Systems and methods of performing NMR spectroscopy and MRI

1. A method of performing Nuclear Magnetic Resonance (NMR) spectroscopy or Magnetic Resonance Imaging (MRI), the method comprising:

a) generating a compound comprising a first nuclear species (I 1 ), a second nuclear species (I 2 ), a third nuclear species (S), a heteronuclear coupling asymmetry (|J 1S −J 2S |) and a nuclear singlet state spin order localized on I 1 and I 2 ;

b) transferring the nuclear singlet state spin order into heteronuclear magnetization localized on S by applying a single, non-recursive pulse sequence at a low magnetic field in the strong coupling regime of protons; and

c) performing NMR spectroscopy or MRI with the compound comprising heteronuclear magnetization localized on S,

wherein |J 1S −J 2S | is non-zero,

wherein the pulse sequence comprises a plurality of sequential radio frequency pulses separated by independent evolution intervals,

wherein the pulse sequence transfers at least about 75% of the nuclear singlet state spin order into heteronuclear magnetization localized on S at any |J 1S −J 2S | when the independent evolution intervals are optimized, and

wherein the pulse sequence comprises the following sequential steps:

a) waiting a time t 1 after generating the compound;

b) applying a 180(+x) pulse on I 1 and I 2 ;

c) waiting a time t 2 ;

d) applying a 90(+y) pulse on S;

e) waiting a time t 3 ;

f) applying a 180(+x) pulse on I 1 and I 2 ;

g) waiting a time t 4 ; and

h) applying a 90(+x) pulse on S.

2. The method of claim 1 , wherein generating a compound comprises hyperpolarizing the compound by parahydrogen induced polarization (PHIP).

3. The method of claim 1 , wherein the compound has a Hamiltonian of

H= 2π[ J 12 ( I 1 ·I 2 )+ J 1S I 1z S z +J 2S I 2z S z ].

4. The method of claim 1 , wherein the pulse sequence comprises a first portion and a second portion, wherein the first portion converts the nuclear singlet state spin order localized on I 1 and I 2 into a pure state which is coupled to S, and wherein the second portion converts the pure state which is coupled to S into longitudinal net magnetization on S.

5. The method of claim 1 , wherein t 1 , t 2 , t 3 and t 4 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into longitudinal net magnetization on S.

6. The method of The method of claim 1 , wherein t 1 and t 2 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into a pure state which is coupled to S, and wherein t 3 and t 4 are selected to maximize transfer of the pure state which is coupled to S into longitudinal net magnetization on S.

7. The method of claim 1 , wherein the pulse sequence transfers at least about 90% of the nuclear singlet state spin order into heteronuclear magnetization localized on S at any |J 1S −J 2S | when the independent evolution intervals are optimized.

8. An NMR spectroscopy or MRI system configured to perform the method of claim 1 .

9. A method of performing Nuclear Magnetic Resonance (NMR) spectroscopy or Magnetic Resonance Imaging (MRI), the method comprising:

a) generating a compound comprising a first nuclear species (I 1 ), a second nuclear species (I 2 ), a third nuclear species (S), a heteronuclear coupling asymmetry (|J 1S −J 2S |) and nuclear singlet state spin order localized on I 1 and I 2 ;

b) transferring the nuclear singlet state spin order into heteronuclear magnetization localized on S by applying a single, non-recursive pulse sequence at a low magnetic field in the strong coupling regime of protons; and

c) performing NMR spectroscopy or MRI with the compound comprising heteronuclear magnetization localized on S,

wherein |J 1S −J 2S | is non-zero,

wherein the pulse sequence comprises a plurality of sequential radio frequency pulses separated by independent evolution intervals,

wherein the pulse sequence transfers at least about 75% of the nuclear singlet state spin order into heteronuclear magnetization localized on S at an |J 1S −J 2S | when the independent evolution intervals are optimized, and

wherein the hyperpolarized sample further comprises a fourth nuclear species (R), and wherein the pulse sequence comprises the following sequential steps:

a) waiting a time t 1 after generating the compound;

b) applying a 180(+x) pulse on S;

c) waiting a time t 2 ;

d) applying a 180(+x) pulse on I 1 and I 2 ;

e) waiting a time t 3 ;

f) applying a 90(+y) pulse on S;

g) waiting a time t 4 ;

h) applying a 180(+x) pulse on S;

i) waiting a time t 5 ;

j) applying a 180(+x) pulse on I 1 and I 2 ;

k) waiting a time t 6 ; and

l) applying a 90(+x) pulse on S.

