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WO2021114499A1 - Procédé de détection sélective d'objet cible à l'aide d'état singulet du spin nucléaire - Google Patents

Procédé de détection sélective d'objet cible à l'aide d'état singulet du spin nucléaire Download PDF

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WO2021114499A1
WO2021114499A1 PCT/CN2020/078140 CN2020078140W WO2021114499A1 WO 2021114499 A1 WO2021114499 A1 WO 2021114499A1 CN 2020078140 W CN2020078140 W CN 2020078140W WO 2021114499 A1 WO2021114499 A1 WO 2021114499A1
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pulse
target
signal
decoupling
singlet
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PCT/CN2020/078140
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English (en)
Chinese (zh)
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姚叶锋
辛家祥
李毅
魏达秀
王嘉琛
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华东师范大学
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Priority claimed from CN201911249189.7A external-priority patent/CN113030145A/zh
Priority claimed from CN201911248840.9A external-priority patent/CN113030144B/zh
Priority claimed from CN201911249153.9A external-priority patent/CN113030815A/zh
Application filed by 华东师范大学 filed Critical 华东师范大学
Publication of WO2021114499A1 publication Critical patent/WO2021114499A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance

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  • the invention belongs to the field of magnetic resonance detection, and specifically relates to a method for selectively detecting a target object by using a nuclear spin singlet.
  • MRI and MRS magnetic resonance imaging
  • spectroscopy both use radio frequency signals of a certain frequency to excite nuclear spins under the action of an external magnetic field, thereby generating resonance signals.
  • Modern MRI and MRS have developed into a very powerful medical diagnostic method, especially suitable for diagnostic testing and scientific research on brain tissue, nervous system and human soft tissue.
  • One of the core technologies in MRI and MRS is pulse sequence. Pulse sequence refers to a pulse or combination of pulses designed for a specific purpose. The pulse sequence can realize the manipulation of the nuclear spins in the object to be tested and generate the expected magnetic resonance signal. Collect the magnetic resonance signal of the test object and perform corresponding data processing to obtain the MRI and MRS of the test object.
  • MRS Magnetic resonance spectroscopy
  • the nuclear spin singlet is a special spin state of the nuclear spin coupling system. This state has the following characteristics: 1.
  • the nuclear spin singlet can be prepared by a reasonably designed pulse sequence; 2.
  • the pulse sequence for preparing the nuclear spin singlet is related to the chemical structure of the molecule, and different molecular structures correspond to different nuclei.
  • the spin singlet prepares a pulse sequence; 3.
  • the spin state does not undergo spin state evolution under the action of the pulse gradient field.
  • the present invention designs a series of singlet magnetic resonance pulse sequences based on nuclear spins.
  • the core design idea of these pulse sequences is to take advantage of the feature that the nuclear spin singlet is not affected by the pulse gradient field.
  • After preparing the nuclear spin singlet of the target nuclear spin coupling system apply a pulse gradient to the target.
  • the field diffuses other magnetic resonance signals other than the target nuclear spin singlet, and maintains the target nuclear spin singlet signal, thereby achieving selective detection of the target nuclear magnetic signal.
  • the method of the present invention has good accuracy, sensitivity, reproducibility and selectivity, can eliminate the interference of other substance signals, and accurately detect the signal of the target molecule from a system with complex composition. It has important application value in the fields of biology, medicine, chemistry, chemical engineering, etc. It is a new and original technology.
  • the nuclear spin singlet preparation pulse sequence can select the signal of a specific target molecule.
  • the chemical structure requirements of this molecule are: at least a pair of mutually coupled nuclear spins of the same type, there is a certain chemical shift difference between the nucleus and nuclear spins, and its chemical shift and coupling constant are relatively stable, and will not follow Changes in the external environment (such as temperature, pH, etc.).
  • the design of nuclear spin singlet preparation pulse belongs to common knowledge in the field.
  • the chemical shift of each spin and the J coupling between spins in a spin coupling system are the key parameters for the preparation of a nuclear spin singlet pulse sequence.
  • the design of the nuclear spin singlet preparation pulse needs to be adjusted accordingly.
  • the target is a dopamine molecule (formula (1)).
  • H a, H b, H d form a three-spin coupling system.
  • the singlet pulse sequence can be designed.
  • the target substance may also include dopamine, taurine, acetylaspartic acid, AGG, hypotaurine, creatine, choline chloride, glucose, glutathione and the like.
  • the implementation process of the method of the present invention includes the following steps:
  • Step 1 Excite the magnetic resonance signal of the target (molecule) in the system to be measured by pulse or pulse combination;
  • Step 2 Select a pulse or pulse combination according to the multi-spin coupling properties of the target, and prepare the nuclear spin coupling system of the target into a nuclear spin singlet through the pulse or pulse combination;
  • Step 3 Decoupling the nuclear spin coupling system of the target within a certain period of time by decoupling pulse (pulse or pulse combination), and maintaining the nuclear spin singlet of the target, and applying The pulse gradient field disperses all non-target nuclear spin singlet magnetic resonance signals in the system to be measured;
  • Step 4 Convert the target nuclear spin singlet into a signal required for magnetic resonance, such as a nuclear magnetic spectrum signal or an imaging signal, by pulse or pulse combination, to achieve selective detection of the target nuclear magnetic signal.
