JP4319641B2 - NMR apparatus and measurement method thereof - Google Patents

Description

  The present invention relates to an NMR (Nuclear Magnetic Resonance) apparatus, and more particularly to an NMR analyzer equipped with a low-temperature probe and a measurement method thereof.

  In the NMR measurement, the ratio of signal to noise (hereinafter referred to as S / N ratio) is extremely important, and in recent years, a low-temperature probe has been used as a means for improving the S / N ratio. Generally speaking, a low-temperature probe is a probe that superconducts a circuit related to the probe and cools the inside of the probe including a preamplifier with a low-temperature helium gas of about 20K, and an oxide superconductor is used as the superconductor. . A technique relating to a low-temperature probe is disclosed in, for example, Patent Document 1.

  If a low-temperature probe and other probes can be switched simultaneously or quickly, there is a great advantage that a new measurement can be performed. For example, as described in Non-Patent Document 1, NMR micro-imaging and high-resolution NMR spectrum measurement can be realized simultaneously or within the same magnetic field environment within a short time. This measurement is particularly advantageous when it changes over time as in a living body.

  The rapid switching between the low-temperature probe and other probes is beneficial in applying an existing measurement method in addition to the above-described new measurement method. Low temperature probes have advantages in S / N ratio, but may not be appropriate with low temperature probes. Typical examples of this include imaging measurement described in Non-Patent Document 2, and measurement using a conductive solvent described in Non-Patent Document 3. In order to perform such a measurement, it is necessary to switch from a low temperature probe to a probe suitable for each measurement. In addition, research institutions often make their own special probes for research purposes, and it is more and more beneficial to switch between low temperature probes and other probes.

  However, a low-temperature probe equipped with a high-precision superconducting circuit and a vacuum cooling system has a high risk of mechanical, thermal, and electrical damage when a magnet is inserted and removed, and it is difficult for a user to replace the low-temperature probe. Further, when inserting and removing the low temperature probe from the magnet, it is necessary to raise the temperature of the probe to room temperature for safety reasons. Therefore, insertion and removal of the low temperature probe usually requires two days or more.

  As described above, it is difficult to replace the low temperature probe, and it is almost impossible to quickly switch between the low temperature probe and the other probes in the current NMR apparatus. Therefore, the advantages of the measurement method such as NMR micro-imaging and high-resolution NMR spectrum measurement obtained by combining a low temperature probe and another probe and switching them simultaneously or in a short time cannot be realized with the current NMR apparatus.

  The difficulty of replacing the low temperature probe also increases the burden on the user. In order to perform measurements that are not appropriate for the above-mentioned cryogenic probes, most research institutions that have introduced cryogenic probes use one magnet exclusively for the cryogenic probe and introduce another magnet in case another probe is needed. ing. The current situation of operating two magnets is a huge burden for research institutions in terms of magnet purchase costs, maintenance costs, installation space, and the like.

  Patent Document 2 of the prior art discloses an NMR apparatus that uses a probe with high versatility to measure a plurality of samples at the same time, and uses two probes simultaneously or alternately as means for solving the problem. . However, the NMR apparatus disclosed in Patent Document 2 can only be used for measurement without using a sample tube because the sample tube cannot be exchanged with the probe inserted. In most bio research, NMR measurement using a sample tube is an indispensable requirement, so the inability to use a sample tube is a very serious limitation.

  Patent Document 3 of the prior art has an object to enable introduction and withdrawal of a sample tube in a state where a probe having a solenoid-like detection coil is inserted, and a magnet structure having a cross-shaped through hole as means for solving the problem. Is disclosed. However, since the NMR apparatus disclosed in Patent Document 3 takes out the power supply line to the shim coil and the gas for adjusting the sample temperature from one side of the through hole, the probe cannot be inserted from both sides of the through hole. Therefore, according to Patent Document 3, one side of the through hole is used as a light introduction path.

US Pat. No. 5,689,187 JP 2003-270313 A JP 2004-309208 A Japanese Patent Publication No. 6-40125 Samuel C.I. Grant, Nanci R.A. Aiken, H.M. Daniel Plant, Stephen Gibbs, Thomas H. et al. Mareci, Andrew G. Webb, and Stephen J. Blackband, NMR Spectroscopy of Single Neurons, Magnetic Resonance in Medicine, Vol. 33, 19-22, 2000 Paul T. Callaghan, Principles of Nuclear Magnetic Resonance Microscopy, Oxford University Press (1993) Peter F.M. Flynn, Debra L. et al. Mattiello, Howard D. W. Hill, and A.A. Joshua Wand, Optimal Use of Cryogenic Probe Technology in NMR Studies of Proteins, Journal of the American Chemical Society, Vol. 122, 4823-4824, 2000

  The problem to be solved by the present invention is to provide an NMR apparatus that can measure a sample inserted into a sample tube with one magnet at the same time or quickly by using a low temperature probe and another probe. It is to be.

  It realizes the advantages of NMR measurement obtained by using a combination of a low temperature probe and other probes, and further reduces the burden on the user by operating two magnets. One method for this purpose is to provide an NMR apparatus that can perform measurement using a low temperature probe and measurement using another probe simultaneously or quickly on a sample that has entered a sample tube with one magnet. It is.

