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WO1996013735A1 - Sonde d'un appareil a resonance magnetique nucleaire (rmn) comportant des bobines en tandem - Google Patents

Sonde d'un appareil a resonance magnetique nucleaire (rmn) comportant des bobines en tandem Download PDF

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Publication number
WO1996013735A1
WO1996013735A1 PCT/US1995/013974 US9513974W WO9613735A1 WO 1996013735 A1 WO1996013735 A1 WO 1996013735A1 US 9513974 W US9513974 W US 9513974W WO 9613735 A1 WO9613735 A1 WO 9613735A1
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WIPO (PCT)
Prior art keywords
flow
coil
probe
region
sample
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WO1996013735A9 (fr
Inventor
Klaus Albert
James L. Sudmeier
Ulrich L. GÜNTHER
William W. Bachovchin
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Eberhard Karls Universitaet Tuebingen
Tufts University
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Eberhard Karls Universitaet Tuebingen
Tufts University
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Priority to AU40152/95A priority Critical patent/AU4015295A/en
Publication of WO1996013735A1 publication Critical patent/WO1996013735A1/fr
Publication of WO1996013735A9 publication Critical patent/WO1996013735A9/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/30—Sample handling arrangements, e.g. sample cells, spinning mechanisms
    • G01R33/307—Sample handling arrangements, e.g. sample cells, spinning mechanisms specially adapted for moving the sample relative to the MR system, e.g. spinning mechanisms, flow cells or means for positioning the sample inside a spectrometer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/32—Excitation or detection systems, e.g. using radio frequency signals
    • G01R33/34—Constructional details, e.g. resonators, specially adapted to MR
    • G01R33/34092—RF coils specially adapted for NMR spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/563—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution of moving material, e.g. flow contrast angiography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/62—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using double resonance

Definitions

  • Nuclear magnetic resonance is a useful technique for determining molecular structure.
  • Nuclei which have an odd atomic number or odd atomic mass possess magnetic moments and angular momenta.
  • Such nuclei when placed in an applied external magnetic field, will precess about the field with a frequency which depends upon the strength of the applied field B 0 and the gyromagnetic ratio ⁇ of the nucleus. Since every distinct nucleus has a unique gyromagnetic ratio, the precession frequency for each is different in a given magnetic field. For commonly used nuclei and conventional magnetic field strengths, the precession frequency is in the radio frequency (RF) range.
  • RF radio frequency
  • NMR is. however, a relatively insensitive spectroscopic technique, and typically requires large amounts of sample, compared to other spectroscopic methods, to yield useful results. This lack of sensitivity has restricted the use of NMR to those cases where considerable sample is available. Although it has been known for many years that NMR signals are enhanced in flowing liquids, the large sample volumes required to create a flow generally offer no benefits for fields such as protein analysis where the small quantities of sample available for analysis would require so much dilution as to negate any advantage gained by flow NMR.
  • the flow probe includes a flow vessel which is positioned by a housing in a high magnetic field, and with tandem transmitter/receiver coils positioned sequentially along a fluid flow path through the vessel.
  • This arrangement permits the use of nuclear Overhauser enhancement, and enhancement by coherence transfer techniques, such as spn-temperature labelling, of resonant signals by excitation of the sample nuclei in the flow volume at the upstream coil and detection at the flow volume of the downstream coil, while controlling difficult experimental factors such as residence time in the field.
  • one or both of the upstream or downstream flow volumes includes a microwave cavity and a source of immobilized free radicals (IFR), which in this instance are configured to couple electron spin polarization to nuclear species, while retaining the closely-spaced high field NMR geometry and its functional advantages.
  • IFR immobilized free radicals
  • the probe apparatus allows unique experimental protocols, for example, simultaneous excitation of a selected nucleus of the sample and also the unpaired electrons of the IFR material. This allows the implementation of electron-nuclear cross- polarization enhancement (also referred to as dynamic nuclear polarization or "DNP") of the sample resonances, with potentially large increases in detection sensitivity of the sample resonances at the downstream coil.
  • DNP dynamic nuclear polarization
  • the flow path may include a reaction chamber situated so as to allow the initiation of a reaction and detection of the intermediates or products of that reaction at the downstream coil.
  • a reaction chamber situated so as to allow the initiation of a reaction and detection of the intermediates or products of that reaction at the downstream coil.
  • certain of the reactants may be labeled or otherwise conditioned before reaction and detection.
  • a recirculation path preferably with an integral pump, is provided to recycle the flowing fluid from a downstream point to a point upstream forming a closed loop flow path.
  • the sample may be recirculated. allowing quite small volumes of sample and solvent to be used even for lengthy measurements taking hours or days.
  • the probe may include a means for varying the size of a central part of the flow path to selectively control the flow time between the upstream and downstream coils. Such variation of the flow time adds an additional dimension in a multidimensional experiment such as reaction monitoring or the like.
  • the probe may be configured with two or more coils which are each tuned to separate nuclear Larmor frequencies with separate impedance matching and tuning means, for fine-tuning the resonance frequency and impedance of one or more of the coils, as may be necessary from one sample to the next.
  • One or more of the coils, preferably the downstream coils, can be doubly-tuned, with one frequency corresponding to the Larmor frequency of deuterium or another suitable lock signal.