  • a signal required for magnetic resonance such as a nuclear magnetic spectrum signal or an imaging signal
  • the targets are various substances with a multi-spin coupling system.
  • step 2 The main purpose of step 2 is to prepare nuclear spin singlets.
  • the nuclear spin singlet of the target is prepared through a reasonably designed pulse or pulse combination sequence.
  • the design steps are briefly described as follows: i. Analyze the target molecule, and divide the spin coupling structure existing in its structure into strong spin coupling structure and/or weak coupling structure; ii. Prepare the respective spin coupling structure in the target molecule Compare the preparation efficiency of each singlet; iii. Select the spin-coupling structure and pulse sequence with the highest singlet preparation efficiency for selective detection of target molecules in the sequence shown in Figure 1.
  • the pulse or pulse combination includes an excitation pulse and a nuclear spin singlet preparation pulse.
  • the function of the excitation pulse is to excite the nuclear spin signal.
  • the parameters such as its form and intensity can be adjusted according to the experimental needs. Usually it is a hard pulse with higher power.
  • the power of the pulse can be adjusted according to the specific molecular system, and the requirement is to be uniform.
  • the role of nuclear spin singlet preparation pulse is to prepare nuclear spin singlet, using the characteristic that nuclear spin singlet will not be dispersed by the pulse gradient field, for signal selection. There are many ways to prepare the pulse of nuclear spin singlet.
  • the pulse shown in Figure 5 is a SLIC pulse (SJ DeVience, RL Walsworth, MS Rosen, Phys. Rev. Lett. 111 (2013) 173002(1-4).), in which the power of the spin lock pulse and the application time ⁇ SL varies with the difference in chemical shifts and coupling constants between nuclear spins.
  • SLIC pulses SJ DeVience, RL Walsworth, MS Rosen, Phys. Rev. Lett. 111 (2013) 173002(1-4).
  • M2S pulses for nuclear spin systems with similar chemical shifts G. Pileio, M. Carravetta and MHLevitt, Proc. Natl.
  • this step contains two key components: 1. Decoupling pulse; 2. Pulse gradient field.
  • the function of the decoupling pulse is to maintain the singlet nuclear spin of the target.
  • the decoupling pulse needs to be designed according to the chemical shift and J coupling of the multi-spin coupling system of the target.
  • the form of the decoupling pulse can be continuous pulse irradiation, or a combination of pulses with a specific timing.
  • the action time of the decoupling pulse can be adjusted according to the nature of the system. The specific time needs to be measured experimentally, that is, the time of the decoupling pulse is changed experimentally, and the signal strength and selectivity of the single state are observed to determine the best Decoupling time.
  • the power of the decoupling pulse is affected by the chemical shift difference of the spin system, and needs to be adjusted according to the magnitude of the chemical shift difference of the spin system.
  • step 3 the nuclear spin coupling system of the target is decoupled by a decoupling pulse, so as to maintain the nuclear spin singlet of the target; the way to achieve decoupling can be through continuous wave decoupling, or a pulse with a specific timing Combine for decoupling.
  • Continuous wave decoupling and pulse combination decoupling are well-known technologies in the field.
  • the choice of decoupling time increases with the increase of the relaxation time of the nuclear spin singlet, generally from milliseconds to seconds, and can be adjusted according to the nature of the system to obtain the best effect.
  • the decoupling time needs to be longer than the pulse gradient field action time.
  • the function of the pulse gradient field is to disperse all other non-nuclear spin singlet nuclear magnetic signals except the target nuclear spin singlet.
  • the effect of the pulse gradient field can be adjusted and optimized by adjusting the intensity, application times and position of the pulse gradient field.
  • the application time is on the order of milliseconds.
  • the power of the pulse gradient field can be adjusted according to the dispersion effect of the pulse gradient field.
  • the direction of the pulse gradient field is the z-axis direction in the same direction as the static magnetic field. The best pulse gradient field effect is to retain only single-state signals.
  • step 3 it is also possible to apply the decoupling pulse alone without applying the pulse gradient field. But in this way, although a certain degree of signal selection can be achieved, the overall effect is poor. In step 3, if the pulse gradient field is applied alone without applying the decoupling pulse, the purpose of selecting the target molecule signal cannot be achieved.
  • step 4 the target nuclear spin singlet is converted into signals required for subsequent magnetic resonance experiments through pulses or pulse combinations, such as nuclear magnetic spectroscopy signals or imaging signals.
  • pulses or pulse combinations such as nuclear magnetic spectroscopy signals or imaging signals.
  • the selection and design of pulses or pulse combinations are the same as those in step 2.
  • the design of the pulse combination is similar, that is, different pulses or pulse combinations are selected according to the multi-spin coupling properties of different targets, and the target nuclear spin singlet is converted into signals required for subsequent magnetic resonance experiments.