  Low temperature probes are known to have high sensitivity but have many limitations. For example, the salt concentration and conductivity of the sample may be low, the input power may be low, and the received NMR signal may be small. In many samples and measurement methods that cannot satisfy this condition, it is preferable to use a probe at room temperature. In addition, depending on the sample, new information can be obtained by performing NMR measurement by combining a high-sensitivity low-temperature probe and another probe without restriction.

  An object of the present invention is to provide an NMR apparatus and a measurement method that realize high-function and high-accuracy measurement by combining a low-temperature probe and another probe and switching them simultaneously or in a short time in view of the above-described problems of the prior art. There is. Another object is to reduce the burden on the user by operating two magnets.

  The configuration of the present invention that solves the above problems will be described.

  In an NMR apparatus comprising a magnet, a probe, and a measurement console, the magnet is provided with two or more holes, at least two of which are orthogonal to each other, and one of the orthogonal holes is inserted into the probe. The probe is configured to penetrate the magnet as a bore, and the probe is provided with a measurement space composed of a sample receiving hole and a signal detection coil perpendicular to the probe center line, and the probe insertion bore among the holes orthogonal to each other is provided. Another orthogonal hole was used as a sample insertion bore, and the two probes were inserted from both ends of the probe insertion bore penetrating the magnet.

  In addition, a gas flow path for introducing and discharging a sample tube is formed in one of the holes of the magnet (hereinafter referred to as sample tube introducing / exiting bore) that goes directly to the probe inserting bore, and further, with respect to the probe center line of the probe inserting bore. Formed on one side only.

  Further, the probe is provided with one or a plurality of grooves so that the shim coil feed line and the temperature adjusting gas can pass therethrough.

  Further, at least one of the probes is provided with a mechanism for cooling the signal detection coil to 0 degrees Celsius or less.

  A moving device for moving the probe in the magnet was attached to the probe and the magnet.

  In addition, a sensor for monitoring whether the sample tube is inserted into the sample receiving hole of the probe is provided so that the probe moving device operates only when the sample tube is not inserted.

  In addition, a sensor for detecting the position of the probe is provided in the probe moving device to avoid a collision between the two probes.

  As another configuration of the present invention that solves the above problems, in an NMR apparatus comprising a magnet, a probe, and a measurement console, two or more holes are provided in the magnet, and at least two holes are orthogonal to each other, The probe insertion bore, which is one of the holes orthogonal to each other, passes through the magnet, and the probe has two or more measurement spaces each including a sample receiving hole and a signal detection coil perpendicular to the probe center line.

  Still another configuration of the present invention that solves the above problem is that in an NMR apparatus comprising a magnet, a probe, and a measurement console, the magnet is provided with two or more holes, and at least two of the holes are orthogonal to each other. The probe insertion bore, which is one of the mutually orthogonal holes, penetrates the magnet, and the probe has a first measurement space made up of a sample receiving hole and a signal detection coil 2 perpendicular to the probe center line. And a second measurement space formed of another signal detection coil is provided in the probe, the first measurement space and the second measurement space are connected by a flow path, and inserted into the first measurement space. The sample in the sample container can be measured even in the second measurement space.

  According to the present invention, it is possible to provide an NMR apparatus that can perform measurement using a low-temperature probe and measurement using another probe simultaneously or quickly on a sample that has entered a sample tube with a single magnet. And new NMR measurement with high accuracy becomes possible.

  For example, NMR micro-imaging and high-resolution NMR spectrum measurement can be realized simultaneously or within a short time within the same magnetic field environment. This measurement is particularly advantageous when it changes over time as in a living body. In addition, the burden on the user due to the operation of the two magnets can be reduced.

  The NMR apparatus of the present invention is an analysis apparatus that detects an NMR signal generated after a predetermined time by applying an RF pulse to a predetermined nucleus in a sample placed in a static magnetic field. FIG. 2 shows a conceptual diagram of the NMR apparatus. The user computer 1 issues a measurement instruction to the transmitter / receiver 12, receives the measurement result from the transmitter / receiver 12, and displays it on the screen. The transmitter / receiver 12 transmits a radio frequency (Radio Frequency, hereinafter referred to as RF) signal to the probe 7 inserted in the superconducting magnet 6 via the transmission / reception switching circuit 5 and irradiates the atomic nucleus of the sample placed in the probe. A free induction decay signal (FID signal) emitted from the nucleus is detected by the probe 7 and amplified by the preamplifier 8 via the transmission / reception switching circuit 5. The amplified FID signal is processed by the transceiver 12 and displayed on the user computer 1.

  The transmitter / receiver 12 includes a control computer 2 that controls the entire measurement in real time, a high-frequency transmitter 3 that generates a transmission RF signal, and a power amplifier 4 that amplifies the transmission RF signal. Also, a receiver 9 that performs frequency conversion and amplification of the FID signal from the preamplifier 8, an analog / digital converter 10 that converts the FID signal into digital data, and a digital signal processor that processes the digitized FID signal. 11.

