WO2010061191A1 - Appareil de polarisation nucléaire dynamique - Google Patents

Appareil de polarisation nucléaire dynamique Download PDF

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Publication number
WO2010061191A1
WO2010061191A1 PCT/GB2009/002763 GB2009002763W WO2010061191A1 WO 2010061191 A1 WO2010061191 A1 WO 2010061191A1 GB 2009002763 W GB2009002763 W GB 2009002763W WO 2010061191 A1 WO2010061191 A1 WO 2010061191A1
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WO
WIPO (PCT)
Prior art keywords
solvent
sample
dissolution
bore
pump
Prior art date
Application number
PCT/GB2009/002763
Other languages
English (en)
Inventor
Joost A. B. Lohman
Mark P. Englefield
Original Assignee
Oxford Instruments Molecular Biotools Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Oxford Instruments Molecular Biotools Limited filed Critical Oxford Instruments Molecular Biotools Limited
Publication of WO2010061191A1 publication Critical patent/WO2010061191A1/fr

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Classifications

    • 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
    • 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
    • G01R33/282—Means specially adapted for hyperpolarisation or for hyperpolarised contrast agents, e.g. for the generation of hyperpolarised gases using optical pumping cells, for storing hyperpolarised contrast agents or for the determination of the polarisation of a hyperpolarised contrast agent
    • 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
    • G01R33/38—Systems for generation, homogenisation or stabilisation of the main or gradient magnetic field
    • G01R33/381—Systems for generation, homogenisation or stabilisation of the main or gradient magnetic field using electromagnets
    • G01R33/3815—Systems for generation, homogenisation or stabilisation of the main or gradient magnetic field using electromagnets with superconducting coils, e.g. power supply therefor
    • 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
    • G01R33/305—Sample handling arrangements, e.g. sample cells, spinning mechanisms specially adapted for high-pressure applications