  • the present invention also includes the following basic steps: (1) Obtain the chemical shift difference and coupling constant between the spins of the target by the traditional NMR measurement method; (2) Pulse the chemical shift difference and the coupling constant of the coupling system Sequence design, determine the power and pulse width of the single-state spin-locked pulse; (3) Implement the designed pulse sequence on the magnetic resonance instrument. These are known knowledge in the field.
  • the pulse sequence in Fig. 5 shows a specific example of the implementation of the above steps.
  • Figure 5 is a schematic diagram of the pulse sequence.
  • the sequence of the evolution of the spin state in this sequence is as follows: the 90-degree radio frequency pulse at A turns the longitudinal magnetization vector from the vertical axis to the x, y plane; after the spin-lock pulse at B is applied, the spin is generated in the state of the system Singlet; the subsequent gradient pulse g 1 can eliminate the observable states other than the spin singlet; during the application of the decoupling pulse at C, the spin singlet is preserved, and other signals are attenuated by the effect of relaxation; then the second A gradient pulse g 2 further eliminates other signals other than the spin singlet, and finally, the ⁇ SL pulse applied at D converts the spin singlet into an observable signal to realize signal detection.
  • the target is AGG in the 1 H spectrum of AGG deuterium aqueous solution (ie, amino acid molecule; L-Alanine-glycine-glycine, AGG; the following target amino acid molecules are specifically AGG)
  • first apply the phase in the y direction according to Figure 5 90° hard pulse and then apply the center frequency between the transmitting center H b , H b'signal and H c , H c'signal , the phase is in the x direction, and the time is ⁇ 1 ( ⁇ 1 is the ⁇ SL in Figure 5 ), the locking pulse with the locking frequency ⁇ SL prepares the singlet state of the AGG molecule; then the z-direction gradient fields g 1 and g 2 and the decoupling pulse ⁇ dec (decoupling time ⁇ m ) are applied; then the emission center is H b , H b 'signal and the H c, H c' between the center frequency of the signal, the phase in the x direction, the time ( ⁇
  • the target is AGG in the 1 H spectrum of a deuterium aqueous solution of a mixture of AGG and leucine, glutamic acid and glycine
  • the center frequency between the signals to prepare the singlet of the AGG molecule then apply the z-direction gradient fields g 1 and g 2 and decoupling pulses; the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient
  • the target is the AGG in the 1 H spectrum of the AGG and insulin mixture deuterium aqueous solution
  • first apply a 90° hard pulse with the phase in the y direction to the sample according to Figure 5, and then apply the phase in the x direction for a time of ⁇ 1 125ms( ⁇ 1 is the ⁇ SL in Fig.
  • the lock pulse with the lock frequency ⁇ SL 18.5 Hz
  • the transmission center of the lock pulse is the center frequency between the H b , H b'signal and the H c , H c'signal
  • Pulse, and then apply the combined pulse of ⁇ 1 - ⁇ x - ⁇ 1 , where ⁇ 1 30.9ms, the purpose is to remove the chemical shift evolution, and then apply
  • the present invention also provides a method for realizing magnetic resonance imaging of a target by using a nuclear spin singlet.
  • the target is prepared into a nucleus by the method for selectively detecting the target using the nuclear singlet as described above.
  • the method includes:
  • Step a Prepare the target into a nuclear spin singlet through the method of selectively detecting the target by using the nuclear spin singlet as described above, and then realize the selection of the target signal through the pulse gradient field and the decoupling pulse Finally, the nuclear spin singlet signal of the target is converted into the signal required for the subsequent steps through a suitable pulse or pulse combination.
  • Step b The main components are various types of magnetic resonance imaging pulse sequences; the target signal obtained in step a can be imaged according to actual imaging requirements to realize magnetic resonance imaging of the target.
  • step b magnetic resonance imaging is performed using the signal of the target obtained in step a, so as to obtain a molecular magnetic resonance image of the target.
  • step b different magnetic resonance imaging pulse sequences can be adopted as required, and the method for obtaining the magnetic resonance imaging pulse sequence is a method known in the art.
  • the magnetic resonance imaging of specific target molecules achieved by the above methods can be applied in many fields, such as early diagnosis and treatment of diseases, evaluation of curative effects, detection of drug molecular metabolism in specific organs, and detection of chemical reaction molecule distribution in reaction vessels for chemical determination.
  • Chemical reaction process, etc. For example, in medicine, if the target is a molecule with high expression of the disease, then this method can be used as a means of early diagnosis and treatment of the disease and evaluation of the efficacy. In the field of pharmacy, if the target is a drug molecule, then this method can be used as a means to detect the metabolism of drug molecules in specific organs. In terms of chemistry/chemical industry, if the target is a chemical reaction molecule, then this method can be used as the distribution of the chemical reaction molecule in the reaction vessel to detect the progress of the chemical/chemical reaction.
  • the pulse sequence in Figure 6 shows a specific example of the implementation of the above steps.