  In the present invention, an NMR apparatus has been realized in which measurement using a plurality of probe coils having different characteristics with respect to a sample contained in a sample tube can be performed with a single magnet, with less labor and in a short time. Hereinafter, a plurality of embodiments of the present invention will be described.

  FIG. 1 is a configuration diagram showing a configuration of an NMR apparatus in which a plurality of probe coils having different characteristics are mounted. The magnet 6 has two holes 28 and 29 that are orthogonal to each other. The probes 7 and 7 'are inserted from both sides of the probe insertion bore 29 parallel to the static magnetic field created by the magnet, and the sample tube 14 is inserted from the sample insertion bore 28 perpendicular to the static magnetic field.

  Hereinafter, a probe at a position suitable for sample tube insertion by the sample insertion bore 28 of the magnet is referred to as a probe A, and a probe at an unsuitable position is referred to as a probe B. In the example of FIG. 1, the probe 7 is the probe A and the probe 7 ′ is the probe B. The probes A and B can be moved along the probe insertion bore 29 by the probe moving devices 13 and 13 ', respectively, and can be used by switching with less labor and a short time. Probes A and B are connected to transmission / reception switching circuits 5 and 5 ', respectively. The RF signal output from the transceiver 12 is transmitted via the switch 15 to the transmission / reception switching circuit 5 connected to a probe (hereinafter referred to as probe A) placed at a position suitable for measurement.

  On the other hand, the FID signal detected by the probe A is amplified by the preamplifier 8 from the transmission / reception switching circuit 5 and then received by the transceiver 12 via the switch 15. With the configuration in which the FID signal passes through the switch 15 via the preamplifier 8, the S / N deterioration due to the switch 15 can be minimized.

  In addition to the configuration shown in FIG. 1, it is possible to integrate the transmission / reception switching circuit 5 and the preamplifier 8 and to arrange the switch 15 between the transmission / reception switching circuit 5 and the probes A and B. Since this configuration has the advantage of simplifying the device configuration, it is effective when S / N degradation is not a problem. It goes without saying that this configuration is more effective if a switch 15 having a small noise figure can be used.

  FIG. 3 is a flowchart showing a main procedure in probe switching according to the first embodiment of the present invention. FIG. 4 is a conceptual diagram showing the state of the sample tube and the probe in the procedure shown in FIG.

  At the start of probe switching, the NMR apparatus senses whether the sample tube 14 is present in the sample receiving hole of the probe A (101), and records the presence or absence of the sample tube in the storage device. FIG. 4A shows a state where the sample tube 14 exists in the sample receiving hole. When the sample tube 14 exists (102), the sample tube 14 is discharged out of the sample receiving hole of the probe A using the sample tube discharge means (103). The state after discharging the sample tube is shown in FIG. Examples of the sample tube discharging means include a sample introduction / extraction gas and a non-magnetic robot arm.

  When the sample tube does not exist or when the sample tube discharge is completed, the probe A is moved (104). Next, the probe B is moved so that the sample receiving hole and the sample insertion bore 28 of the magnet coincide with each other (105). The distance between the two probes is determined taking into account the length of each probe housing and the electrical, magnetic, thermal and hydrodynamic coupling of the measurement space.

  FIG. 4C shows a state after the movement of the probes A and B is completed. In this state, the probe 7 'becomes a new probe A and the probe 7 becomes a new probe B according to the above definition.

  Next, referring to the record in the storage device, if the sample tube has been inserted in the initial state (106), the sample tube 14 is inserted into the new probe A using the sample tube discharging means (107). The probe switching procedure is terminated. FIG. 4D shows a state after the sample tube is inserted into the new probe A. If the sample tube has not been inserted in the initial state, the probe switching procedure is terminated when the movement of the probe B is completed without inserting the sample tube. However, the last sample tube insertion operation can be determined by the user's instruction regardless of the presence or absence of the sample tube in the initial state.

  The probe switching operation is started when the user instructs the control computer 2 to switch the probe via the user computer 1 shown in FIG. This instruction can be performed interactively by the user or by a program prepared in advance. The end of the probe switching operation is confirmed by the control computer 2, and the next operation set in advance by the user can be performed. For example, measurement using a new probe can be automatically started.

  FIG. 5 is a cross-sectional view illustrating details of the probe and the magnet according to the first embodiment. The magnet 6 has a sample insertion bore 28 and a probe insertion bore 29 that are orthogonal to each other. Further, a temperature adjusting gas introduction bore 26 is provided on the opposite side of the sample insertion bore 28.

  The region where the temperature adjusting gas introduction bore 26 intersects with the sample insertion bore 28 and the probe insertion bore 29 is a magnetic field central region where the static magnetic field created by the magnet 6 is strongest, and NMR measurement is performed in this magnetic field central region. A shim coil 31 serving as an electromagnet is disposed in the vicinity of the magnetic field center region, and the amount of current flowing through the shim coil 31 is changed to improve the uniformity of the magnetic field. In order to supply current to the shim coil 31, the shim coil power supply line 32 is pulled out to the outside of the magnet 6 through the edge side of the probe insertion bore 29.