  • Novel protocols utilizing the probes include multidimensional and spin-temperature labeling procedures.
  • Figure 1 depicts a generalized NMR apparatus.
  • Figure 2 shows an NMR probe according to the present invention.
  • Figure 3 illustrates RF coils disposed around a flow vessel in the subject NMR probe.
  • Figure 4 is a schematic representation of one embodiment of the subject NMR probe disposed in a magnet.
  • Figure 4A shows another embodiment similar to that of Figure 4.
  • Figures 5 shows an embodiment of the subject probe having a microwave cavity.
  • Figure 6 shows an embodiment of the subject probe with a reaction chamber and flow delay.
  • Figure 7 shows a ⁇ H spectrum detected by a probe embodiment with toroidal coil.
  • Figure 8 shows detection sensitivity of the probe as a function of flow rate and flip angle.
  • Figure 9 shows ⁇ C spectra of ethanol detected by the probe.
  • Figure 10 shows ⁇ C spectra of ⁇ -pinene detected by the probe.
  • Figure 11 shows another probe with multiple stages.
  • Figure 12 illustrates one embodiment of a flow delay element for use in probes of the invention.
  • FIGS 13A and 13B illustrate another flow delay element.
  • Figure 14 illustrates a pulse sequence for a two-dimensional NMR measurement procedure.
  • Figure 15 illustrates a 'H-decoupled 15 N spectrum of 80% N-methyl formamide in CDC1 3 . Sweep width 1850Hz. Spectrum from bottom to top: Statis spectra; flow rate of 6.0 mL/min with CPD decoupling, toroid inactive; flow rate of 6.0 mL/min with CPD on toroidal cell during recycle delay; DEPT spectrum under optimized conditions.
  • flow NMR refers to NMR spectroscopy of flowing fluids.
  • Fluids contemplated for use in the invention include liquids, gases, supercritical fluids, and other fluids which are compatible with the probes of the present invention.
  • the lack of sensitivity of NMR techniques has been a severe hindrance to use of
  • NMR methods particularly in cases where the sample spectrum is complex and data acquisition times are long.
  • the importance of increasing sensitivity can hardly be overstated.
  • the amount of sample available for spectroscopic measurement is frequently very small, and the difficulty of performing NMR analysis on minute quantities of sample often results in long data acquisition times if only small amounts are available, or else delays until more sample can be obtained. If the sample is unstable, long analysis times are simply not possible.
  • the probe of the present invention increases sensitivity and decreases the time needed to accumulate sufficient data. The subject probe thereby makes the study of unstable compounds more facile.
  • the amount of NMR instrument time available is limited and is carefully rationed; increased sensitivity helps to allocate this important resource more broadly.
  • the probe also makes possible the use of lower concentrations of sample as well as smaller quantities of sample.
  • concentration of the sample may be of crucial importance. For certain samples, for instance molecules which are capable of self-aggregation, changes in concentration may result in changes in the NMR spectrum, so that they can be detected, if at all. only when extremely dilute. Reaction products or intermediates may be both short-lived and present in minuscule quantities, and hence may be unobservable by NMR unless the sensitivity can be enhanced by an order of magnitude or more.
  • the probe of the present invention therefore makes it possible to perform NMR measurements over a range of conditions which are not amenable to conventional systems.
  • Figure 1 shows the general features of an NMR apparatus which has a large electromagnet 1 generally maintained in a superconducting state within a housing filled with liquid helium and insulated by an outer shell filled with liquid nitrogen, a probe 2 which fits centrally within the housing to position a sample in a region of high and uniform magnetic fields, and a control and measurement system 3 which provides the necessary drive signals and receives the NMR signals for irradiation, detection and processing to derive a spectrum from a sample inserted in the apparatus and held by the probe.
  • a control and measurement system 3 which provides the necessary drive signals and receives the NMR signals for irradiation, detection and processing to derive a spectrum from a sample inserted in the apparatus and held by the probe.
  • a conventional probe includes a vessel which holds the sample, an RF coil which surrounds the sample, and various tuning and impedance matching elements; generally speaking, trimmer capacitances and inductors which are connected to non-magnetic rods which serve as control elements for performing fine adjustments of the coil. These elements all connect to input-output terminals at the base of the probe, and the probe thus adapts the samples to reside in the inaccessible cryogenic center of the magnet and enables the necessary controls and measurement signals to be taken without interfering with the magnet.
  • the coils used in the subject probe may optionally be double tuned to the resonant frequencies of two different nuclear species, and the RF receiver coils in the subject probe are preferably configured to allow quadrature detection, or quadrature processing of detected fields.
  • the probe of the present invention may be used with any magnet capable of providing a strong magnetic field, including permanent (iron) magnets, electromagnets, and superconducting magnets. When reference is made to a highly uniform field, it is understood that such uniformity may be achieved by providing a set of "shim" coils, which are energized to supplement and correct the basic static field.
  • FIG. 2 illustrates a basic embodiment of the probe 20 according to the present invention.
  • probe 20 includes a vessel section 22 to be positioned in the magnet field, connectors 24a. 24b for placing the vessel in a flow segment, and coils 26 and 28 placed consecutively along the flow path through the vessel.