  • Figure 6 is a schematic diagram of the pulse sequence.
  • the sequence of the evolution of the spin state in this sequence is as follows: the 90-degree radio frequency pulse at A turns the longitudinal magnetization vector from the vertical axis to the x, y plane; after the spin-lock pulse at B is applied, the spin is generated in the state of the system Singlet; the subsequent gradient pulse g 1 can eliminate the observable states other than the spin singlet; during the application of the decoupling pulse at C, the spin singlet is preserved, and other signals are attenuated by the effect of relaxation; then the second A gradient pulse g 2 further eliminates other signals other than the spin singlet, and finally the ⁇ SL pulse applied at D converts the spin singlet into the signal required for subsequent imaging experiments. Finally, the three-dimensional imaging pulse sequence realizes molecular imaging of the target molecule.
  • the target is an acetylaspartic acid molecule
  • the RF center as the center frequency between the signals of the amino acid molecule H c and H c' .
  • the present invention also provides a method for using nuclear spin singlet selectivity to perform magnetic resonance spectroscopy detection of a target in a designated space.
  • the magnetic resonance signal in the designated space is selected by magnetic resonance imaging layer selection technology.
  • the nuclear spin singlet selectivity is used to select the signal of the target in the magnetic resonance signal in the specified space, and finally the target in the specified space is realized.
  • the magnetic resonance spectrum of the signal is realized.
  • the method includes:
  • Step i Select the magnetic resonance pulse sequence with the function of layer selection, and select the magnetic resonance signal in the designated space through the magnetic resonance imaging gradient layer selection technology;
  • Step ii Using the method described above, using nuclear spin singlet selectivity to select the target signal in the magnetic resonance signal obtained in step i; including selecting different preparations according to the specific spin coupling characteristics of the target system Magnetic resonance pulse sequence of singlet nuclear spin;
  • Step iii Convert the signal obtained in Step ii into a detectable signal, and perform detection.
  • the magnetic resonance spectroscopy of a specific target molecule in a designated space realized by the above method can be applied in many fields. It can be used for early diagnosis and treatment of disease, evaluation of curative effect, detection of drug molecular metabolism in specific organs, and detection of chemical reaction molecule distribution in reaction vessels. Used to determine the progress of chemical/chemical reactions, etc. For example, in medicine, if the target is a molecule with high expression of disease, then this method can use MRI to select the signal of a specific part of the organism, and then observe the molecule with high expression of disease through signal selection. This method can be used as a means of early diagnosis and treatment of diseases and evaluation of efficacy.
  • this method can be used as a means to detect the metabolism of drug molecules in specific organs.
  • this solution can be used as the distribution of the chemical reaction molecule in the reaction vessel to detect the progress of the chemical/chemical reaction.
  • the method of selecting layers by magnetic resonance imaging gradient in step i is a method well known in the art.
  • different magnetic resonance pulse sequences with layer selection function can be selected according to actual needs.
  • the designated space in step i refers to the position of the specific part of the observation object in the space.
  • step ii refers to the method of selectively detecting a target by using nuclear spin monomorphism as described above.
  • the signal obtained in step iii can be converted into an observable signal by designing a pulse or a combination of pulses according to actual needs.
  • the pulse sequence of Fig. 7 shows a specific example of the implementation of the above steps.
  • Figure 7 is a schematic diagram of the pulse sequence.
  • the sequence of the evolution of the spin state of the sequence is as follows: the 90-degree radio frequency pulse at A turns the longitudinal magnetization vector from the vertical axis to the x, y plane; the subsequent waveform pulse at E and the matching gradient pulse g z achieve a specific spatial position signal Selection; then the spin singlet is generated in the state of the system after the spin-lock pulse is applied at B; the subsequent gradient pulse g 1 can eliminate the observable states other than the spin singlet; during the application of the decoupling pulse at C, The spin singlet is preserved, and other signals are attenuated under the influence of relaxation; then the second gradient pulse g 2 further eliminates other signals other than the spin singlet, and finally the ⁇ SL pulse applied at D turns the spin singlet Converted into signals required for subsequent MRS experiments. Finally, the signal is observed to realize the MRS spectrum of a specific molecule in a
  • the locking pulse frequency ⁇ SL 17.22Hz
  • action time ⁇ 1 105ms ( ⁇ 1 in FIG. 7 i.e. In ⁇ SL )
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized.
  • the gradient field intensity is 5 Gauss/cm
  • the action time is 1 ms
  • the decoupling pulse power ⁇ dec 90 Hz
  • the decoupling time ⁇ m 50ms.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized.
  • the gradient field intensity is 5 Gauss/cm
  • the action time is 1 ms
  • the decoupling pulse power ⁇ dec 90 Hz
  • the decoupling time ⁇ m 50 ms.
  • the beneficial effect of the present invention is that: the present invention is different from other previous magnetic resonance imaging and spectroscopy technologies in that a significant feature and innovation point is that it can realize the magnetic resonance imaging and spectroscopy of specific molecules.