  Probes A (7) and B (7 ') are inserted from both sides of the probe insertion bore 29. In the example of FIG. 5, the probe A is a low-temperature probe in which the probe coil 21 is stored in the low-temperature container 27, but the probe A may not be a low-temperature probe. Probes A and B are attached to the magnet 6 via probe attachment devices 13 and 13 '. The function of the probe mounting device 13 will be described later.

  The sample receiving hole 18 of the probe A coincides with the sample insertion bore 28 of the magnet, and the sample tube 14 is inserted from the sample insertion bore 28. Here, the sample receiving hole 18 is formed in a direction perpendicular to the center line of the probe.

  A spinner 20 is attached to the sample tube 14 for sample introduction / extraction and sample rotation. A bearing 16 is installed adjacent to the spinner 20. The bearing 16 ejects the sample driving gas sent through the sample driving gas channel 17 provided at the outer edge of the sample insertion bore 28 toward the spinner 20 to realize introduction and rotation of the sample.

  The sample driving gas channel 17 is formed only on one side (the upper side in the figure) with respect to the probe insertion bore 29, and the sample driving is ensured irrespective of the probe moving state in the probe insertion bore 29. With this configuration, the sample tube 14 can be kept stable in the sample insertion bore 28 while the probe is moving. Therefore, compared with a case where the sample tube 14 is taken out of the sample insertion bore 28, a simple apparatus configuration is more efficient. Measurement is possible.

  The sample tube sensor 19 disposed near the bearing 16 performs the sample tube presence / absence sensing operation shown in FIG.

  Probes A (7) and B (7 ') each have sample receiving holes 18 and 18' orthogonal to the probe insertion bore 29, and a probe housing is sandwiched between the sample receiving holes 18 and 18 '. Probe coils 21 and 21 'are arranged. In the example shown in FIG. 5, the probes 7 and 7 'each have one solenoid type probe coil. The shape of the probe coil that can be mounted may be a saddle type, a birdcage type, or a modified type thereof. Further, the number of probe coils may be two or more.

  Probe coils 21 and 21 'are connected to adjusting circuits 22 and 22', respectively. The adjustment circuits 22 and 22 'have a function of adjusting the characteristic impedance and resonance frequency of the probe coils 21 and 21' to predetermined values. Adjustment circuits 22 and 22 'are connected to external connection terminals 24 and 24' through coaxial cables 23 and 23 '. The transmission / reception switching circuits 5 and 5 'shown in FIG. 1 are connected to the external connection terminals 24 and 24'. The probe A, which is a low temperature probe, has a low temperature preamplifier 25 between the adjustment circuit 22 and the external connection terminal 24.

  FIG. 6 is a cross-sectional view illustrating the probe and the probe moving device according to the first embodiment. The diameter of the probe 7 '(same for the probe 7) is different between a portion inserted into the shim coil 31 shown in FIG. There are two or more probe grooves 42 in the portion that is not inserted into the shim coil 31, and the shim coil power supply line 32 is drawn out of the magnet through the probe groove 42. The probe groove 42 also functions to discharge the gas entering the probe insertion bore 29 from the temperature adjusting gas bore 26 and the sample driving gas flow path 28 to the outside of the magnet 6. The probe support portion 41 is a guide that prevents the probe 7 ′ from shaking in the probe insertion bore 29. The probe groove 42 may be provided in only one of the probes 7 and 7 ', or may be provided in two.

  The probe moving device 13 is attached to the magnet 6 using a mounting plate 34. The probe 7 ′ (the same applies to the probe 7) is attached to the probe moving device 13 by the probe fixing portion 37. The mounting plate 34 is connected to the probe moving device main body 36 by a probe moving rail 35. The probe moving rail 35 penetrates the probe fixing portion 37, and the probe fixing portion 37 can move along the probe moving rail 35 with the probe 7 ′ attached. A probe driving shaft 38 is fixed to the probe fixing portion 37, and the interval between the probe fixing portion 37 and the probe moving device main body 36 can be adjusted using the probe driving shaft 38. A probe driving unit 39 for adjusting the probe driving shaft 38 is set in the probe moving device main body 36. A probe position detection sensor 40 is also mounted on the probe moving device body 36.

  FIG. 7 is a flowchart showing an example of a measurement method using Example 1 of the present invention. Using a low-temperature probe and a room temperature probe for imaging, the probe (or coil) is alternately measured while being switched in a short time. The “coil switching” portion in the figure relates to the configuration of the second embodiment of the present invention and will be described later.

  The measurement method shown in FIG. 7 can be applied to research using biological samples such as metabolomics and metabonomics. By imaging using a room temperature probe, the concentration of a metabolite at a specific site in a cell is measured, and a low temperature metabolite is measured by quickly switching to a low temperature probe. Due to the characteristics of living organisms that change with time, it is desirable to perform imaging and spectroscopy within the shortest possible time and in the same environment. Thus, the present invention is extremely suitable for the above applications. Needless to say, the measurement method of the present invention is effective when the sample is a sample that changes with time in addition to a biological sample and the substance distribution in the sample and the spectrum are taken.