  • Arrows F indicate the flow axis.
  • upstream and downstream will be used without reference to whether the flow is actually up or down in the illustration of Figure 2: the actual flow direction may be selected depending on considerations of filling and bleeding of the vessel and other such factors.
  • upstream and downstream generally identifying the downstream coil 26. illustrated in Figure 2. as the "primary” coil, meaning the one which performs a principal or ultimately intended nuclear magnetic resonance measurement, unless otherwise indicated or clear from the context.
  • the RF signal induced in coil 26 will be subject to Fourier transform analysis, and the frequency spectra of the precessing nuclei will be generated from the signals therein.
  • each coil 26. 28 has associated therewith circuitry 27 and 29. respectively, for performing fine adjustments to the tuned frequency and impedance.
  • Each coil is connected by leads, of which two. 30a and 30b. are shown, to shielded input-output junctions 33 in the base of the housing.
  • the circuitry 27. 29 are located above or below the actual coil regions, so as not to affect field uniformity, but are illustrated adjacent to the flow region for expository clarity.
  • Input-output junctions are set up to match an RF signal cable of standard impedance characteristics.
  • a series of adjustment/control rods 34 of a non-magnetic material extend from outside the probe housing to the circuitry 27, 29 for performing fine adjustments of the capacitors or inductors and the coils.
  • the probe is set up to apply to and to receive RF signals from nuclei in two distinct regions along the flow path.
  • the advantages of this construction will be discussed below in various examples. A more detailed description of the coils and flow vessel will be given with respect to Figure 3.
  • the coils 26. 28 are shown disposed sequentially about the flow vessel 22.
  • the coils are shown as saddle coils, but it will be understood by one skilled in the art that other known coil configurations for applying RF fields may be used.
  • the flow vessel 22 extends through a conditioning zone 40. a transition zone 45 and a primary detection zone 50. In the present invention, various forms of conditioning or measurement are contemplated in zone 40 upstream of the primary coil as well as. in certain embodiments, a reentrant flow path for effecting enhanced measurements.
  • Figure 4 shows the probe of Figure 3 disposed within the magnet.
  • a pump 64 such as a pneumatically driven pump
  • a recirculation loop 62 both shown in phantom, are preferably provided when analyzing small amounts of sample.
  • the RF coils 26 and 28 are transmitter/receiver coils, and each coil preferably further includes an additional, generally one or more concentric coil (not shown in the figure) surrounding the same flow volume, as is known in the art. for providing a field/frequency lock (e.g. a deuterium lock) or a nuclear magnetic resonant frequency different from that of the respective accompanying coil, as for example in decoupling and heteronuclear correlation experiments.
  • a field/frequency lock e.g. a deuterium lock
  • a nuclear magnetic resonant frequency different from that of the respective accompanying coil
  • one or more of the coils can be tuned to more than one frequency, e.g., such as tuned to both *H and D.
  • the pump mechanism can be (optionally) partially disposed or completely disposed outside of the probe housing, particularly where it is desirable to use an induction motor or the like.
  • coil refers to an electrical conductor, e.g., wire or tape with non-zero inductance, which is often coiled shaped and which can be used to transmit and receive radiofrequency signals
  • RF coils are preferably made of copper or other electrically conductive but non-ferromagnetic materials.
  • the RF field generated by a coil is preferably orthogonal to the strong applied magnetic field B 0 .
  • Exemplary RF coil configurations which may be useful in the present invention are solenoidal. saddle. Helmholtz. modified Helmholtz. Golay, and toroidal coils. Preferred embodiments employ coils providing uniform fields.
  • the invention will be applied to difficult measurement problems which have arisen in modern NMR equipment having very high magnetic fields.
  • the degree of resolution and sensitivity obtainable depend on the field strength as well as on the homogeneity achievable in the field.
  • Typical high- performance machines are characterized by proton resonant frequencies of 400 MHz to 750 MHz. corresponding to magnetic fields of 9.4 to about 18 Tesla: however, the principles of the present invention are not limited to such machines.
  • the terms "high field” and "high magnetic field” as used herein are intended to refer to a magnetic field with a field strength of about at least 0.5 Tesla (T). preferably in the range of about at least IT to about 24T. and more preferably about at least 2J T to about 24T.
  • FIG 4A schematically shows the design of a sequential-coil flow-probe in one prototype embodiment.
  • the 13 C transmit/receive downstream coil 26 surrounded a 5 mm o.d. Pyrex vessel with a volume of 0J9 ml and was surrounded by a 'H decoupling coil (not shown) of conventional type.
  • the Pyrex cell was joined to Teflon tubing with Teflon tape.
  • a prepolarization chamber which is large compared to the detection coil helps the sample attain Boltzmann equilibrium and NOE enhancement before detection.
  • Two types of prepolarization chambers have been constructed, giving comparable enhancements.
  • the other, depicted as a toroidal coil 28a was used as the upstream coil to enclose a large volume. with a geometry that allowed it to be mounted close to the homogenous region of the magnet, and has a large filling factor with good Q (T.E. Glass and H.C. Dorn, J. Magn. Reson. 51, 527 (1983)).