  • the realization of this feature and innovation is based on the innovative use of nuclear spin singlet.
  • the present invention makes use of the characteristic that nuclear spin singlet is not affected by pulse gradient field for the first time, and the specific selectivity of molecular structure in the preparation process of nuclear spin singlet, so as to realize the selection of magnetic resonance signal of specific molecule and combine it Applied to magnetic resonance imaging and spectroscopy.
  • the present invention can truly realize magnetic resonance imaging of specific molecules.
  • the present invention can observe the magnetic resonance spectra of specific molecules in the designated parts of the test object, and thereby realize the measurement of the spatial distribution of the specific molecules in the test object.
  • the method or its variants can be combined with existing magnetic resonance imaging and spectroscopy to derive more magnetic resonance molecular imaging and spectroscopy technologies.
  • the method can be used to monitor the content and distribution of endogenous target substances in the organism without injecting exogenous probe molecules into the organism. Therefore, the target can be detected without damaging tissues and cells; this method can also be used to monitor the content and distribution of target molecules in chemical reactors. It can detect the signal of the target in the chemical reactor without destroying or interfering with the chemical reaction, so as to realize the observation of the chemical reaction process.
  • the method can also be combined with some exogenous targeting probe molecules, and by preparing the singlet of the targeting probe molecules, the detection of the content and distribution of the targeting probe molecules in the observation object can be realized.
  • This method has important application value in the fields of biology, medicine, chemistry, chemical industry, industrial production and so on.
  • Fig. 1 is a schematic diagram of a magnetic resonance pulse sequence for selective detection of target molecules by using nuclear spin singlet.
  • 1 H represents the hydrogen channel
  • G z represents the pulse gradient channel in the z direction.
  • Figure 2 is a schematic diagram of a three-dimensional imaging sequence based on monomorphic filtering.
  • 1 H represents a hydrogen channel
  • G x , G y , and G z represent pulse gradient channels in the x, y, and z directions, respectively.
  • Fig. 3 is a schematic diagram of MRS sequence using nuclear spin singlet to realize magnetic resonance signal selection.
  • 1 H represents a hydrogen channel
  • G x , G y , and G z represent pulse gradient channels in the x, y, and z directions, respectively.
  • Figure 4 is a schematic diagram of the molecular structure of dopamine of formula (1).
  • Fig. 5 is a schematic diagram of a pulse sequence for preparing a nuclear spin singlet based on spin locking to realize the selection of a specific molecular magnetic resonance signal.
  • 1 H represents the hydrogen channel
  • G z represents the pulse gradient channel in the z direction.
  • the black rectangle at A represents 90 pulses
  • the black rectangle at B represents the spin-lock pulse
  • the box at C represents the decoupling pulse
  • the black rectangle at D represents the spin-lock pulse
  • g 1 and g 2 represent gradient pulses.
  • ⁇ SL and ⁇ SL are the power and time of the spin-locked pulse
  • ⁇ dec and ⁇ m are the power and time of the decoupling pulse.
  • Fig. 6 is a pulse sequence for magnetic resonance molecular imaging based on spin-locked preparation of nuclear spin singlet states.
  • 1 H represents a hydrogen channel
  • G x and G y represent pulse gradient channels in the x and y directions, respectively.
  • the black rectangle at A represents 90 pulses
  • the black rectangle at B represents the spin-lock pulse
  • the box at C represents the decoupling pulse
  • the black rectangle at D represents the spin-lock pulse
  • g 1 , g 2 , g 3 and g 4 represent Gradient pulse.
  • ⁇ SL and ⁇ SL are the power and time of the spin-locked pulse
  • ⁇ dec and ⁇ m are the power and time of the decoupling pulse.
  • Fig. 7 is an MRS pulse sequence for preparing nuclear spin singlet based on spin locking.
  • 1 H represents the hydrogen channel
  • G z represents the pulse gradient channel in the z direction.
  • the black rectangle at A represents 90 pulses
  • the black rectangle at B represents the spin-lock pulse
  • the box at C represents the decoupling pulse
  • the black rectangle at D represents the spin-lock pulse
  • the multilobe shape at E represents the layer selection pulse
  • g 1 , G 2 and g z represent gradient pulses.
  • ⁇ SL and ⁇ SL are the spin lock pulse action time
  • ⁇ dec and ⁇ m are the power and action time of the decoupling pulse.
  • Fig. 8 is a schematic diagram of a pulse sequence for preparing nuclear spin singlets based on multi-pulse technology to realize the selection of magnetic resonance signals of specific molecules.
  • 1 H represents the hydrogen channel
  • G z represents the pulse gradient channel in the z direction.
  • the black rectangle at A represents a 90-degree pulse
  • the square at B represents a 180-degree pulse
  • the black rectangle at C represents a 90-degree pulse
  • the square at D represents a decoupling pulse
  • the black rectangle at E represents a 90-degree pulse
  • the square at F represents
  • g 1 and g 2 represent gradient pulses.
  • ⁇ 1 and ⁇ 2 represent the time interval between pulses.
