CN102753201A - Systems and methods for producing hyperpolarized materials and mixtures thereof - Google Patents

Abstract

The present disclosure provides various methods and systems for manufacture, transport and delivery of material including highly polarized nuclei that is in a hyperpolarized state.

Description

Be used to make the system and method for hyperpolarization material and its mixture

The related application cross reference

The priority right that No. the 61/238th, 647, the U.S. Provisional Patent Application case that the application's case is advocated to file an application on August 31st, 2009.The application's case is also relevant with following case: the U.S. Provisional Patent Application case the 60/775th that on February 21st, 2006 filed an application; The U.S. Provisional Patent Application case the 60/802nd that on May 23rd, No. 196 1 filed an application; The U.S. Provisional Patent Application case the 61/042nd that on April 3rd, No. 699 1 filed an application; The U.S. Provisional Patent Application case the 61/042nd that on April 4th, No. 239 1 filed an application; The U.S. Provisional Patent Application case the 61/111st that on November 4th, No. 398 1 filed an application; No. the 12/193rd, 536, patent application that the U.S. Provisional Patent Application case of filing an application on August 31st, No. 050 1 was filed an application on August 18th, the 61/238th, No. 647 1 and the international application case of filing an application on April 6th, 2009 PCT/US2009/39696 number.The full text of the disclosure of each is incorporated herein by reference in the above-mentioned patent application case.

Technical field

The present invention relates to comprise the warp improvement material and its manufacturing technology of hyperpolarization nuclear.

Background technology

Nearest experiment shows, and the hyperpolarization of various nuclears can be gone through existing from a molecular transition to another molecule of taking place during the chemical reaction.For example, show the hyperpolarization in the Sodium Pyruvate (" HP ") ¹³C endorses by the cancerous tissue metabolism and produces HP lactate, alanine etc.

Findable another instance is to produce the HP fumarate, and it can and make said acid and the aqueous slkali reaction is made with formation HP fumarate subsequently through the nuclear in the hyperpolarization fumaric acid at first.HP Sodium Pyruvate (that is the Sodium Pyruvate that, comprises hyperpolarization nuclear) can be made in a similar manner.Show that in for example these reacted, the polar amount of being lost during the chemical reaction was less.

These be in the chemical reaction at least a precursor molecules through hyperpolarization thus at least a end product of chemical reaction also through the instance of the chemical reaction of hyperpolarization.

In each of above-mentioned instance, utilize dynamical nuclear polarization (DNP) to make the precursor molecules hyperpolarization.In the method, the molecule of treating hyperpolarization and the polarization agent that contains the free electron source (being generally triphenylmethyl radical (TA)) are mixed.In some cases, electron paramagnetic agent (EPA) can be used in combination with TA or use separately.

This hyperpolarization methods is debatable in vivo using, and this is because the strong taboo of TA/EPA is used in vivo using.Therefore, TA/EPA must remove before injection HP material in strictness.Yet the polarization level that exists in the HP material behind the filtration TA/EPA is also unclear at present.In addition, FDA does not set up the safe exposure level of a small amount of TA/EPA as yet.In addition, this technological use is not suitable for the instant transportation or the storage of hyperpolarization material.

The whole bag of tricks that high nuclear polarization can use the those skilled in the art to know produces in the material that contains nonzero spin nuclear.In these the most simply be make material stand high magnetic field (usually, B＞10T) (usually, T＜100mK), the saturated nuclear polarization that wherein arbitrary nonzero spin is examined is high with extremely low temperature.

Regrettably, under the described conditions, the relaxation time of great majority nuclear is very long, and this is that molecular motion weakens greatly because under low temperature, and molecular motion is the main source of nuclear magnetic relaxation.For solving this shortcoming, used multiple relaxation agent to shorten the T in the high B/T environment ₁, comprise dysprosium, gadolinium, oxygen and other.

A kind of replacement scheme of using relaxation agent is to include polarization agent (for example triphenylmethyl radical) in and will polarize subsequently and transfer to the nuclear the target material from said polarization agent.This approach has the advantage that does not need said low temperature or High-Field, and has been used for producing very high polarization in small quantity of material clearly.It has become the basis of the commercially available research device of commodity telegraphy (Hypersense)

by name.