  • the toroid 28a was made by winding six turns of commercially available coil wire (silver-plated copper) around a Teflon spool. The sense of winding was reversed after the first three turns to reduce the inductance of the coil and facilitate tuning to high frequencies (S.B.W. Roeder and E. Fukushima. J. Magn. Reson. 59. 307 (1984)).
  • the toroidal coil 28a was insulated with Teflon tape to prevent arcing.
  • Teflon tape Around the spool inside the toroid. approximately 1.3 m of Teflon tubing (1/16 inch inner diameter) was wound up, holding 1.6 ml of sample. This design avoids excessive sample mixing during the passage through the toroid.
  • An alternative design employing a double-saddle Helmholtz coil around a 10 mm diameter Pyrex cell has also been tested, and provided comparable results.
  • the tuning circuit for the upstream coil 28a including three non-magnetic high voltage Johanson variable piston capacitors (0.8 - lOpF). was mounted above the transmit receive coil of a commercially available BRUKER I C probe which was suitably modified to receive the additional coil and tuning circuitry, and good grounding was achieved by a solid connection to the housing of the probe. Connection to the circuit was made with a non-magnetic 50 ohm coaxial cable lowered through the magnet bore and fastened to a Sealectro SMB jack on top of the probe.
  • the center of the toroid coil 28a lies 3.2 cm above the primary transmit/receive coil 26.
  • Figure 7 shows a 'H "spectrum" recorded with the toroidal coil. The signal has a width of almost 20 KHz and is shifted by almost 20 KHz, relative to that obtained at the decoupler coil of the primary coil 26 below. The sharp signals visible in the center of the spectrum come from the decoupler coil which resonates with the toroid.
  • the low power output of the proton decoupler of a BRUKER AM 400 NMR instrument was further amplified by a 2W linear amplifier to apply a composite pulse or continuous wave (CW) RF signal to the toroidal coil.
  • CW continuous wave
  • Series crossed diodes and a 400MHz bandpass filter on the amplifier output were employed for reducing noise in both observe and deuterium lock channels.
  • the 90° flip angle of the toroid was approximately 140 ms.
  • the acquisition time t aq is determined by the necessary sweep width and digital resolution (in practice, acquiring for 2 to 3 times -TS, the effective transverse-relaxation time). Keeping pulse repetition time -T rep less than T ⁇ , choosing pulse angle ⁇ equal to the "Ernst angle" (Ernst et al., supral and applying matched filters before processing leads to optimal (S/N) ⁇ . In flow experiments, -T rep must be suited to the flow rate so that T ⁇ p equals x £
  • et , the sample lifetime in the detection cell (t det volumes/flow rate).
  • a circuit that untunes the decoupler coil during acquisition would most likely remove this problem, and this would be provided in a further embodiment by a synchronous switching circuit that connects an additional inductive or capacitive circuit element to the decoupler coil to shift its resonance and damp oscillations during acquisition.
  • a compromise that provided a better duty cycle (89%) for the toroidal coil 28a was chosen with a flow rate of 6 ml/min and a repetition time of 2.2 s. This set of parameters allows the sample to experience only one 90° pulse in the detection cell; however the prepolarization and NOE buildup are both reduced.
  • Figure 9B shows the spectrum at a flow rate of 6 ml/min without any RF pulses applied to the toroid 28a, in which it is seen that the S/N ratio is approximately twice that of the static spectrum.
  • the NOE enhanced spectrum induced by a CPD sequence applied through the toroid 28a (gated off during acquisition) is shown in Figure 9C.
  • a NOE enhancement factor of 2.3 is achieved.
  • DEPT (Distortionless Enhancement of Polarization Transfer) spectra ( Figure 9D) give an even higher enhancement; however it suffers from the fact that the signals of quartemary carbons completely disappear from the spectrum.
  • the DEPT spectrum has been recorded with a shorter repetition time and an increased number of scans ( 16 scans, but the same total acquisition time), in view of its dependence on the relatively shorter relaxation times of the protons.
  • ⁇ OE can be obtained for flowing samples, or that enhancement can be accomplished with relatively small amounts of RF power.
  • the amounts of ⁇ OE enhancement are orders of magnitude less than that achieved in flow D ⁇ P (S. Stevenson and H.C. Dorn. Anal. Chem. 66: 2293(1994)), but for many applications, e.g.. metabolic studies and LC detection, it should be well worth the modest addition in hardware to recover this normally wasted sensitivity.
  • the invention also contemplates a probe including a flow chamber having an ⁇ MR detection region, and further including a microwave cavity located along the flow path for polarization conditioning or signal enhancement of a nuclear type of interest.
  • a microwave cavity 52 is provided at the upstream coil 28. and an environment of immobilized free radicals 54 in the flow region 40.
  • the microwave cavity 52 is situated in the magnetic field, and the material passing along the flow path is simultaneously subjected to the stationary magnetic field B 0 and to interaction with the captive electrons of the radicals immobilized in the microwave cavity, as well as the RF fields B] from the upstream coil.
  • a representative example of operation of this probe follows.
  • a sample is introduced at an upstream flow position and flows into the microwave cavity 52 to interact with a source of immobilized free radicals (IFR) on a solid support.