  • ⁇ dec and ⁇ m are the power and time of the decoupling pulse.
  • FIG. 10 is: a) AGG leucine, glutamic acid and glycine, a mixture of deuterium aqueous monopulse 1 H spectra; b) prepared based on nuclear spin singlet, H c to achieve AGG molecule, H c 'group selection signal The spectrum of sexual observations.
  • AGG insulin aqueous mixture of deuterium 1 H single pulse spectrum b) prepared based on nuclear spin singlet, H c to achieve AGG molecules selectively observed spectrum signal H c 'group.
  • FIG 12 is: a) DA deuterium aqueous monopulse 1 H spectra; b) preparing nuclear spin singlet, DA molecules Based on H a, H b group selectively observed spectrum signal pair.
  • Figure 13 is: a) Single pulse 1 H spectrum of DA deuterium aqueous solution, in which the mass fraction of DA is 0.0006%; b) Based on the preparation of nuclear spin singlet, the spectrum of selective observation of the H d group signal of DA molecule is realized.
  • Figure 14 is: a) a single pulse 1 H spectrum of a deuterium taurine aqueous solution; b) a spectrum of selective observation of the signals of the 1, 2 groups of taurine molecules based on the preparation of nuclear spin singlets.
  • 16 is: a) NAA deuterium aqueous monopulse 1 H spectra; b) prepared based on nuclear spin singlet, NAA achieve molecule H b, the signal observed selective H b 'groups spectra.
  • FIG 17 is: a) NAA mouse brain tissue with a mixture of single-pulse 1 H spectra; b) prepared based on nuclear spin singlet, NAA achieve molecule H b, the signal observed selective H b 'groups spectra.
  • Figure 18 is: a) the actual photo and schematic diagram of the sample.
  • the sample is: a 4mm inner diameter glass nuclear magnetic sample tube contains a mixture of 60% water and 40% deuterium water.
  • the glass nuclear magnetic sample contains 4 small glass tubes with a 0.9mm outer diameter, each containing 24% NAA deuterium.
  • b) Spin echo imaging image of the above sample; c) Magnetic resonance molecular imaging image of NAA molecule; d) Magnetic resonance molecular imaging image of AGG molecule; e) Magnetic resonance molecular imaging image of DA molecule.
  • Figure 19 is: a) Spin echo imaging image of the test sample, the white frame indicates the signal selection area in the layer selection; b) the conventional MRS spectrum of the white frame selection area; c) the MRS spectrum of the AGG molecule; d) the MRS of the NAA molecule Spectrum; e) MRS spectrum of DA molecule.
  • the sample is the same as the sample in Example 10, which is: a 4mm inner diameter glass nuclear magnetic sample tube contains a mixed water of 60% water and 40% deuterium water, and the glass nuclear magnetic sample contains 4 small glass tubes with an outer diameter of 0.9mm, respectively It contains 24% NAA deuterium aqueous solution, 11.2% AGG deuterium aqueous solution, mixed water of 40% water and 60% deuterium water, and 10% DA deuterium aqueous solution.
  • Figure 20 is a flowchart of the main steps in the embodiment.
  • Fig. 21 is a schematic flow chart of a method for selectively detecting a target object using nuclear spin singlet in the present invention.
  • FIG. 22 is a schematic flow chart of a method for realizing magnetic resonance imaging of a target by using a singlet of nuclear spin in the present invention.
  • FIG. 23 is a schematic flowchart of a method for detecting a target in a designated space by magnetic resonance spectroscopy using nuclear spin singlet selectivity according to the present invention.
  • the spin system can be roughly divided into a strong coupling system and a weak coupling system. Depending on the nature of the spin system, the corresponding pulse sequence also needs to be adjusted;
  • the parameters in the pulse sequence are closely related to the molecular characteristics of the sample. In order to obtain a better signal selection effect, the experimental parameters in the pulse sequence need to be optimized;
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the pulse sequence shown in Figure 5 first apply a 90° hard pulse with the phase in the y direction to the sample, and then apply the center frequency between the emission center H b , H b'signal and H c , H c'signal , and the phase is at x direction, time is ⁇ 1 , locking pulse with locking frequency ⁇ SL prepares the singlet of AGG molecules; then z-direction gradient fields g 1 and g 2 and decoupling pulse ⁇ dec are applied; then the emission center is H b , H b 'signal and the H c, H c' between the center frequency of the signal, the phase in the x direction, the time ⁇ 1, the locking of the locking frequency ⁇ SL pulses; last data sampling.
  • Decoupling pulse power ⁇ dec 85Hz
  • decoupling time ⁇ m 50ms.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • H b AGG molecule, H b 'and H c, H c' spin coupling system is formed independently, and may be prepared in a single-state selection signal. Since the H c, H c 'high signal strength, to H c, H c' as the characteristic selection signal, a signal AGG molecules can obtain better signal sensitivity.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the method of using the pulse sequence shown in FIG. 5 is the same as that in Embodiment 1.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • Experimental sample amino acid molecule, deuterium aqueous solution of a mixture of L-Alanine-glycine-glycine (AGG) and bovine insulin, in which the mass fraction of AGG is 0.05% and bovine insulin is 1.04%.