  FIG. 8 is a flowchart showing another measurement method using Example 1 of the present invention. As the probe, a low temperature probe for low sensitivity nuclear measurement and a room temperature probe for hydrogen (1H) nucleus measurement are used. Examples of the low-sensitivity nucleus include a carbon isotope (13C) nucleus and a nitrogen isotope (15N) nucleus. The measurement is performed alternately while switching the above probes. Such a measuring method is effective as a measuring method for acquiring the FID signal of the low sensitivity nucleus and the FID signal of the 1H nucleus. This measurement method is particularly effective in measuring biological metabolites such as urine.

  13C, 15N, etc. have a small amount of natural abundance, and an isotope replacement method is used in which 12C, 14N in the sample is replaced with 13C, 15N in order to increase the intensity of the FID signal. However, when measuring biological metabolites such as urine, measurement is often performed with a small natural abundance without using the isotope substitution method. For this reason, a highly sensitive low temperature probe is preferred. According to the measurement method of the present invention, a larger amount of information can be obtained by putting a body fluid such as urine into a sample tube and performing measurement alternately with two probes having different characteristics.

  As an example, 13C is a low-temperature probe, and 1H has a configuration in which measurement is performed with a room temperature probe. A weak 13C FID signal is measured with a low temperature probe, while a strong 1H FID signal is measured with a room temperature probe to avoid radiation damping. Radiation damping is a phenomenon in which when the current induced in the probe coil by the FID signal is large, the current further affects the sample nucleus and disturbs the movement of the nuclear spin, and appears particularly when measuring 1H nuclei with a low temperature probe. It adversely affects NMR measurement. Since the sample is a biological metabolite, the measurement of 13C and the measurement of 1H are preferably performed in the same environment within as short a time as possible. This condition is satisfied by using the NMR apparatus and measurement method of the present invention.

  As another form of the first embodiment, there is a configuration in which the magnet 6 has a plurality of sample insertion bores 28. In the case of this configuration, the plurality of sample insertion bores 28 are arranged radially toward the axis of the probe insertion bore 29. In this configuration having a plurality of sample insertion bores 28, a different sample tube is inserted for each sample insertion bore, and the probe is rotated in a state of being inserted into the probe insertion bore 29, whereby the sample in the sample tube selected by the user is obtained. Can be measured.

  Next, another embodiment for achieving the object of the present invention, which is to mount a plurality of probe coils, will be described.

  FIG. 9 is a block diagram of the NMR apparatus according to Example 2. The probe 7 is inserted from one side of the probe insertion bore 29 into the magnet 6 having the sample insertion bore 28 and the probe insertion bore 29. The probe 7 has two or three or more sample receiving holes 18, and the direction of the sample receiving holes 18 is a direction perpendicular to the static magnetic field generated by the magnet 6. Hereinafter, a probe coil at a position suitable for sample tube insertion by the sample insertion bore 28 of the magnet is referred to as coil A, and all probe coils at unsuitable positions are referred to as coil B.

  The switching of the probe coil A can be realized with less effort and a short time by the probe moving device 13 attached to the probe 7. The coil switching procedure may be “probe movement” by integrating “probe A movement” and “probe B movement” from the procedure of the first embodiment shown in FIG.

  The configuration of the NMR apparatus from the transmission / reception switching circuit 5 to the user computer 1 is the same as that according to the first embodiment. Needless to say, the switch 15 may be provided separately as shown in FIG. Further, the measurement method according to the first embodiment presented in FIGS. 7 and 8 can be equally applied to the second embodiment.

  FIG. 10 is a cross-sectional view illustrating details of the probe and the magnet according to the second embodiment. The difference from the cross-sectional view of the first embodiment shown in FIG. 5 is that two or more probe coils and attached circuits are mounted in the probe 7.

  In the configuration of FIG. 10, the probe 7 has two probe coils 21 and 21 ′, and the probe coil 21 is placed in a cryogenic container 27 and cooled to 0 degrees Celsius or less. Adjustment circuits 22 and 22 'for adjusting the characteristic impedance and resonance frequency of each probe coil are attached to the probe coils 21 and 21'. A low temperature preamplifier 25 is also attached to the low temperature probe coil 21.

  When the low temperature probe coil 21 and the room temperature probe coil 21 'are mounted in one probe 7, a structure in which the low temperature probe coil 21 is closer to the probe insertion port than the room temperature probe coil 21' as shown in the drawing is preferable in terms of the cooling mechanism.

  Compared to Example 1, the NMR apparatus according to Example 2 has the advantage that the space required for inserting the probe is halved. As is apparent from FIG. 9, the NMR apparatus according to the second embodiment can insert a probe if a space longer than the length of the probe housing is outside the magnet 6 on one side of the probe insertion bore 29. On the other hand, the NMR apparatus according to Example 1 shown in FIG. 1 requires a space longer than the length of the probe housing on both sides of the probe insertion bore. Therefore, the second embodiment is more advantageous than the first embodiment in terms of space utilization.