Definitions

  • the invention relates to DNP apparatus, that is apparatus for carrying out dynamic nuclear polarisation on a sample prior to subjecting the sample to a nuclear magnetic resonance (NMR) process.
  • NMR nuclear magnetic resonance
  • Dynamic nuclear polarisation is used to enhance the nuclear polarisation of samples for use in applications such as nuclear magnetic resonance (NMR) analysis including nuclear magnetic resonance imaging (MRI) and analytical high-resolution NMR spectroscopy (MRS).
  • NMR nuclear magnetic resonance
  • MRI nuclear magnetic resonance imaging
  • MRS analytical high-resolution NMR spectroscopy
  • MRI is a diagnostic technique that has become particularly attractive to physicians as it is noninvasive and does not involve exposing the patient under study to potentially harmful radiation such as X-rays.
  • Analytical high resolution NMR spectroscopy is routinely used in the determination of molecular structure.
  • MRI and NMR spectroscopy lack sensitivity due to the normally very low polarisation of the nuclear spins of the materials used.
  • the dynamic nuclear polarisation technique has been developed to improve the polarisation of nuclear spins.
  • a liquid sample is mixed with a polarising agent and placed in a sample cup which is mounted to a sample holding tube or sample positioning device.
  • the sample holding tube is then inserted into the bore of a superconducting magnet located in a cryostat so as to bring the sample to a working volume within the bore, the working volume being located in a microwave cavity defined by a DNP insert.
  • the superconducting magnet generates a magnetic field of suitable strength and homogeneity in the working volume.
  • the sample is cooled and solidified by exposing it to liquid helium in the bore and then irradiated with microwaves while it is exposed to the magnetic field and in its frozen state.
  • the sample is then lifted out of the liquid helium to a position in which it is still subject to the magnetic field although this may be less homogeneous and remains at a low temperature.
  • Hot solvent is then supplied into the sample holding tube, typically through a dissolution tube or stick, to the working volume so as to dissolve the polarised sample.
  • the solution is then rapidly extracted and transferred for subsequent use either for analysis in an NMR system or, in the case of in vivo applications, injection into a patient.
  • the solvent is prepared for delivery by superheating it to a temperature above its boiling point. During this process, the pressure on the solvent will increase and when a desired pressure is reached, i.e. sufficient to ensure rapid delivery, a valve is opened and the solvent released. Transfer to the NMR apparatus is further aided by the use of a chase gas.
  • the first is that when the desired pressure is reached, the temperature of the solvent may not be at a required level.
  • a second problem is that when the superheated solvent is released, the accompanying sudden drop in pressure can cause bubbles of gas to form in the sample.
  • the use of a chase gas may lead to the formation of gas bubbles in the solvent. The presence of gas bubbles impairs the quality of the subsequent analysis of the sample in the NMR apparatus.
  • GB-A-2448054 describes a fluid path system for dissolution and transport of a hyperpolarised material in which solvent is supplied from a syringe.
  • DNP apparatus comprising: a cryostat within which is located a superconducting magnet and defining a bore surrounded by the magnet; a sample positioning device for insertion into the bore to locate a sample at an irradiation position coupled to a microwave source, the sample positioning device being movable to a dissolution position following DNP of the sample; a solvent supply system comprising one or more conduits for conveying heated solvent under pressure and is characterized in that the apparatus further comprises a pump for causing heated solvent to be conveyed along the one or more conduits to the sample at the dissolution position, and for conveying the dissolved, polarised sample to NMR apparatus connected in use to the DNP apparatus; and a heating system for heating solvent in the pump, and in that the conduits of the solvent supply system extend to the dissolution position without passing through that part of the cry
  • the conduits of the solvent supply system can be much more accurately controlled since most of the solvent supply system is located externally of the cryostat. It also avoids the need for a chase gas since the same solvent can be used to transfer the sample.
  • the conduits of the solvent supply system extend through a side wall of the cryostat. This minimizes the length of conduit which will be cooled by the cryostat and consequently minimizes the time for which solvent is cooled as it is supplied to the dissolution position.
  • the conduits could extend through the remote part of the bore of the cryostat to that through which the sample positioning device is inserted since typically this will be relatively short in length and again will minimize the amount of cooling.
  • the pump comprises a piston/cylinder device, the piston being controllable to apply pressure in a controlled manner to solvent in the cylinder. This is similar to using a syringe.
  • Movement of the piston can be controlled by a mechanical device utilising a pressure monitor to maintain constant pressure on the solvent but more conveniently the piston is coupled to a control means such as a source of fluid or gas pressure, for example a pneumatic actuator.
  • the solvent supply device may be replenished with solvent by simply regularly filling it, for example by withdrawing the piston in the case of piston/cylinder arrangement.
  • the apparatus further comprises a solvent reservoir which can be selectively coupled to an outlet of the pump whereby reducing the pressure applied to solvent by the pump causes fresh solvent to be delivered from the solvent reservoir to the pump.
  • a solvent reservoir which can be selectively coupled to an outlet of the pump whereby reducing the pressure applied to solvent by the pump causes fresh solvent to be delivered from the solvent reservoir to the pump.
  • the dissolved sample can be supplied to separate NMR apparatus in a conventional manner but in the preferred approach, NMR apparatus having a cryostat within which is located a superconducting magnet and defining a bore surrounded by the magnet is located adjacent the DNP apparatus, the bore of the NMR apparatus being coupled to the bore of the DNP apparatus.
  • NMR apparatus having a cryostat within which is located a superconducting magnet and defining a bore surrounded by the magnet is located adjacent the DNP apparatus, the bore of the NMR apparatus being coupled to the bore of the DNP apparatus.
  • the apparatus further comprises a dissolution docking device in the bore at the dissolution position which can be sealingly engaged by the sample positioning device, the solvent supply system comprising: a solvent supply conduit having an outlet connected to an inlet port of the dissolution docking device and an inlet connected to an output port of a first valve, an inlet port of the first valve being connected to the pump; and the dissolution docking device having an outlet port through which dissolved sample is conveyed, whereby when the first valve is opened, solvent is delivered via the input port to the sample at the dissolution position, at least a portion of the sample dissolves in the solvent, and the dissolved sample portion is delivered to the outlet port.