  • AGG L-Alanine-glycine-glycine
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the method of using the pulse sequence shown in FIG. 5 is the same as that in Embodiment 1.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 8.
  • the RF center needs to be moved to the center frequency between the Ha and H b signals on the benzene ring.
  • First apply a 90° hard pulse with the phase in the x direction to the sample, and then apply a combined pulse of ⁇ 1 - ⁇ x - ⁇ 1 , where ⁇ 1 30.9ms, the purpose is to remove the chemical shift evolution, and then apply
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • the power of the decoupling pulse needs to be optimized.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the method of using the pulse sequence shown in FIG. 5 is the same as that in Embodiment 1.
  • the locking pulse emission center between the center frequency on the benzene ring with H a H b signal then applying a z-direction gradient field g 1 and g 2 and decoupling pulse.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • This experiment needs to increase the number of accumulations of signal acquisition. In the experiment of Fig. 13b, the cumulative number of times is 4000.
  • the nuclear spin singlet of the spin-coupling system H a , H b , and H d was prepared by using the pulse sequence shown in Fig. 8 to realize the selection of the signal of the H d group of the DA molecule while suppressing other signals.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 8.
  • the center of the radio frequency needs to be moved to the center frequency between the No. 1 hydrogen and No. 2 hydrogen signals on the methylene group.
  • First apply a 90° pulse with the phase in the x direction to the sample, and then apply a combined pulse of ⁇ 1 - ⁇ x - ⁇ 1 , where ⁇ 1 10ms, apply
  • After the single state of the taurine molecule can be obtained from the pulse of, where ⁇ 2 6.8ms; then z-direction gradient fields g 1 and g 2 and decoupling pulses are applied.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • the nuclear spin singlet of the spin coupling system H 1 , H 2 was prepared by using the pulse sequence shown in Fig. 8 to realize the selection of the H 1 and H 2 signals of the taurine molecule, and realize the selection of other signals at the same time. Suppress (see Figure 14).
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the method of using the pulse sequence shown in FIG. 5 is the same as that in Embodiment 1.
  • the lock pulse emission center between the center frequency H b, H b 'signal thus prepared creatine molecule singlet; then applying a gradient field in the z direction g 1 and g 2 and decoupling pulse.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • Test result Using the pulse sequence shown in Figure 5, by preparing the nuclear spin singlet of the spin-coupling system H b , H b' , the selection of the creatine molecular signal was realized, and the suppression of other signals was realized at the same time (see Figure 15).
  • NAA N-acetylaspartic acid molecule
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the method of using the pulse sequence shown in FIG. 5 is the same as that in Embodiment 1.
  • the locking pulse emission center between the center frequency H b, H b 'signal in order to produce a single molecule state NAA; then applying a gradient field in the z direction g 1 and g 2 and decoupling pulse.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • Experimental sample a mixture of NAA deuterium aqueous solution (NAA mass fraction is 1.1%) and mouse brain tissue.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method single pulse sequence and pulse sequence shown in Figure 5.
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 10 Gauss/cm, and the action time is 1 ms.
  • a 4mm inner diameter glass NMR sample tube contains a mixed water of 60% water and 40% deuterium water, and 4 small 0.9mm outer diameter glass tubes are placed in the glass NMR sample (see Figure 18a). Inside the small glass tube are 24.2% NAA deuterium aqueous solution, 11.2% AGG deuterium aqueous solution, 40% water and 60% deuterium water mixed water, and 10.5% DA deuterium aqueous solution with mass fraction.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method spin echo imaging sequence and pulse sequence shown in Figure 6.
  • the spin singlets of NAA, AGG, and DA are prepared separately to realize the selection of these molecular signals, and then the molecular imaging of each of these molecular signals is performed.
  • the specific experimental steps are as follows:
  • the intensity and action time of the gradient fields g 1 and g 2 need to be optimized, usually the gradient field intensity is 5 Gauss/cm, and the action time is 1 ms.
  • the spin echo imaging result is shown in Figure 18b.
  • the large gray disc is formed by the mixed water of 60% water and 40% deuterium water in the 4mm inner diameter glass nuclear magnetic sample tube, which represents the cross section of the 4mm inner diameter glass nuclear magnetic sample tube.
  • the small discs represent the cross-sections of different small glass tubes, and the brightness is related to the concentration of the solution in the small glass tubes.
  • the black circle comes from the wall of the small glass tube.
  • the results of NAA molecular imaging are shown in Figure 18c.
  • the method of the present invention can perform selective molecular imaging from a complex mixed system, so as to obtain the spatial distribution of a certain specific substance. This provides a method for detecting a specific biochemical molecule in a biological body and realizing its molecular imaging.