  The NMR apparatus according to Example 2 is more advantageous than the NMR apparatus according to Example 1 in the probe switching procedure. In the first embodiment, since two probes are switched, as shown in FIG. 3, at least two stages of movement operations are necessary to avoid a collision between the probes. However, in the second embodiment, since there is no danger of collision, the probe moving operation can be realized at least in one stage.

  The NMR apparatus according to the second embodiment is more advantageous than the NMR apparatus according to the first embodiment in terms of the number of probe coils that can be further mounted. The NMR apparatus of Example 2 can mount three or more probe coils by the mounting method in the probe. However, when using two probes mounted with one probe coil as in the NMR apparatus of the first embodiment, a maximum of two probe coils can be mounted regardless of the mounting method.

  However, the NMR apparatus according to Example 2 is disadvantageous in comparison with the NMR apparatus according to Example 1 in terms of manufacturability because the internal structure of the probe is complicated.

  A configuration similar to the second embodiment in which a plurality of probe coils having different characteristics are mounted as one probe is disclosed in Patent Document 4. However, the known example described in Patent Document 4 is different from Example 2 in its purpose and configuration. The purpose of Example 2 is to quickly switch and use probe coils having different characteristics, which is different from the simultaneous measurement of a plurality of samples which is the object of Patent Document 4.

  In the second embodiment, the axis of the sample tube and the probe center line are not parallel. However, in Patent Document 4, the axis of the sample tube and the axis of the probe are parallel. For this reason, in the configuration of the second embodiment, a sufficient distance can be set between the plurality of probe coils. For example, probe coils having different characteristics such as a low temperature probe coil and a normal temperature probe coil can be mounted. Further, the probe coil used for measurement can be easily moved to a space with good magnetic field uniformity by the probe moving device, and there is no restriction on the mounting space due to the magnetic field uniformity. On the other hand, in the configuration of Patent Document 4, the space for mounting a plurality of probe coils is restricted by the size of the space having the magnetic field uniformity required for measurement, which is disadvantageous compared to the second embodiment in terms of probe coil mounting. is there. Further, the configuration disclosed in FIG. 6 of Patent Document 4 is more disadvantageous than the second embodiment because the diameter of the probe is added as a constraint condition for mounting the probe coil.

  FIG. 11 shows another embodiment that achieves the object of the present invention to mount a plurality of probe coils having different characteristics. Example 3 is an NMR apparatus implemented by integrating the configurations of Example 1 and Example 2 as is clear when compared with FIGS. 1 and 9.

  Probes 7 and 7 ′ are inserted into the magnet 6 having the sample insertion bore 28 and the probe insertion bore 29 from both sides of the probe insertion bore 29. The probes 7 and 7 ′ have two or more sample receiving holes 18, and the direction of the sample receiving holes 18 is a direction perpendicular to the static magnetic field generated by the magnet 6.

  The third embodiment is more advantageous than the first and second embodiments in that more probe coils can be mounted without complicating the probe internal structure. The NMR apparatus according to Example 3 is particularly effective when a low temperature probe coil is used. In order to use a low temperature probe coil, a structure for cooling the probe coil is often mounted in the probe housing. It is difficult, if not impossible, to mount a plurality of probe coils and their adjustment circuits inside the probe on which the cooling structure is mounted. When using a low temperature probe coil, two probes may be inserted into the probe insertion bore. When one probe is a low-temperature probe mounted with one low-temperature probe coil and the other probe is mounted with a plurality of room temperature probe coils, various measurements can be performed by combining the low-temperature probe coil and the room temperature probe coil.

  On the other hand, in the probe switching procedure, the NMR apparatus according to Example 3 requires at least two stages of moving operations as shown in FIG. 3 in order to avoid collision between probes. This point is more complicated than the operation in the second embodiment and is a disadvantage of the third embodiment.

  FIG. 12 shows still another embodiment that achieves the object of the present invention to mount a plurality of probe coils having different characteristics.

  The probe 7 is inserted from one side of the probe insertion bore 29 into the magnet 6 having the sample insertion bore 28 and the probe insertion bore 29. The probe 7 has a sample receiving hole 18 perpendicular to the static magnetic field created by the magnet 6. The probe 7 has a flow measurement space 61 in addition to the sample receiving hole, and the flow measurement space 61 from the bottom of the sample receiving hole 18 is connected by a sample circulation circuit 60. The sample in the sample container 51 inserted into the sample receiving hole 18 is measured using a probe coil provided around the sample receiving hole 18. In addition, the liquid substance in the sample container 51 is transported using the sample circulation circuit 60 and measured in the flow measurement space 61.

  FIG. 13 is a sectional view showing a part of the probe and magnet in more detail. The sample insertion bore 28 of the fourth embodiment is provided at a position away from the magnetic field center of the magnet 6. A flow measurement space 61 is provided at the magnetic field center of the magnet 6. According to the configuration of the fourth embodiment, measurement using two or more probe coils can be performed simultaneously without moving the probe 7.