  • IFR immobilized free radicals
  • Suitable sources of IFR are known, and may be. for example, silica-phase immobilized nitroxide radicals (R. Gitti et al.. J. Am. Chem. Soc. 110. 2294 ( 1988)).
  • Other free radicals such as phenoxide have been reported, and the choice of species may depend in part on considerations of compatibility with the sample as well as empirical selection factors such as efficiency and ease of preparation.
  • the microwave cavity is a conductive walled chamber which resonates at the microwave frequency, discussed further below.
  • the following protocol seeks to enhance the polarization (hence detectable signal) of a with a small gyromagnetic ration nucleus by introducing the desired spin into an abundant electron species and coupling that spin into the nucleus.
  • the technique used is analogous to the classical technique of cross-polarization-magic angle spinning (CP-MAS) used to couple spin polarization between pairs of nuclei in solids, to take advantage of the greater excited state population available in one species.
  • CP-MAS cross-polarization-magic angle spinning
  • This polarization coupling requires that the target nucleus be conditioned to change spin upon receiving the quantum of energy available from a spin transition in the abundant donor nucleus, generally a proton. Because the electron gyromagnetic ratio is much greater than that of e.g.
  • the probe of Figure 5 provides necessary elements for controlling such a coupling interaction between electrons and nuclei. As described further below, this is done using the upstream cavity and coil by spin-locking both the electrons and the nuclei of interest away from the static magnetic field B 0 and arranging that the strength of the orthogonal magnetic fields induced by the two irradiation sources satisfies the Hartman-Hahn condition on gyromagnetic ratios for spin coupling of two particles. -5 -
  • the nuclear type of interest is excited by spin-locking according to established methods (for details of suitable spin-locking procedures, see e.g. G.A. Morris and R. Freeman. J. Am. Chem. Soc. 101. 760 (1979)). so that the spin is locked in the magnetic field Bi of the RF coil, which in this case is the X-Y plane, orthogonal to B 0 .
  • the microwave transmitter establishes a standing microwave field with a magnetic component rotating in the X-Y plane, which interacts with the spin of the unpaired electrons of the immobilized free radical phase so that these electrons are also spin-locked and in the desired orientation.
  • the two fields are preferably locked in phase relation.
  • B 0 low static magnetic fields
  • this may be accomplished with a doubly resonant cavity/coil configuration.
  • suitable frequency dividing and phase feedback controls possibly with special mixing or doubling resonators operative in the short microwave region.
  • the amplitudes of the two locked fields are adjusted to satisfy the Hartman-Hahn ratio.
  • the electrons are spin-locked before the nuclei, though electron spin-locking can be accomplished simultaneously or after spin-locking the nuclei, and the RF field then applied to the nuclei to bring both spin systems into alignment.
  • the polarization of the excited free radicals is then transferred to the spin-locked nucleus of interest as the fluid flows over the solid support. Since electrons have a much greater energy difference between up and down spins, this leads to a greatly enhanced population of the coupled spin polarization in the flowing nuclei. When the fluid flows downstream, this increased polarization is detected at the second coil as a greatly enhanced signal in the spectrum of the nuclei.
  • the construction of the upstream coil in combination with the microwave cavity and immobilized free radicals thus provides a structure for exciting electron spin and coupling this spin to a heteronucleus.
  • This mechanism may in theory produce signal enhancements of up to 2628 for 1 ⁇ c and 6570 for 1 ⁇ N. Such enhancements would correspond to reductions in data acquisition time for a two hour experiment to seconds.
  • the embodiment of the invention shown in Figure 4 may be used for the following protocol.
  • the active regions of the first and second flow volumes 40b and 50a. and the first and second RF coils 28 and 26 are each connected to RF transmitter(s) and receiver(s) and tuned to the same nuclear resonant frequency. No recirculation loop is needed for this experiment.
  • a sample is introduced into the flow vessel and flows to the region of the first coil 28.
  • a soft pulse sequence or other specially calculated selective ⁇ C pulse or RF signal is applied to the first coil 28 to excite (or. in a related protocol, to invert) individual ⁇ >C resonances, e.g., the resonance of a particular carbon atom in a first reactant molecule, or a selected set of resonances.
  • FIG. 6 is a schematic view of the probe of Figure 4 showing the reaction chamber 60 located in the position 45 of the flow vessel intermediate the two coils. For the practice of this method. Figure 6 also shows a flow delay element 70 and a reactant injector 65 connected to the reactor 60 in the flow path.
  • the embodiment shown in Figure 6 is used for the study of a variety of chemical reactions, such as molecular rearrangements in a similar manner.
  • the first reactant molecule passes through the first flow volume where it is excited by the first coil as described above. It then enters the reactor.
  • the reactor need not introduce another chemical reactant. but may simply initiate a rearrangement or fragmentation reaction, e.g. by cooling, irradiation with ultraviolet light, or contact with an immobilized catalyst or enzyme in the reactor.
  • the intermediates or products of the reaction are detected by the second RF coil, thus revealing information about the course of the reaction or rearrangement.
  • the delay element provides a definite and preferably variable delay path to precisely control the time instant following initiation at which downstream detection occurs.