  • a 4mm inner diameter glass NMR sample tube contains a mixed water of 60% water and 40% deuterium water, and 4 small 0.9mm outer diameter glass tubes are placed in the glass NMR sample (see Figure 18a). Inside the small glass tube are 24.2% NAA deuterium aqueous solution, 11.2% AGG deuterium aqueous solution, 40% water and 60% deuterium water mixed water, and 10.5% DA deuterium aqueous solution with mass fraction.
  • Measuring instrument BrukerAVANCE III 500MHz nuclear magnetic resonance instrument.
  • the spectrometer is equipped with a gradient power amplifier in 3 directions.
  • the probe is a 5mm liquid probe with 3 gradient coils.
  • Measurement method spin echo imaging sequence and pulse sequence shown in Figure 7.
  • the signal layer is selected for the sample first.
  • Layer selection methods and experiments are well-known knowledge in the field.
  • the layer selection is excited by a hard pulse and then a combination of sinc wave pulse and gradient field is used to select the specific spatial signal of the sample.
  • the selection of molecular signals is achieved through the preparation of nuclear spin singlets of specific molecules, and finally the magnetic resonance spectroscopy observation of these molecular signals is carried out.
  • the experimental parameters for specific molecular signal selection are as follows:
  • the intensity and action time of 1 and g 2 need to be optimized.
  • the gradient field intensity is 5 Gauss/cm
  • the action time is 1 ms
  • the decoupling pulse power ⁇ dec 90 Hz
  • the decoupling time ⁇ m 50 ms.
  • the intensity and action time of 1 and g 2 need to be optimized.
  • the gradient field intensity is 5 Gauss/cm
  • the action time is 1 ms
  • the decoupling pulse power ⁇ dec 90 Hz
  • the decoupling time ⁇ m 50 ms.
  • the intensity and action time of g 2 and g 2 need to be optimized.
  • the gradient field intensity is 5 Gauss/cm
  • the action time is 1 ms
  • the decoupling pulse power ⁇ dec 90 Hz
  • the decoupling time ⁇ m 50 ms.
  • the spin echo imaging result of the sample is shown in Figure 18a.
  • the large gray disc is formed by the mixed water of 60% water and 40% deuterium water in the 4mm inner diameter glass nuclear magnetic sample tube, which represents the cross section of the 4mm inner diameter glass nuclear magnetic sample tube.
  • the small discs represent the cross-sections of different small glass tubes, and the brightness is related to the concentration of the solution in the small glass tubes.
  • the black circle comes from the wall of the small glass tube.
  • the white box in Figure 18a indicates the signal selection area in the layer selection.
  • Fig. 18b is a conventional MRS spectrum of the area indicated by the white box in Fig. 18a.
  • Figure 18c A molecular MRS spectrum after nuclear spin singlet preparation and signal selection of AGG molecules. It can be seen that NAA and DA in the spectrum have basically disappeared, and the signal of water (HDO) has also been greatly suppressed.
  • Figure 18d and Figure 18e show the molecular MRS spectra of NAA and DA. From these molecular MRS spectra, it can be found that the method of the present invention can perform molecular selective MRS from a complex mixed system, thereby obtaining the spatial distribution of a certain specific substance. This provides a method for detecting a specific biochemical molecule in the organism and realizing its molecular MRS.

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Abstract

L'invention concerne un procédé de détection sélective d'un objet cible à l'aide d'un état singulet de spin nucléaire. La caractéristique d'un état singulet de spin nucléaire n'étant pas affectée par un champ de gradient pulsé est utilisée, et après que l'état singulet de spin nucléaire d'un système de couplage de spin nucléaire d'un objet cible est préparé, le champ de gradient pulsé est appliqué à l'objet cible afin de disperser d'autres signaux de résonance magnétique autres que l'état singulet de spin nucléaire de l'objet cible, et un signal d'état singulet de spin nucléaire de l'objet cible est maintenu, ce qui permet de réaliser la détection sélective d'un signal magnétique nucléaire de l'objet cible. Le procédé de détection sélective d'un objet cible à l'aide d'un état singulet de spin nucléaire dans la présente invention présente une bonne précision, une bonne sensibilité et une bonne sélectivité ; au moyen du procédé, l'interférence d'autres signaux physiques peut être éliminée, et des signaux de molécules d'objets cibles peuvent être détectés avec précision et obtenus à partir d'un système avec des composants complexes ; et le procédé a une valeur d'application significative dans des domaines tels que la biologie, la médecine, la chimie et l'ingénierie chimique.
PCT/CN2020/078140 2019-12-09 2020-03-06 Procédé de détection sélective d'objet cible à l'aide d'état singulet du spin nucléaire WO2021114499A1 (fr)

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CN201911249189.7A CN113030145A (zh) 2019-12-09 2019-12-09 利用核自旋单态选择性检测目标物的方法
CN201911248840.9A CN113030144B (zh) 2019-12-09 2019-12-09 利用核自旋单态实现对目标物进行磁共振成像的方法及应用
CN201911249153.9A CN113030815A (zh) 2019-12-09 2019-12-09 利用核自旋单态选择性对指定空间中目标物进行磁共振波谱检测的方法
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