effectively equivalent nuclei; thereby providing a contrast agent having a non-equilibrium singlet state nuclear spin population, wherein the contrast agent molecule can be detected after the application of a second sequence of one or more radiofrequency pulses to transfer singlet order to polarization.   
     
     
         2 . The method of  claim 1 , wherein J XX′ , the scalar coupling between X and X′, is greater than J XY , the scalar coupling between X and Y; J XY′ , the scalar coupling between X and Y′; J X′Y , the scalar coupling between X′ and Y; and J X′Y′ , the scalar coupling between X′ and Y′. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the scalar coupling between X and X′ is between about 10 and about 300 Hertz (Hz). 
     
     
         5 . The method of  claim 1 , wherein X and X′ are both  13 C or  15 N nuclei. 
     
     
         6 . The method of  claim 5 , wherein the molecule has a molecular structure wherein X and X′ are directly bonded to each other. 
     
     
         7 . The method of  claim 6 , wherein X and X′ are free of directly bonded hydrogen atoms. 
     
     
         8 . The method of  claim 5 , wherein Y and Y′ are both  1 H or  19 F nuclei. 
     
     
         9 . The method of  claim 1 , wherein the molecule has a rigid molecular structure. 
     
     
         10 . The method of  claim 1 , wherein the molecule is selected from the group consisting of a diarylacetylene, diacetylene, an oxalate diester, a cyclooctyne or a lactone or lactam analog thereof, a dibenzocyclooctyne or a lactone or lactam analog thereof, a pyridazine, a phthalazine, and a gem-difluoro compound. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the molecule has a symmetric molecular structure, X is chemically equivalent to X′, and Y is chemically equivalent to Y′. 
     
     
         13 . The method of  claim 1 , wherein the hyperpolarizing is performed by dynamic nuclear polarization (DNP). 
     
     
         14 . The method of  claim 1 , wherein the contrast agent can be provided and detected without undergoing a molecular structure transformation. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein Y and Y′ are  1 H nuclei, and the one or more radiofrequency pulses are hydrogen-only pulse sequences. 
     
     
         17 . The method of  claim 1 , wherein the contrast agent has pharmaceutical activity. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the non-equilibrium singlet state nuclear spin population can persist for a time that is greater than about 3 times the longitudinal relaxation time constant (T 1 ). 
     
     
         21 - 23 . (canceled) 
     
     
         24 . A method of imaging a target, the method comprising:
 providing a molecule comprising at least four non-zero-spin nuclei X, X′, Y, and Y′, wherein X and X′ are a first pair of chemically equivalent or effectively equivalent nuclei, and Y and Y′ are a second pair of chemically equivalent or effectively equivalent nuclei;   hyperpolarizing the molecule to provide a hyperpolarized molecule;   applying a first sequence of one or more radiofrequency pulses to the hyperpolarized molecule to transfer a spin state population between the first and second pair of nuclei, thereby providing a contrast agent having a non-equilibrium singlet state nuclear spin population;   contacting the contrast agent with the target;   applying a second sequence of one or more radiofrequency pulses to convert singlet order to magnetization;   generating a nuclear magnetic resonance signal; and   detecting the nuclear magnetic resonance signal, thereby imaging the target.   
     
     
         25 . The method of  claim 24 , wherein the target is one of a cell, a tissue, an organ, and a subject. 
     
     
         26 . The method of  claim 24 , wherein the contacting comprises administering a pharmaceutical formulation comprising the contrast agent to a subject. 
     
     
         27 . The method of  claim 26 , wherein the subject is a mammal. 
     
     
         28 - 42 . (canceled) 
     
     
         43 . A contrast agent prepared according to the method of  claim 1 .