Yet, be mixed with outside relaxation agent or polarization agent and have a plurality of shortcomings.At first, it makes material shift out back depolarization when still being solid-state from high B/T environment usually equally effectively.This makes hyperpolarization material stored apart from the unusual difficulty of the arbitrary larger distance of polarizer, and therefore requires to place polarizer very near the MR machine of planning to implement to use the research of hyperpolarization material.Secondly, most of relaxation agent or polarization agent have toxicity usually.This makes said reagent be difficult to use in vivo MR research.

For this reason, developed avirulence and can be removed in addition and can not make the unpolarized alternative relaxation agent of material.For example, United States Patent (USP) the 6th, 651, No. 459 teaching is used ³He is as relaxation agent, and it passes through will ³The He layer is adsorbed in by carrying out on the high surface substrate of treating hyperpolarization material structure. ³The feasible quick relaxation of material that underlies of quantum tunneling in the He overlying strata, thus cause the nuclear polarization in the high B/T environment saturated fast. ³He is chemically inert, and can before high B/T environment heating, remove fully from material in addition, thereby solves the problem of in vivo using.United States Patent (USP) the 6th, 651, No. 459 further teaching is used ⁴He removes the polarization material surface ³He so that the heating after depolarization minimize.

An aspect of said method is ³He is relaxation and its substrate layer that contacts closely effectively only.Therefore, must before polarization, material manufacture be become the very high surface area substrate, this can apply the material processed difficulty.

Therefore, need make the method for hyperpolarization (" HP ") material in the industry, wherein said material is not mixed with the outside relaxation agent or the polarization agent of arbitrary kind.More generally, still need to make, transport and use the improved route of high degree of polarization material in the industry.The present invention provides these ways to solve the problem.

Summary of the invention

Advantage of the present invention will be set forth in explanation subsequently and will be obvious from explanation subsequently.Additional advantages of the present invention will realize and obtain through said method and system, and will in written description of the present invention and its claims and accompanying drawing, point out particularly.

By reaching these with other advantage and according to the object of the invention (as being embodied among this paper), in one embodiment, the present invention provides the method that produces the material that contains hyperpolarization nuclear.Said method comprises that first format material is changed into high surface to be disposed.Then, in the polarization cryostat, make said first material in the temperature that is lower than about 10K be enough to a certain extent to increase in fact under the polar magnetic field of at least one nuclear in said first material and be exposed to ³He.The temperature of said first material is increased and do not make said first material fusing or distillation, thereby make nuclear in said first material hyperpolarization that becomes.If desired, make said first material and at least a other material reaction comprise the mixture of hyperpolarization nuclear with formation subsequently.

Further according to the present invention, said mixture can be solution.If desired, can be before the reactions step or make said first material fusing as the part of reactions step.Can said first material be exposed to ³After the He said first material is exposed to ⁴He.If desired, can with said first material with the hyperpolarization state storage in independent cryostat.Can first material be transported to the site away from its hyperpolarization position in independent cryostat, make said first material and at least a other material reaction comprise the mixture of hyperpolarization nuclear with formation subsequently.According to preferred embodiment, the nuclear in said first material comprises at least a material that is selected from by the following group that forms: ¹³C, ¹⁵N, ¹H, ³¹P with ²⁹Si.

Further according to the present invention, said method can further be included in the initial temperature increase and make nuclear in said first material become to increase the temperature of said first material in fact after the hyperpolarization, and does not make said material fusing or distillation.For example, can make temperature from being lower than the T of first material in fact ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material in fact ₁Second temperature of the temperature during the experience minima.According to an embodiment, make the temperature of first material be increased to the temperature of about 200K from the temperature that is lower than about 10K.According to another embodiment, can be in the presence of magnetic field increase with the temperature that the speed of falling to the polarization loss of the nuclear in first material makes first material of giving less than about 90%.According to some preferred embodiment, can be in the presence of magnetic field increase with the temperature that the speed of falling to the polarization loss of the nuclear in first material makes first material of giving less than about 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 5%.If desired, can make first material reach second temperature after with the position of first transport of materials to the fringing field that is positioned at the MR system.