  • Delay element 70 may for example consist of a telescoping U-tube in the flow path, which provides a variable path-length of fixed cross-section connecting the flow paths. The use of such a delay element results in a very dependable and repeatible mechanism for time sampling of the reactant products, since the sampling delay can be controlled without changing the transit times through either the first or the second coil.
  • the embodiment shown in Figure 6 is also used in yet other novel protocols.
  • the first coil and the second coil are each used as both transmitters and receivers.
  • the first coil obtains an NMR spectrum of the first reactant according to standard protocols.
  • the reactant then flows to the reactor where a reaction is initiated (e.g. by heat, light or the like, as described above).
  • a reaction is initiated (e.g. by heat, light or the like, as described above).
  • the spectrum of newly evolving intermediates or products is detected by the second coil.
  • a difference spectrum is then generated by subtracting the first spectrum from the second spectrum. This has the effect of canceling solvent peaks and other peaks common to both spectra, e.g., to filter spin-temperature labeled peaks.
  • This procedure has the advantage of reducing receiver dynamic range problems associated with large solvent peaks.
  • the differencing operation may be performed on intermediate or transformed data sets rather than fully analyzed spectra, greatly reducing computational load and/or storage requirements.
  • a flow chamber identical to the lower one would be provided.
  • flow chambers, reaction vessels and delay portions and the like may be provided in modular, snap- together embodiments.
  • the invention further contemplates a probe as shown in Figure 1 1 including a flow chamber having two NMR detection regions, and further including a premagnetization volume and a reaction chamber, both upstream of both coils, and a delay path intermediate the two coils.
  • a premagnetization volume 80 is provided in the flow region 40, and a reaction chamber 60 is included in the flow volume 40 upstream of the first coil.
  • the probe also includes a delay element 70 and a second detection coil.
  • An exemplary protocol for operation of this probe follows in Example 4. after a general discussion of the additional elements of the premagnetization volume and reaction chamber.
  • the premagnetization volume is preferably made of a nonmagnetic material, for example Teflon or Pyrex.
  • Teflon or Pyrex One premagnetization volume suitable for allowing such residence time is the upper chamber already shown in the region of the upper coil in Figure 6. which may perform this function when operation of the upper coil is not required.
  • a length of Teflon tubing 75 is wound around a spool.
  • This construction allows one to select a residence time in the field by selecting an appropriate size and length of tubing, while arranging that the fluid arrives as a bolus with substantially uniform residence characteristics.
  • Another exemplary embodiment employs a Pyrex flow vessel having a large diameter relative to the diameter of the flow vessel immediately upstream to augment residence time.
  • the flow vessel comprises an outer tubular member and an inner tubular member, fitted together with a fluid-tight seal, sharing an axis and having a length along that axis.
  • One tubular member is movable relative to the other, and the volume within the vessel may be varied by sliding the movable member along the shared axis, much like the telescoping delay path configurations described above. This construction capitalizes on the increased volume of the delay section, without any changes in coil or magnet shims, but does not necessarily utilize the available space in the high field very efficiently.
  • the illustrated reaction chamber is a small flow volume of the flow vessel, preferably constructed of a nonmagnetic material, arranged to produce turbulent mixing or intimate and complete contact or treatment of the sample as it passes through the chamber.
  • the reaction chamber will have fittings by which flow tubing for the sample and a reagent or reagents may be connected.
  • the reaction chamber may also be constructed with a temperature-control arrangement such as a heater.
  • the reaction chamber may be equipped to initiate or facilitate or complete a process by irradiation, by using, for example, ultraviolet light or a laser light source.
  • One reaction chamber suitable for use in the probe of the present invention has been described in U.S. Patent 5,198,766. of inventors M. Spraul and M. Hofmann.
  • Fluid may be made to flow in the loop 62 by a pump which may be pneumatically powered, preferably by an air source such as is commonly present in NMR machines for spinning sample turbines in the magnet assemblies.
  • the pump is made of nonmagnetic materials, and is preferably a peristaltic or impellor pump.
  • Example 4 In a representative protocol for the probe of Figure 1 1. the fields and chambers in the active regions of the first and second flow volumes A and B are well matched, and the coils 26 and 28 are also well matched.
  • a sample is introduced at a position upstream of the flow region and flows into the premagnetization volume 80 in the static magnetic field.
  • the volume of chamber 80 is sufficiently large that the residence time of a flowing bolus of fluid is long compared to T,, insuring adequate premagnetization and thus maximum sensitivity of detection.
  • the sample then flows to the reaction chamber 60, where a process is initiated or a reactant is introduced. This initiates a set of chemical changes which evolve over a period of time.
  • the sample flows on. to the first detection region A.
  • a first NMR spectrum is obtained by coil 28 by a conventional method.
  • the sample then flows to the delay element 70, where the reaction is allowed to further evolve for a defined period.
  • the sample then flows to the second detection region B. where a second NMR spectrum is obtained, using signals on coil 26.
  • the same measurement conditions are applied to a single sample which has evolved as it flows between coils.
  • the spectrum obtained at the first coil 28 is subtracted from the spectrum obtained at the second coil 26.
  • the resulting difference spectrum reveals only those components of the spectrum (lines or line amplitudes) which have changed during the reaction course.