10. The method of claim 9 , wherein t 1 , t 2 , t 3 , t 4 , t 5 and t 6 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into longitudinal net magnetization on S.

11. The method of claim 9 , wherein t 1 , t 2 and t 3 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into a pure state which is coupled to S, and wherein t 4 , t 5 and t 6 are selected to maximize transfer of the pure state which is coupled to S into longitudinal net magnetization on S.

12. A method of performing Nuclear Magnetic Resonance (NMR) spectroscopy or Magnetic Resonance Imaging (MRI), the method comprising:

a) generating a compound comprising a first nuclear species (I 1 ), a second nuclear species (I 2 ), a third nuclear species (S), a fourth nuclear species (R) and a nuclear singlet state spin order localized on I 1 and I 2 ;

b) transferring the nuclear singlet state spin order into heteronuclear magnetization localized on S by applying a pulse sequence at a low magnetic field in the strong coupling regime of protons; and

c) performing NMR spectroscopy or MRI with the compound comprising heteronuclear magnetization localized on S;

wherein the pulse sequence comprises the following sequential steps:

a) waiting a time t 1 after hyperpolarizing the sample;

b) applying a 180(+x) pulse on S;

c) waiting a time t 2 ;

d) applying a 180(+x) pulse on I 1 and I 2 ;

e) waiting a time t 3 ;

f) applying a 90(+y) pulse on S;

g) waiting a time t 4 ;

h) applying a 180(+x) pulse on S;

i) waiting a time t 5 ;

j) applying a 180(+x) pulse on I 1 and I 2 ;

k) waiting a time t 6 ; and

l) applying a 90(+x) pulse on S.

13. The method of claim 12 , wherein the compound has a Hamiltonian of

H= 2π[ J 12 ( I 1x I 2x +I 1y I 2y +I 1z I 2z )+ J 1S I 1z S z +J 1R I 1z R z +J 2S I 2z S z +J 2R I 2z R z +J SR S z R z ].

14. The method of claim 12 , wherein t 1 , t 2 , t 3 , t 4 , t 5 and t 6 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into longitudinal net magnetization on S.

15. The method of claim 12 , wherein t 1 , t 2 and t 3 are selected to maximize transfer of the nuclear singlet state spin order localized on I 1 and I 2 into a pure state which is coupled to S, and wherein t 4 , t 5 and t 6 are selected to maximize transfer of the pure state which is coupled to S into longitudinal net magnetization on S.

16. A method of performing Nuclear Magnetic Resonance (NMR) spectroscopy or Magnetic Resonance Imaging (MRI), the method comprising:

a) determining J-couplings for a compound comprising a first nuclear species (I 1 ), a second nuclear species (I 2 ), a third nuclear species (S), a heteronuclear coupling asymmetry (|J 1S −J 2S |) and a nuclear singlet state spin order localized on I 1 and I 2 ;

b) calculating optimal evolution intervals for a single, non-recursive pulse sequence at low magnetic field in the strong coupling regime of protons using the J-couplings, the pulse sequence comprising a sequential plurality of radio frequency pulses separated by independent evolution intervals;

c) generating the compound;

d) transferring the nuclear singlet state spin order into heteronuclear magnetization localized on S by applying the pulse sequence with optimal evolution intervals to the compound; and

e) performing NMR spectroscopy or MRI with the compound comprising heteronuclear magnetization localized on S,

wherein |J 1S −J 2S | is non-zero,

wherein the pulse sequence transfers at least about 75% of the nuclear singlet state spin order into heteronuclear magnetization localized on S at any |J 1S −J 2S |, and

wherein calculating optimal evolution intervals comprises inverting a density matrix expression representing the evolution of spin states of the compound during application of the pulse sequence to the compound, minimizing the difference between a density matrix expression representing the evolution of spin states of the compound during application of the pulse sequence and a desired state which is coupled to S, or a combination thereof.

17. The method of claim 16 , wherein determining J-couplings for a compound comprises experimentally determining J-couplings, theoretically calculating J-couplings and combinations thereof.