Nuclear singlet states as a contrast mechanism for NMR spectroscopy

Patent metadata

Field	Value
Publication number	US-9804239-B2
Application number	US-201314380919-A
Country	US
Kind code	B2
Filing date	Feb 28, 2013
Priority date	Feb 29, 2012
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

Methods and systems for Nuclear Magnetic Resonance (NMR) spectra of complex chemical mixtures are described. The methods and systems allow undesired NMR spectral background to be removed or suppressed and target spectral peaks to be uncovered, for example, when strong background signals overlap weaker peaks. In some embodiments, the methods and systems employ a quantum filter utilizing nuclear spin singlet states.

First claim

What is claimed is:

1. A method comprising:
selectively creating a nuclear spin singlet state in a target molecule, so as to detect presence of the target molecule within a sample, wherein the sample contains a mixture of molecules and includes at least some background molecules that are different from the target molecule; and
preserving spin polarization of the singlet state while saturating the spin magnetizations of background molecules, so as to suppress spectroscopic signals from the background molecules and to enhance spectroscopic contrast between the target molecule and the background molecules,
wherein the act of selectively creating the nuclear spin singlet state comprises:
applying to the target molecule a sequence of pulses having parameters that are optimized so as to achieve the desired nuclear spin singlet state in the target molecule while minimizing singlet nature of the nuclear spin states of the background molecules.

2. The method of claim 1 , further comprising converting the spin polarization of the singlet state back to transverse magnetization for signal readout, by controllably applying RF (radiofrequency) pulses.

3. The method of claim 1 , wherein the act of preserving spin polarization of the singlet state while saturating spin magnetization of the background molecules comprises: applying a substantially continuous spin-locking RF field.

4. The method of claim 3 , further comprising applying the spin-locking RF field at an average resonance frequency of coupled protons in the target molecule.

5. The method of claim 3 , further comprising applying the spin-locking RF field at a frequency other than an average resonant frequency of coupled protons in the target molecule, so as to further enhance spectroscopic signals from the target molecule.

6. The method of claim 1 , wherein the act of saturating spin magnetization of background molecules comprises:
using a polyhedral, spherically symmetric phase cycle that substantially removes non-singlet signals.

7. The method of claim 1 , wherein the target molecule is one of: aspartate, threonine, and glutamine.

8. The method of claim 7 , wherein the background molecules comprise at least one of: N-acetylaspartate, myo-inositol, and glutamate.

9. The method of claim 1 , wherein the sequence of pulses is a pulse sequence depicted in FIG. 1A, 1B, 5A or 5B .

10. An NMR (nuclear magnetic resonance) system, comprising:
an NMR transceiver including an RF generator configured to generate a sequence of RF fields that have controllable parameters; and
a controller configured to generate and optionally relay a set of instructions to the transceiver to controllably apply the RF field sequence to a sample, so as to selectively create a nuclear spin singlet state in a target molecule, then preserve spin polarization of the singlet state while saturating the spin magnetizations of background molecules within the sample, thereby suppressing spectroscopic signals from the background molecules and enhancing spectroscopic contrast between the target and background molecules,
wherein the controller is further configured to optimize the parameters of the RF field sequence so as to convert the spin polarization of the singlet state back to transverse magnetization, for signal readout from the target molecule.

11. The system of claim 10 , wherein the RF field sequence includes a spin-locking RF field that is resonant with the spins and is substantially continuous, and wherein the spin-locking RF field is applied after the nuclear spin singlet state has been selectively created in the target molecule, thereby preserving spin polarization of the singlet state while saturating spin magnetizations of the background molecules.

12. The system of claim 10 , wherein the target molecule is aspartic acid and the background molecules comprise N-acetylaspartic acid, and wherein the optimized parameters of the RF field sequence comprise:
transmit frequency v=385 Hz;
chemical shift δav=2.71 ppm; and
singlet creation delay times τ 1 , τ 2 and τ 3 and relaxation delay time τ 4 ,
where τ 1 =9 ms (milliseconds), τ 2 =10.3 ms, τ 3 =11.5 ms, and τ 4 =1 sec.