  A probe coil 21 ′ is provided around the sample receiving hole 18 to measure a sample 52 in the sample container 51. A sample advancing channel 54 and a sample return channel 55 are provided at the bottom of the sample receiving hole 18. When the sample container 51 is inserted, it is coupled to the sample circulation circuit valve 53 at the bottom of the sample container 51 to circulate the sample. The circuit 60 is configured. The sample circulation circuit 60 includes a sample circulation circuit valve 53, a sample advancing channel 54, a sample return channel 55, and a sample circulator 56.

  The liquid substance released from the sample 52 placed in the sample container 51 enters the sample advancing channel 54 through the sample circulation circuit valve 53. The sample advancing channel 54 passes through the cryogenic probe coil 21 placed in the cryocontainer 27. When the liquid substance passes through the low temperature probe coil 21 in the sample advancing channel 54, the measurement using the low temperature probe coil 21 is performed. The shim coil 31 is disposed so as to surround the probe coils 21 and 21 '. The liquid substance enters the sample return channel 55 and returns to the sample container 51 through the sample circulation circuit valve 53 in the sample circulator 56 that provides power for the sample circulation circuit 60. The sample circulator 56 receives power and a control signal from the sample circulator control line 57 and is connected to the outside through the sample circulator terminal 58.

  12 is a closed circuit, a configuration in which the liquid substance that does not have a return flow path and flows through the traveling flow path is directly discharged to the outside of the probe 7 is also possible. An external field introduction mechanism 59 is attached to the magnet sample insertion bore 28 so that an external field can be freely applied to the sample 52. Examples of external fields include light, chemical substances, sound waves, and ultrasonic waves.

  One method of using the NMR apparatus according to Example 4 is drug development. For example, a biological sample such as a mouse is placed in the sample container 51 and inserted into the sample receiving hole 18 of the probe through the sample insertion bore 28. Then, the drug is administered using the external field introduction mechanism 59. The imaging coil is used as the probe coil 21 ′ to obtain a drug distribution image in the biological sample, and at the same time, metabolites such as urine of the biological sample transported through the sample circulation circuit valve are measured by the low temperature coil 21. By carrying out such a measurement method, it is possible to obtain the drug distribution in the biological sample and at the same time obtain the amount of substance in the metabolite of the biological sample, thereby improving the efficiency of drug development.

  Another example of how to use the NMR apparatus according to Example 4 is plant metabolism studies. For example, rice is grown as a sample 52 in the sample container 51. By performing imaging and metabolite spectrum measurement simultaneously while applying light and fertilizer from the external field introduction mechanism 59, the growth mechanism of rice can be captured at the molecular biology level.

  According to the present invention, at least two or more probes having one or more probe coils installed in one magnet can be inserted, and a sample insertion bore that can be used for introducing an external field in addition to inserting a sample. Is provided. Accordingly, the present invention can be applied to applications in which NMR measurement and other measurements such as mass spectroscopy, infrared spectroscopy, and chromatography are performed simultaneously or in conjunction with each other.

The block diagram of the NMR apparatus by Example 1 of this invention. The conceptual diagram of a NMR apparatus. The flowchart which shows the probe switching procedure by Example 1 of this invention. The conceptual diagram which shows the state in the middle of the probe switching by Example 1 of this invention. Sectional drawing which shows the probe and magnet by Example 1 of this invention. Sectional drawing which shows the probe moving apparatus and the attachment part of a probe by Example 1 of this invention. The flowchart which shows the measuring method by Example 1 of this invention. The flowchart which shows another measuring method by Example 1 of this invention. The block diagram which shows the NMR apparatus by Example 2 of this invention. Sectional drawing which shows the probe and magnet by Example 2 of this invention. The block diagram which shows the NMR apparatus by Example 3 of this invention. The block diagram which shows the NMR apparatus by Example 4 of this invention. Sectional drawing which shows the probe and magnet by Example 4 of this invention.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1 ... User computer, 2 ... Control computer, 3 ... High frequency transmitter, 4 ... Power amplifier, 5 ... Transmission / reception switching circuit, 6 ... Superconducting magnet, 7 ... Probe, 8 ... Preamplifier, 9 ... Receiver, 10 ... Analog / Digital converter, 11 ... Digital signal processor, 12 ... Transmitter / receiver, 13 ... Probe moving device, 14 ... Sample tube, 15 ... Switch, 16 ... Bearing, 17 ... Sample drive gas channel, 18 ... Sample receiving hole , 19 ... Sample sensor, 20 ... Spinner, 21 ... Probe coil, 22 ... Adjustment circuit, 23 ... Coaxial cable, 24 ... Terminal, 25 ... Low temperature preamplifier, 26 ... Temperature adjustment gas flow path, 27 ... Low temperature container, 28 ... Sample insertion bore, 29 ... Probe insertion bore, 31 ... Shim coil, 32 ... Shim coil feeder, 34 ... Plate member for attaching probe moving device, 35 ... Probe transfer Rail, 36 ... probe moving device main body, 37 ... probe fixing portion, 38 ... probe driving shaft, 39 ... probe driving portion, 40 ... probe position detection sensor, 41 ... probe support portion, 42 ... probe groove, 51 ... sample container, 52 ... Sample, 53 ... Sample circulation circuit valve, 54 ... Sample travel channel, 55 ... Sample return channel, 56 ... Sample circulator, 57 ... Sample circulator control line, 58 ... Sample circulator terminal, 59 ... External field Introduction mechanism, 60 ... sample circulation circuit, 61 ... flow measurement space.