Further according to the present invention, said method can be additionally included in the initial temperature increase and make nuclear in said first material become after the hyperpolarization to remove the step of said first material from the polarization cryostat.As another instance, said method can further be included in the initial temperature increase makes nuclear in said first material become after the hyperpolarization said first material transfer in the transfer of cryogenic thermostat.Therefore, can the transfer of cryogenic thermostat be transported to the terminal use.Can first material be transferred to the transfer vessel from the transfer of cryogenic thermostat subsequently.Transfer vessel can comprise and is used for making first material to remain in the permanent magnet or the electromagnet in magnetic field.Said method can further comprise makes temperature from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature during the experience minima.Can first material transfer raised the temperature to second temperature in the transfer vessel in fact simultaneously.Can in magnetic field, in less than about 30 seconds, raise the temperature to second temperature with the intensity between about 0.1 tesla (Tesla) and about 10 teslas.

Further according to the embodiment that is disclosed, said method can further comprise the step of first material arrangements in the mixing arrangement of the fringing field that is arranged in the MR system.Preferably, at least a portion of reactions step takes place in mixing arrangement.If the use transfer vessel was preferably closed the magnet of transfer vessel or make its passivation or so with its shielding before carrying out the operation of MR system.

Further according to the present invention, said first material can comprise that acid and said at least a other material can comprise alkali.On the other hand, said first material can comprise that alkali and said at least a other material can comprise acid.Therefore, said acid can comprise the acid that is selected from by the following group that forms: acetic acid, formic acid, lactic acid and acetone acid.Preferably, said acid warp on one of which or above carbon potential point ¹³The C isotope strengthens.According to an embodiment, said at least a other material comprises sodium, for example is sodium hydroxide and/or sodium bicarbonate form.According to another aspect, first material can be liquid, solid and/or gas under standard temperature and pressure (STP) (" STP ").According to an embodiment, can first material be frozen into the high surface configuration, so that it has greater than about 0.1m ²The surface area of/g and volume ratio.

Further, the method for magnetic resonance (MR) research of the individuality that comprises human individual or other organism is provided according to the present invention.Said method comprises the mixture that comprises hyperpolarization nuclear that generation is as described herein; Throw and give individuality with said mixture; Make radiation that said individuality is exposed to selected frequency exciting the nuclear spin transition in the hyperpolarization nuclear, and detect magnetic resonance signal from said individuality.

Further according to the present invention, said method can further comprise at least one from the signal generator image, kinetics flow-data, diffusion data, data perfusion, physiological data or the metabolite data that are detected.Hyperpolarization in mixture nuclear preferably has at least 5 seconds T under the field intensity in the 0.01-5T scope under the temperature in 20-40 ℃ of scope ₁Value.

The present invention further provides the method that produces the material that comprises hyperpolarization nuclear.Said method is included under the situation that does not have free electron source (for example, TA, preceding text are discussed) or paramagnetism impurity (for example, EPA, preceding text are discussed) and is being lower than the polarized state that in the presence of magnetic field, increases by first material under the temperature of about 10K; Increase the temperature of first material and do not make its fusing, hyperpolarization so that the nuclear in first material becomes; And make first material and at least a other material reaction comprise the mixture of hyperpolarization nuclear with formation.Said mixture can comprise solution and other types of mixtures.

Further according to the present invention, methods described herein can comprise that first material wherein comprises the embodiment of methyl.As another instance, methods described herein can comprise that gained mixture wherein comprises the embodiment of paired key tuberculosis.Preferably, at least a portion of said key tuberculosis is through hyperpolarization.

The present invention further provides the method that produces the material that contains hyperpolarization nuclear.Said method comprises first format material that methyl is changed into high surface configuration, increases the nuclear polarization of said first material, and the temperature that in less than about 30 seconds time period, makes said first material is from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature during the experience minima, and do not make said first material fusing or distillation.The present invention also provides the method that produces the material that contains hyperpolarization nuclear.Said method comprises first format material that methyl is changed into high surface configuration, increases the nuclear polarization of said first material, and the temperature that in less than about 30 seconds time period, makes said first material is from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature during the experience minima, and do not make said first material fusing or distillation, wherein when increasing temperature, fall less than about 90% polarization loss.Further, can make said first material and at least a other material reaction comprise the mixture of hyperpolarization nuclear with formation according to the present invention.According to some preferred embodiment, when increasing temperature, fall less than about polarization loss of 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 5%.