  • the difference procedure also effectively cancels the solvent and other large constant peaks, such as those due to excess reagents, which can be a significant factor in reducing dynamic range difficulties when the desired resonances are weak.
  • the time delay introduced by the delay element 70 may be changed in a systematic manner, allowing the study of the reaction course over time. This time delay may be used as one dimension of a two-dimensional experiment, as described elsewhere. Further, provided the two coils, chambers and surrounding field conditions have been matched sufficiently closely, the difference procedure may be applied to intermediate blocks of data or data transforms, thus greatly reducing the volume of data processing or storage required to obtain useful spectra. Returning to the description of the time delay path element 70.
  • Figure 12 illustrates an embodiment of a delay element 70' which provides a set of telescoping U-tubes 100 which can be disposed in the flow path as part of the flow vessel 22.
  • extension (or compression) of the telescopic portion 104 between each of the U-tubes 100 varies the length of the flow path through the delay element 70' and. when the flow velocity is constant, permits incremental increases (or decreases) in the time it takes for a bolus of sample conditioned in the upstream coil to reach a downstream position for further mixing and detection.
  • Figure 13A and 13B illustrate an embodiment of a delay element 70" which provide a set of nested, telescoping U-tubes 100' which permit radial expansion of the delay element in the intercoil region, thereby making use of space within the probe without reconfiguring the coils or magnets.
  • the tube support members 106 are moved relative to the axis of the telescopic portion 104 by an air or fluid actuated mechanism.
  • delay element 70 can be provided in a plurality of valves for switching tubing of different lengthes in and out of the intercoil flow path of fluid vessel 22.
  • a carousel can be supplied which comprises individual coils of different lengthes of tubing. The carousel is rotated to couple an inlet and outlet of a given tubing as part of the fluid vessel 22 within the intercoil space by a fluid-tight coupling.
  • tubing of various length can be connected and provided in the flow path of fluid vessel 22 by the use of selectively actuated pinch-valves.
  • Applicans provide a time-delay, e.g., by variable volume or flow path length, in the flow path of the intercoil space for both one- dimensional and multi-dimensional NMR experiments.
  • a time-delay e.g., by variable volume or flow path length
  • the pulse generator e.g. periodicity of nutation pulses
  • other acquisition parameters one can optimize sensitivity of a flow measurement.
  • the inclusion of time-delay element which can be varied by the operator, as shown in Figure 6. can permit the acquisition of spectra at incremental time points after a reaction has been initiated.
  • the dimensions of the time-delay element can provide a time-delay in the range of milliseconds to resolve the formation or fate of short-lived intermediates..
  • the time delay feature of the subject probe can be used to generate two-dimensional (or multi-dimensional) NMR spectra.
  • An important strength of modern NMR spectroscopy is the ability to drive the dynamics of the spin system through a series of coherence transformations such that the resultant observable magnetization reflects desired combinations of evolutions and interactions.
  • Coherence transformations can be used not only for transferring magnetization from one spin to another (such as described in detail above), but also for "filtering" purposes to select only those spin systems with a given property.
  • Coherence transformations can be used, for example, in a two-dimensional (2D) NMR experiment to display correlations between coupled spins.
  • a typical proton homonuclear 2D experiment involves the interaction of each proton ( ' H nucleus) with all of its coupling partners, such as through-space or through-bond couplings.
  • the protons are excited during the preparation time period by an application of an RF nutation pulse at the proton resonant frequency through the upstream coil.
  • the resulting coherence evolves under influence of the chemical shift during the t, evolution time period as the conditioned fluid flows through the fluid vessel in the intercoil space.
  • the coherence is then transferred between coupled protons during the mixing period by applying a second RF pulse to the protons via the downstream coil.
  • the FID is sampled at the downstream coil.
  • the resulting FID signal is modulated not only by the chemical shift evolution of the protons during the detection period but also by the spin evolution period of coupled protons.
  • Such experiments include Correlation SpectroscopY (COSY) and NoE Spectroscopy (NOESY) experiments.
  • COSY Correlation SpectroscopY
  • NOESY NoE Spectroscopy
  • correlation of (- 1 )-coherence through J-coupling can be used to establish that the coherences belong to the same coupling network.
  • Other homonuclear experiments, as well as the appropriate configuration of the subject probe will be apparent to those skilled in the art in light of the present disclosure. Similar multi-dimensional experiments can be performed in heteronuclear embodiments of the subject probe, as for example.
  • 2-dimensional NMR experiments specifically designed for the detection of proton-coupled , 5 N or 13 C chemical shifts.
  • polarization transfer experiments based on an INEPT or reverse-INEPT pulse sequence between the upstream and downstream coils such as a reverse Heteronuclear Multiple Quantum Coherence (HMQC) 2-D experiment, can be used to make resonance assignments.
  • HMQC Heteronuclear Multiple Quantum Coherence

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  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

Une sonde RMN (20) délimite une enceinte de flux de courant (22) pourvue d'une première et d'une seconde zone de flux dans le champ intense d'un appareil à résonance magnétique nucléaire. Une bobine d'excitation/détection, pouvant être de type classique pour une détection homo ou hétéronucléaire, entoure la seconde zone de flux, d'aval, tandis que la première zone, d'amont, est excitée par une antenne pour conditionner ou améliorer une mesure en aval. La bobine aval (26) est accordée pour détecter des résonances hétéronucléaires alors que la bobine amont peut être accordée pour l'amélioration du même type de résonance ou d'un genre différent. Une cavité, de concert avec la bobine amont (28a), autorise une excitation cohérente du transfert et des populations entre électrons et noyaux.