Claims (13)

In an NMR apparatus consisting of a magnet, a probe, and a measurement console,
Two or more holes are provided in the magnet, and at least two of the holes are orthogonal to each other, and a probe insertion bore that is one of the orthogonal holes penetrates the magnet. The probe is provided with a measurement space composed of a sample receiving hole and a signal detection coil perpendicular to the probe center line, and the other one of the holes orthogonal to the probe insertion bore is a sample insertion bore. Two probes are inserted from both ends of the probe insertion bore penetrating the magnet, a sensor for detecting the presence or absence of sample insertion is provided in the sample insertion bore, and the probe moves in the probe insertion bore Attaching a moving device to the probe and the magnet ,
A gas passage for introducing / extracting a sample tube is provided in the sample insertion bore orthogonal to the probe insertion bore, and the gas passage for introducing / extracting the sample tube is formed only on one side of the probe center line, and the sample insertion bore A gas flow path for sample rotation and sample introduction / extraction, and at least one of the probes is provided with one or a plurality of grooves on the outer periphery thereof, so that the power supply line of the shim coil and the temperature adjusting gas are provided. An NMR apparatus characterized by being inserted . In the measuring method of the NMR apparatus which consists of a magnet, a probe, and a measurement console, when the NMR apparatus according to claim 1 is provided in the NMR apparatus and the measurement space is switched, the sample tube is a sample of the probe. An NMR apparatus measurement method characterized by monitoring whether the probe is inserted into a receiving hole and moving the probe when a sample tube is not inserted. In Claim 2 , when the sample tube is inserted into the sample receiving hole of the probe, the operation of discharging the sample tube out of the sample receiving hole of the probe and the switching of the probe in order of avoiding the collision between the probes are performed. An NMR apparatus measurement method, comprising: sequentially performing an operation to be performed and an operation to insert the sample tube into a sample receiving hole of a new probe. Oite to claim 1, wherein the NMR probe to be inserted from one side of the probe insertion bore, characterized in that provided at least two in the vertical direction measurement space of the sample receiving hole and the signal detecting coil to the probe center line apparatus. 5. The NMR apparatus according to claim 4 , wherein a mechanism for cooling at least one of the signal detection coils to 0 degrees Celsius or less is provided in the probe. 5. The NMR apparatus according to claim 4 , wherein a moving device for moving the probe in the probe insertion bore is attached to the probe and the magnet. In the measuring method of the NMR apparatus which consists of a magnet, a probe, and a measurement console, when the NMR apparatus according to claim 1 is provided in the NMR apparatus and the measurement space is switched, the sample tube is a sample of the probe. It is monitored whether the sample tube is inserted, and if a sample tube is inserted, the sample tube is once discharged out of the sample receiving hole, and then the probe is moved to receive a sample in a new measurement space. A measurement method of an NMR apparatus, wherein the sample tube is inserted into a hole. Oite to claim 1, NMR apparatus characterized by being configured so as to provide vertically the probe a plurality of measurement space of the sample receiving hole and the signal detecting coil to the probe centerline. 9. The NMR apparatus according to claim 8 , wherein a moving device for moving the probe in the probe insertion bore is attached to the probe and the magnet. In an NMR apparatus consisting of a magnet, a probe, and a measurement console,
Two or more holes are provided in the magnet, and at least two of the holes are orthogonal to each other, and a probe insertion bore that is one of the orthogonal holes penetrates the magnet. The probe is provided with a measurement space composed of a sample receiving hole and a signal detection coil perpendicular to the probe center line, and the other one of the holes orthogonal to the probe insertion bore is a sample insertion bore. Two probes are inserted from both ends of the probe insertion bore penetrating the magnet, a sensor for detecting the presence or absence of sample insertion is provided in the sample insertion bore, and the probe moves in the probe insertion bore Attaching a moving device to the probe and the magnet ,
The probe is provided with a first measurement section composed of a sample receiving hole and a signal detection coil in a direction perpendicular to the probe center line, and a second measurement space composed of another signal detection coil. The space and the second measurement space are connected by a flow path, and the sample inserted from the sample insertion bore into the sample receiving hole inserted in the first measurement space can be measured in the second measurement space. An NMR apparatus. 11. The NMR apparatus according to claim 10 , wherein a mechanism for cooling at least one of the signal detection coils to 0 degrees Celsius or less is provided in the probe. 12. The NMR apparatus according to claim 11 , wherein the sample inserted into the first measurement space is contained in a sample container, and the sample container has a valve that is opened when the sample container is inserted into the sample receiving hole. In the measuring method of the NMR apparatus which consists of a magnet, a probe, and a measurement console, the NMR apparatus according to claim 10 is provided in the NMR apparatus, and NMR is performed by simultaneously or switching from the first measurement space and the second measurement space. A measurement method of an NMR apparatus characterized by acquiring a signal.

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