The present invention also further provides the method that produces the material that contains hyperpolarization nuclear.Said method comprises hyperpolarization first material, and the temperature that makes said first material is from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature during the experience minima, and do not make said first material fusing or distillation.

The present invention also further provides the method that produces the material that contains hyperpolarization nuclear.Said method comprises first format material changed into high surface configuration, and in the polarization cryostat, makes said first material in the temperature that is lower than about 10K be enough to increase in fact under the polar magnetic field of said first material and be exposed to ³He.Said method also comprises the mixture that makes said first material and at least a other material reaction comprise hyperpolarization nuclear with formation.

The present invention also provides the method that produces the mixture that comprises hyperpolarization nuclear; It comprises provides the predecessor that comprises hyperpolarization nuclear; Predecessor is arranged in the stray magnetic field of MR system, and makes predecessor and at least a other material reaction comprise the mixture of hyperpolarization nuclear with formation.

Further, be provided for producing the system implementation example of the material that contains hyperpolarization nuclear according to the present invention.Said system comprises the polarization cryostat, and it has and is used to make first material that is formatted into high surface configuration to be exposed to being lower than under the temperature of about 10K ³The container of He and through adjusting and be configured to be provided at the magnet in the polar magnetic field that is enough to increase in fact said first material to a certain extent.Said system further comprises first thermal source, and it is used to increase the temperature of said first material and does not make fusing of said first material or distillation, thereby makes nuclear in said first material hyperpolarization that becomes.Said system also further is provided for making said first material and at least a other material reaction to comprise the mixing arrangement of the mixture of hyperpolarization nuclear with formation.

Further according to the present invention, said mixture can be solution.Said system can further comprise second thermal source, and it is used to melt said first material to allow said first material reaction.Second thermal source can comprise with said first material and is mixed together the material in mixing arrangement.For example, can make said first material fusing through the material that first material is fallen into first material mixing.As another instance, can before the material of the contact and first material mixing, make said first material fusing.Said system can further comprise and be used for said first material is exposed to ³After the He said first material is exposed to ⁴The member of He.

According on the other hand, said system can further comprise the transfer of cryogenic thermostat, said first material with the hyperpolarization state storage in the transfer of cryogenic thermostat.The transfer of cryogenic thermostat preferably is suitable for first transport of materials is arrived the site away from the hyperpolarization position of first material.According to preferred embodiment, the nuclear in said first material comprises at least a material that is selected from by the following group that forms: ¹³C, ¹⁵N, ¹H, ³¹P with ²⁹Si.

According on the other hand, said system can comprise the member that is used for not making first material being become increase the temperature of said first material in fact after the hyperpolarization said material fusing or distillation.Said system can through adjust and configuration so that temperature from being lower than the T of first material in fact ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material in fact ₁Second temperature of the temperature during the experience minima.Said optimum system choosing ground warp adjust and configuration so that the temperature of said first material is increased to the temperature of about 200K from the temperature that is lower than about 10K.

Further according to the present invention, said system can comprise the transfer vessel that is used for receiving from the transfer of cryogenic thermostat first material.Transfer vessel preferably includes and is used for making said first material to remain in the magnet in magnetic field.According to another embodiment, said system comprises the mixing arrangement that is used for receiving from transfer vessel said first material.Mixing arrangement and transfer vessel are preferably operated in the fringing field of MR system through adjusting and be configured to.The magnet of transfer vessel can be what close before adjusting and be configured to carry out the operation of MR system.

Further according to said system, first material can be liquid, solid and/or gas under STP.First material preferably is and has greater than about 0.1m ²The surface area of/g and the configuration of the high surface of volume ratio.

The present invention provides the system of magnetic resonance (MR) research of the individuality that comprises human individual or other organism.Said MR system comprises that the member that is used to produce the mixture that comprises hyperpolarization nuclear as described herein throws mixture and give individual syringe with being used for.Said system further comprise at least one be used for making radiation that individuality is exposed to selected frequency with the radio-frequency coil of the nuclear spin transition that excites hyperpolarization nuclear be used to detect detector from the magnetic resonance signal of individuality.