13. The system of claim 10 , wherein the target molecule is glutamine and the background molecules comprise glutamate, and wherein the optimized parameters of the RF field sequence comprise:
transmit frequency v=385 Hz;
chemical shift δ av =2.23 ppm; and
singlet creation delay times τ 1 , τ 2 and τ 3 , and relaxation delay time τ 4 ;
where τ 1 =22 ms (milliseconds), τ 2 =15 ms, τ 3 =11.1 ms, and τ 4 =500 ms.

14. The system of claim 10 , wherein the target molecule is threonine and the background molecules comprise myo-inositol, and wherein the optimized parameters of the RF field sequence comprise:
Transmit frequency v=790 Hz;
chemical shift δ av =3.87 ppm; and
singlet creation delay times τ 1 , τ 2 and τ 3 , and relaxation delay time τ 4 ;
where τ 1 =40 ms (milliseconds), τ 2 =52 ms, τ 3 =1.85 ms, and τ 4 =200 ms.

15. The system of claim 10 , wherein the RF sequence is a pulse sequence depicted in FIG. 1A, 1B, 5A or 5B .

16. A method comprising:
selectively creating a nuclear spin singlet state in a target molecule, so as to detect presence of the target molecule within a sample, wherein the sample contains a mixture of molecules and includes at least some background molecules that are different from the target molecule; and
preserving spin polarization of the singlet state while saturating the spin magnetizations of background molecules, so as to suppress spectroscopic signals from the background molecules and to enhance spectroscopic contrast between the target molecule and the background molecules,
wherein an NMR spectrum of the target molecule is similar to, and substantially overlaps with, an NMR spectrum of the background molecules.

17. The method of claim 16 , further comprising converting the spin polarization of the singlet state back to transverse magnetization for signal readout, by controllably applying RF (radiofrequency) pulses.

18. The method of claim 16 , wherein the act of preserving spin polarization of the singlet state while saturating spin magnetization of the background molecules comprises:
applying a substantially continuous spin-locking RF field.

19. The method of claim 18 , further comprising applying the spin-locking RF field at an average resonance frequency of coupled protons in the target molecule.

20. The method of claim 19 , wherein the RF field sequence includes a spin-locking RF field that is resonant with the spins and is substantially continuous, and wherein the spin-locking RF field is applied after the nuclear spin singlet state has been selectively created in the target molecule, thereby preserving spin polarization of the singlet state while saturating spin magnetizations of the background molecules.

21. The method of claim 19 , wherein the target molecule is aspartic acid and the background molecules comprise N-acetylaspartic acid, and wherein the optimized parameters of the RF field sequence comprise:
transmit frequency v=385 Hz;
chemical shift δav=2.71 ppm; and
singlet creation delay times τ 1 , τ 2 and τ 3 and relaxation delay time τ 4 ,
where τ 1 =9 ms (milliseconds), τ 2 =10.3 ms, τ 3 =11.5 ms, and τ 4 =1 sec.

22. The method of claim 19 , wherein the target molecule is glutamine and the background molecules comprise glutamate, and wherein the optimized parameters of the RF field sequence comprise:
transmit fre

Assignees

• Harvard College

Inventors

• Walsworth Ronald L
• Devience Stephen J
• Rosen Matthew S

Classifications

• G01R33/4616

  using specific RF pulses or specific modulation schemes, e.g. stochastic excitation, adiabatic RF pulses, composite pulses, binomial pulses, Shinnar-le-Roux pulses, spectrally selective pulses not being used for spatial selection · CPC title

• G01R33/4608

  RF excitation sequences for enhanced detection, e.g. NOE, polarisation transfer, selection of a coherence transfer pathway · CPC title

• G01R33/465 Primary

  applied to biological material, e.g. in vitro testing · CPC title

• G01N24/08

  by using nuclear magnetic resonance (G01N24/12 takes precedence) · CPC title

• G01R33/32

  Excitation or detection systems, e.g. using radio frequency signals · CPC title