PCT/US1995/013974 1994-10-26 1995-10-26 Sonde d'un appareil a resonance magnetique nucleaire (rmn) comportant des bobines en tandem Ceased WO1996013735A1 (fr)

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AU40152/95A AU4015295A (en) 1994-10-26 1995-10-26 Tandem coil nmr probe

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US08/329,715 1994-10-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046743A1 (fr) * 2002-11-19 2004-06-03 Oxford Instruments Superconductivity Limited Appareil d'inspection d'echantillons destine a combiner la resonance magnetique nucleaire avec la spectroscopie de masse a resonance cyclotron ionique (icr)
EP1860452A1 (fr) 2006-05-24 2007-11-28 Hitachi, Ltd. Appareil et procédé pour mesure de résonance magnétique nucléaire d'un débit de circulation
EP2359164A4 (fr) * 2008-12-10 2012-05-30 Abqmr Inc Appareil à résonance magnétique nucléaire, procédés et technologie associée
WO2013092996A1 (fr) 2011-12-23 2013-06-27 Stichting Katholieke Universiteit Appareil à résonance magnétique à polarisation nucléaire dynamique à cycle rapide
US9519037B2 (en) 2011-11-10 2016-12-13 Mayo Foundation For Medical Education And Research Spatially coincident MRI receiver coils and method for manufacturing
CN106596671A (zh) * 2016-12-25 2017-04-26 厦门大学 模块化固相可变温电化学核磁共振联用探头杆
CN109254026A (zh) * 2017-07-13 2019-01-22 克洛纳有限公司 核磁测量仪器
WO2021089366A1 (fr) * 2019-11-04 2021-05-14 Koninklijke Philips N.V. Réduction d'artéfacts (b0) de champ magnétique par homogénéisation active du champ magnétique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4531093A (en) * 1983-05-05 1985-07-23 Southwest Research Institute Method and apparatus for coal analysis and flow measurement
US4629987A (en) * 1983-09-08 1986-12-16 Southwest Research Institute Method and apparatus for nuclear magnetic resonant measurement of flow velocity
US4638251A (en) * 1984-10-29 1987-01-20 Southwest Research Institute Method and apparatus for measuring flow of non-homogeneous material in incompletely filled flow channels
US5352979A (en) * 1992-08-07 1994-10-04 Conturo Thomas E Magnetic resonance imaging with contrast enhanced phase angle reconstruction

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4531093A (en) * 1983-05-05 1985-07-23 Southwest Research Institute Method and apparatus for coal analysis and flow measurement
US4629987A (en) * 1983-09-08 1986-12-16 Southwest Research Institute Method and apparatus for nuclear magnetic resonant measurement of flow velocity
US4638251A (en) * 1984-10-29 1987-01-20 Southwest Research Institute Method and apparatus for measuring flow of non-homogeneous material in incompletely filled flow channels
US5352979A (en) * 1992-08-07 1994-10-04 Conturo Thomas E Magnetic resonance imaging with contrast enhanced phase angle reconstruction

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046743A1 (fr) * 2002-11-19 2004-06-03 Oxford Instruments Superconductivity Limited Appareil d'inspection d'echantillons destine a combiner la resonance magnetique nucleaire avec la spectroscopie de masse a resonance cyclotron ionique (icr)
EP1860452A1 (fr) 2006-05-24 2007-11-28 Hitachi, Ltd. Appareil et procédé pour mesure de résonance magnétique nucléaire d'un débit de circulation
EP2359164A4 (fr) * 2008-12-10 2012-05-30 Abqmr Inc Appareil à résonance magnétique nucléaire, procédés et technologie associée
US9519037B2 (en) 2011-11-10 2016-12-13 Mayo Foundation For Medical Education And Research Spatially coincident MRI receiver coils and method for manufacturing
WO2013092996A1 (fr) 2011-12-23 2013-06-27 Stichting Katholieke Universiteit Appareil à résonance magnétique à polarisation nucléaire dynamique à cycle rapide
US9945918B2 (en) 2011-12-23 2018-04-17 Stichting Katholieke Universiteit Rapid cycle dynamic nuclear polarization magnetic resonance apparatus
CN106596671A (zh) * 2016-12-25 2017-04-26 厦门大学 模块化固相可变温电化学核磁共振联用探头杆
CN109254026A (zh) * 2017-07-13 2019-01-22 克洛纳有限公司 核磁测量仪器
CN109254026B (zh) * 2017-07-13 2023-09-05 克洛纳有限公司 核磁测量仪器
WO2021089366A1 (fr) * 2019-11-04 2021-05-14 Koninklijke Philips N.V. Réduction d'artéfacts (b0) de champ magnétique par homogénéisation active du champ magnétique
US11921177B2 (en) 2019-11-04 2024-03-05 Koninklijke Philips N.V. Magnetic field (BO) artifact reduction throught active shimming

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