Further according to the present invention, said system can further comprise at least one member of the signal generator image, kinetics flow-data, diffusion data, data perfusion, physiological data or the metabolite data that are used for receiving from self-detector.

The present invention also is provided for producing the example system of the material that comprises hyperpolarization nuclear.Said system comprises the member that is used under the temperature that is being lower than about 10K under the situation that does not have free electron source or paramagnetism impurity, in the presence of magnetic field, increasing the polarized state of first material.Said system further comprises and is used for increasing the temperature of first material and does not make its fusing so that the member that the nuclear of first material becomes hyperpolarization.Said system also comprises and is used to make said first material and at least a other material reaction to comprise the member of the mixture of hyperpolarization nuclear with formation.

Further according to the present invention, institute's exposing system can use first material that comprises methyl.If desired, can use institute's exposing system to make the mixture that comprises paired key tuberculosis.Preferably, at least a portion of said key tuberculosis is through hyperpolarization.

Further, be provided for producing the system of the material that contains hyperpolarization nuclear according to announcement embodiment.Said system comprises the member of the member that is used for first format material that comprises methyl is changed into high surface configuration and the nuclear polarization that is used to increase said first material.Said system further comprise be used to make said first material temperature in less than about 30 seconds time period from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature of experience during minima and do not make the member of said first material fusing or distillation.

Further, be provided for producing the system of the material that contains hyperpolarization nuclear according to the present invention.Said system comprises the member of the member that is used for first format material that comprises methyl is changed into high surface configuration and the nuclear polarization that is used to increase said first material.Said system further comprise be used to make said first material temperature in less than about 30 seconds time period from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature of experience during minima and do not make the member of said first material fusing or distillation is wherein fallen less than about 90% polarization loss during heating steps.According to some preferred embodiment, during heating steps, fall less than about polarization loss of 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 5%.

Further according to the present invention, said system can comprise and is used to make said first material and at least a other material reaction to comprise the member of the mixture of hyperpolarization nuclear with formation.

Further according to the present invention, be provided for producing the system of the material that contains hyperpolarization nuclear again.Said system comprises that member that is used for hyperpolarization first material and the temperature that is used to make said first material are from being lower than the T of first material ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material ₁Second temperature of the temperature of experience during minima and do not make the member of said first material fusing or distillation.

Further according to the present invention, be provided for producing the system of the material that contains hyperpolarization nuclear again.Said system comprise be used for first format material change into high surface configuration member, have and be used to make said first material to be exposed to being lower than under the temperature of about 10K ³The polarization cryostat of the member of He and be used to produce the magnet in the polar magnetic field that is enough to increase in fact said first material.Said system also comprises and is used to make said first material and at least a other material reaction to comprise the mixing arrangement of the mixture of hyperpolarization nuclear with formation.

Further, be provided for producing the system of the mixture that comprises hyperpolarization nuclear according to announcement embodiment.Said system comprises member that is used for providing the predecessor that comprises hyperpolarization nuclear and the member that is used for predecessor is arranged in the stray magnetic field of MR system.Said system further comprises and is used to make predecessor and at least a other material reaction to comprise the member of the mixture of hyperpolarization nuclear with formation.

According to another embodiment, the present invention provides other embodiment that makes the hyperpolarization material.A said exemplary methods comprises providing treats polar first material, increases the polarization of at least one nuclear that is contained in said first material, and with the polarization transfer of the increase of said at least one nuclear another nuclear in said first material.

According to others; Said first material preferably includes methyl rotor (methyl rotor) group; In polarization the polarization of at least one proton in the said methyl rotor group is increased, and in transfer step with the polarization transfer of the increase of said at least one proton another nuclear in said first material.Said first material was preferably disposed paramagnetic agent and polarization agent in fact before polarization.For example, said first material was preferably disposed TA and EPA in fact before polarization.Said first material is preferably through using ¹²⁹Xe, ¹³C, ¹⁵N, ¹H, ²H, ³¹P, ¹⁹F with ²⁹An alternative one of which of among the Si at least one or an above atom site and strengthen through isotope.