  • the solvent supply system comprising: a solvent supply conduit having an outlet connected to an inlet port of the dissolution docking device and an inlet connected to an output port of a first valve, an inlet port of the first valve being connected to the pump; and the dissolution docking device having an outlet port through which dissolved sample is conveyed, whereby when the first valve is opened, solvent is delivered via
  • the apparatus further comprises a second valve downstream of the
  • NMR apparatus through which solvent and dissolved sample can flow; and a control system for controlling both valves in synchronism.
  • the dissolved sample can be incremented through the NMR apparatus enabling several NMR pulse sequences to be carried out on different portions of the sample thus allowing a variety of NMR experiments to be executed during a single dissolution.
  • An example of this approach is described in more detail in WO-A-2007/104975.
  • Figure 1 is a schematic overview of a combined DNP NMR apparatus
  • FIGs 2A and 2B are schematic longitudinal sections through the dissolution dock of the Figure 1 example with the sample cup in the DNP working volume and the docking position respectively; and, Figure 3 illustrates the solvent supply system.
  • FIG. 1 illustrates a cryostat 1 of conventional form. Typically this will have a number of radiation shields and coolant containing vessels defining a central, elongate bore 2.
  • a first superconducting magnet 3 is located in the cryostat 1 surrounding an upper portion of the bore 2 for use in dynamic nuclear polarisation while a second superconducting magnet 4 of NMR apparatus 74 is located in the cryostat 1 below the first magnet 3 and surrounding the bore 2 for use in an NMR process.
  • the NMR apparatus will be of conventional form and also include gradient coils, rf coils and a control system (not shown).
  • VTI variable temperature insert
  • the device 14 carrying a sample cup 18 at its leading end within which a sample to be hyperpolarised is located in use.
  • the sample positioning device 14 is inserted into the VTI 10 to bring the sample in the sample cup 18 to a working region 12.
  • Liquid helium or other coolant is then supplied through the bore 2 to cool the sample in the sample cup to a very low temperature and it is then irradiated with microwaves to achieve hyperpolarisation in a conventional manner.
  • the frozen, hyperpolarised sample in the sample cup 18 is moved further down the bore 2 using the sample positioning device 14 until the sample cup engages a dissolution dock or docking device 20 to be described in more detail below.
  • Heated solvent under pressure is then supplied to the dissolution dock 20 via a conduit 70 of a solvent supply system to be described below, the conduit 70 extending through a side wall of the cryostat 1 so as to dissolve the hyperpolarised sample, the dissolved sample then being conveyed into a working region 22 defined by an NMR probe 24 of the NMR apparatus. An NMR experiment can then be performed on the sample.
  • the sample cup 18 is located on the end of the sample positioning device 14.
  • the sample cup 18 has a lower wall 34 provided with inlet and outlet ports 36, 38.
  • the dissolution dock 20 has a main body 44 through which extends solvent inlet and outlet conduits 40,42.
  • the dissolution dock is sealed in the end of the VTI 10 by an O-ring vacuum seal 114.
  • Figure 2B illustrates the apparatus when the sample cup 18 has been docked with the dissolution dock 20.
  • the sample cup 18 is pushed down to engage the dissolution dock 20, and is received within a cylindrical spigot portion 32 of the dissolution dock 20.
  • the inlet port 36 is aligned with the inlet conduit 40 and the outlet port 38 is aligned with the outlet conduit 42.
  • a seal 116 seals between the dissolution dock 20 and the sample cup 18 to isolate the solvent inlet and outlets while a seal 118 isolates the solvent outlet from the VTI sample space.
  • FIG. 3 illustrates the solvent supply system.
  • Solvent is provided in a pump defined by a 20ml syringe 50 formed by a cylinder 52 and piston 54.
  • Typical solvents are water and methanol.
  • the syringe 50 is surrounded by a heater coil 56 whose temperature is sensed by a sensor 58.
  • a second sensor is provided to measure the temperature of the syringe 50 .
  • a typical temperature is close to the boiling point of the solvent, for example 90 ° C in the case of water.
  • the pressure under which the solvent is maintained is controlled by the piston 54 from a pneumatic actuator 62 using an electronic pressure regulator
  • the syringe 50 is connected to an inlet port of a first valve 64 whose outlet is connected to a double flowpath valve 66.
  • the outlet of the first valve 64 is coupled through the valve 66 to a further double flow path valve 68 and from there to a conduit 70.
  • Conduit 70 delivers the solvent to the dissolution dock 20 via inlet 40.
  • the outlet 42 from the dissolution dock 20 passes through a one-way flow valve 72 and from there to the NMR apparatus 74 via a conduit 112 (see also Figures 2A and 2B).
  • the output from the NMR apparatus 74 is connected to a second flow control valve 76 whose outlet is connected to a waste 78 or sample collection device.
  • the positions of the flow control valves 64, 76 are controlled by a controller 80 which turns each valve on and off together so as to increment solvent through the dissolution dock 20 and NMR apparatus 74.
  • solvent in the syringe 50 which is maintained under pressure, is suddenly released by opening the first flow control valve 64 and, when provided, the second flow control valve 76.
  • the solvent passes through the conduit 70 under pressure controlled by the pneumatic cylinder 62 into the dissolution dock at a typical speed of 5ml/sec, dissolves the sample, and then passes out of the dissolution dock with the dissolved sample to the NMR apparatus 74.
  • the double flow path valve 66 can be adjusted to connect a solvent reservoir 100 to the outlet of the first flow control valve 64.
  • the piston 54 is withdrawn by suitably controlling the pneumatic actuator 62 so that solvent is drawn from the reservoir 100 into the syringe 50.
  • the first flow control valve 64 is closed and the double flow path valve 66 moved back to the position shown in Figure 3.
  • the system can also be purged when the double flow path valve 66 is in its second position (not shown) by supplying purge gas through a conduit 102 via a valve 104. It is also possible to supply a sample to the NMR apparatus bypassing the DNP apparatus. This is achieved by supplying the sample to the dual flowpath valve 68 (in the position shown in Figure 3) along a conduit 106 from where it passes along a conduit 108 through a one-way flow valve 110 to the conduit 112.
  • solvent can be supplied from syringe 50 directly to NMR apparatus 74, for instance to load the NMR apparatus with solvent prior to dissolving the polarised sample. This is achieved by selecting the second position of dual flow path valve 68 (not shown), causing the solvent to pass from the syringe 50 via conduit 108 and 112 to NMR apparatus 74.
  • the presence of the one-way valve 72 prevents samples supplied along the conduit 106 from entering the dissolution dock 20.