According on the other hand, the polarization step preferably includes and makes said first material be exposed to the polarization environment.This preferably includes in following at least one: the temperature that (i) reduces said first material; The magnetic field that (ii) makes said first material stand to increase wherein makes said first material be exposed to the polarization environment and reaches and be enough to make at least one proton polarization that is contained in said first material to reach the time of thermodynamical equilibrium.Said first material can be solid, liquid and/or gas under STP.Preferably, said method comprises that further taking out said said first material of first material while from polarization environment (for example, cryostat) is solid-state step.And the polarization time preferably is enough to make said at least one the proton polarization in the methyl.

According to another preferred aspect; Said method can further comprise passes zone that magnetic field reduces to the second position with said first material from polarization environment guiding, moves on to another nuclear after the polarization step, to promote polarization said at least one consideration convey from said first material.Preferably, with said first material through greater than T ₂But less than T ₁Time period shift from the polarization environment and pass zone that magnetic field reduces to the said second position.For example, if desired, can with said first material less than 1.0 seconds, less than 0.1 second, less than 0.01 second in or in about 0.001 second from the polarization environment transfer to the said second position.

According to more another others, the said second position can comprise the low temperature environment with magnetic field.For example, the said second position can comprise the transfer of cryogenic thermostat that contains magnet, and wherein said magnet applies magnetic field to said first material under low temperature.Preferably, said first material is solid-state after the polarization step and through said first material is quickened it is directed to the said second position.Can be through the guiding of first material being passed conduit and it is directed to the said second position with Compressed Gas.For example, available Compressed Gas passes conduit with the speed that surpasses 10m/s, 100m/s or 1000m/s with the guiding of first material.Said Compressed Gas preferably includes helium, and can comprise ³He.

According to some others again, the said second position can comprise the melting vessel that is used to melt said first material.In one embodiment, the zone of said magnetic field reduction can comprise magnetic shield so that the magnetic field intensity in the zone that magnetic field reduces is reduced to the value less than the earth background field.If desired, heat said first material before said method can further be included in and discharge in the polarization environment time.Heating steps preferably makes the temperature of said first material from being lower than the T of first material ₁Temperature (T during the experience minima _Min) be increased to the T that is higher than first material ₁Temperature (T during the experience minima _Min) second temperature and said first material melted in fact or distil.

According to another embodiment; The present invention provides the method for making the hyperpolarization material; It comprises providing treats polar first material that is the high surface powder type; In container, in the polarization environment, the polarization of at least one nuclear that is contained in said first material is increased: (i) to reduce the temperature of said first material and the magnetic field that (ii) makes said first material stand to increase through carrying out in following at least one.Making said first material be exposed to the polarization environment reaches and is enough to make at least one nuclear polarization that is contained in said first material to reach the time of thermodynamical equilibrium.Said method comprises that further the polarization transfer with the increase of said at least one nuclear passes the step of the zone of magnetic field reduction to the second position with said first material from the guiding of polarization environment simultaneously to another nuclear in said first material.

According to others, said high surface first material is exposed to ³He reaches the time of at least one nuclear polarization that is enough to make in the material and is contained. ³He can make said high surface format first material and be exposed to after exposing ⁴He is to remove ³He.Be exposed to ⁴Behind the He, can heat said first material and said first material is melted in fact or distil, thereby make nuclear in the material hyperpolarization that becomes.The temperature that heating preferably makes said first material is from being lower than the T of first material ₁Temperature (T during the experience minima _Min) be increased to the T that is higher than first material ₁Temperature (T during the experience minima _Min) second temperature and said first material melted in fact or distil.First material is remained in the magnetic field.First material is preferably greater than T ₂And less than T ₁Time in from the polarization environment be directed to the second position.The second position preferably includes the low temperature environment with magnetic field.For example, the said second position can comprise the transfer of cryogenic thermostat that contains magnet, and wherein said magnet applies magnetic field to said first material under low temperature.

According to said method on the other hand; Said first material technology that is selected from by the following group that forms capable of using polarizes: (i) dynamical nuclear polarization; (ii) nuclear Overhauser effect (Nuclear Overhauser effect); The (ii) polarization of para-hydrogen induced (iii) makes the nuclear of said first material be exposed to the hyperpolarization nuclear of hyperpolarized gas in advance, (iv) makes said first material be exposed to powerful environment and its combination.