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  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Electromagnetism (AREA)
  • Sampling And Sample Adjustment (AREA)

Abstract

Un appareil PND comprend : un cryostat (1) à l’intérieur duquel est situé un aimant supraconducteur (3) et définissant un alésage (2) présentant des extrémités d’entrée et de sortie opposées et entourées par l’aimant. Un dispositif de positionnement d’échantillon (14) est prévu pour insertion dans l’extrémité d'entrée de l’alésage (2) pour localiser un échantillon en une position d’irradiation couplée à une source micro-onde. Une plate-forme de dissolution (20) est située au niveau de l'extrémité de sortie de l’alésage (2) vers laquelle le dispositif de positionnement d’échantillon (14) se déplace après la PND d’un échantillon; et un circuit d'arrivée de solvant achemine le solvant chauffé sous pression, sans traverser l’alésage (2), vers un échantillon au niveau de la plate-forme de dissolution (20) et achemine l’échantillon polarisé, dissoute à l’appareil RMN. Les conduits du circuit d'arrivée de solvant s'étendent vers la position de dissolution sans traverser cette partie de l’alésage cryostat à travers lequel le dispositif de positionnement d'échantillon est introduit.
PCT/GB2009/002763 2008-11-27 2009-11-26 Appareil de polarisation nucléaire dynamique WO2010061191A1 (fr)

Applications Claiming Priority (2)

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EP08170056.9 2008-11-27
EP08170056 2008-11-27

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040066193A1 (en) * 2000-11-03 2004-04-08 Ardenkjaer-Larsen Jan Henrik Methods and devices for dissolving hyperpolarised solid material for nmr analyses
US20060079765A1 (en) * 2004-10-13 2006-04-13 Liebel-Flarsheim Company Powerhead of a power injection system
WO2006077361A2 (fr) * 2005-01-21 2006-07-27 Oxford Instruments Molecular Biotools Limited Procede pour realiser une polarisation dynamique nucleaire
WO2007007022A1 (fr) * 2005-07-12 2007-01-18 Oxford Instruments Molecular Biotools Limited Ensemble aimant pour applications de polarisation nucléaire dynamique et/ou de résonance magnétique nucléaire
GB2448054A (en) * 2007-03-28 2008-10-01 Gen Electric Fluid path system for dissolution and transport of a hyperpolarized material
WO2009027645A2 (fr) * 2007-08-24 2009-03-05 The Universtiy Of Nottingham Améliorations apportées ou liées à des procédés et appareil servant à la préparation d'un échantillon pour analyse

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040066193A1 (en) * 2000-11-03 2004-04-08 Ardenkjaer-Larsen Jan Henrik Methods and devices for dissolving hyperpolarised solid material for nmr analyses
US20060079765A1 (en) * 2004-10-13 2006-04-13 Liebel-Flarsheim Company Powerhead of a power injection system
WO2006077361A2 (fr) * 2005-01-21 2006-07-27 Oxford Instruments Molecular Biotools Limited Procede pour realiser une polarisation dynamique nucleaire
WO2007007022A1 (fr) * 2005-07-12 2007-01-18 Oxford Instruments Molecular Biotools Limited Ensemble aimant pour applications de polarisation nucléaire dynamique et/ou de résonance magnétique nucléaire
GB2448054A (en) * 2007-03-28 2008-10-01 Gen Electric Fluid path system for dissolution and transport of a hyperpolarized material
WO2009027645A2 (fr) * 2007-08-24 2009-03-05 The Universtiy Of Nottingham Améliorations apportées ou liées à des procédés et appareil servant à la préparation d'un échantillon pour analyse

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARDENKJAER-LARSEN J H ET AL: "Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC.; US, vol. 100, no. 18, 2 September 2003 (2003-09-02), pages 10158 - 10163, XP002280244, ISSN: 0027-8424 *
COMMENT A ET AL: "Producing over 100 ml of highly concentrated hyperpolarized solution by means of dissolution DNP.", JOURNAL OF MAGNETIC RESONANCE (SAN DIEGO, CALIF. : 1997) SEP 2008, vol. 194, no. 1, September 2008 (2008-09-01), pages 152 - 155, XP002527750, ISSN: 1557-8968 *
SOWERBY A: "Molecules in minute detail", CHEMISTRY AND INDUSTRY (LONDON) 20050905 SOCIETY OF CHEMICAL INDUSTRY GB, no. 17, 5 September 2005 (2005-09-05), pages 21 - 23, XP001536760 *

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