The present invention further provides the method that forms hyperpolarised solution, and it comprises makes the first material hyperpolarization that under STP, is liquid as indicated above, and makes the said first hyperpolarization material and second material mixing to form solution.Can make the reaction of first material and second material to form solution.First material can comprise that the acid and second material comprise alkali, otherwise or.Acid can comprise one or more in acetic acid, lactic acid, acetone acid and the formic acid.In one embodiment, acid can through be selected from by ¹³C, ¹⁵N, ¹H, ²H, ³¹P, ¹⁹F with ²⁹One or more isotopes of the group that Si forms substitute and strengthen through isotope at one of which or an above atom site.According on the other hand, said second material can comprise sodium, for example is sodium hydroxide and/or sodium bicarbonate form.

According to others, said first material can be solution under STP, and said method can further comprise said first material and second material mixing to form second solution.In another embodiment, method as indicated above is provided, wherein said first material is a solid under STP, and said method further comprises said first material and second material mixing to form solution.In another embodiment, said method can further comprise said first material and second material mixing to form suspension.In one embodiment, said first material is a solid under STP, and said method can further comprise said first material and second material mixing to form colloid.In another embodiment, said first material can be solid under STP, and said method can further comprise said first material and second material mixing to form emulsion.In an embodiment again, said first material can be solid under STP, and said method can further comprise said first material and second material mixing to form composite.In another embodiment, said method can comprise that said first material is encapsulated in capsule to be sealed in the medium.Said capsule envelope medium can be porous.

According on the other hand, said method can further comprise first material that is the hyperpolarization state is stored in the transfer of cryogenic thermostat, and will be stored in said first transport of materials in the transfer of cryogenic thermostat to the site away from its hyperpolarization position.If desired, can be with the position of said first transport of materials to the fringing field that is positioned at the MR system.Said method can comprise subsequently that the temperature that makes said first material is from being lower than T _MinFirst temperature be increased to and be higher than T _MinSecond temperature.Can be subsequently with the mixing arrangement of first material arrangements in the fringing field that is arranged in the MR system.Can make first material and second material at mixing arrangement internal reaction (for example, with chemical mode) subsequently.Preferably, before carrying out the operation of MR system, the magnet of transfer vessel is closed.Can implement above-mentioned steps, no matter the initial mechanism that is used to make the first material hyperpolarization how.According to another embodiment, said first material is partially or completely through deuterate.

According to another embodiment, method as indicated above is provided, but said method further comprise make said first material temperature from being lower than T _MinFirst temperature be increased to and be higher than T _MinSecond temperature, make said first material be arranged in the transfer of cryogenic thermostat simultaneously or it be directed to transfer vessel.If desired, can subsequently said first material be directed in the transfer vessel, wherein said transfer vessel through adjust and configuration so that under the temperature of magnetic field that said first material remains in raising and the fusing point that is lower than said first material.For example, said transfer vessel can comprise magnet and can be at least in transfer vessel part keep the temperature of said first material by means of dry ice.According on the other hand, said method can further comprise said first material and second material mixing to form mixture.The magnetic field that blend step can be included in raising exists makes said first material melt down.Blend step can be when being directed to said first material in the transfer vessel, when said first material is arranged in transfer vessel or taking place when being arranged in another container of fringing field of MR system.First material and second material can be at the transfer vessel internal reactions.

The present invention also is provided for making the system of hyperpolarization material.Said system comprises and being used for treating the member of polar first material delivery to the polairzed area, being used for making when the polairzed area member that the polarization of at least one nuclear that said first material contained increases and being used for the polarization transfer of the increase of said at least one the nuclear member to another nuclear of said first material.If desired; Said first material can comprise methyl rotor group; And can be by being used for increasing the polarization that polar member increases at least one proton of methyl rotor group, and can be by transfer component with the polarization transfer of the increase of said at least one proton another nuclear in said first material.Said first material was preferably disposed paramagnetic agent and polarization agent in fact before polarization.

According to said system on the other hand, the member that is used for shifting can comprise and be used for guiding the zone of passing the magnetic field reduction to move on to the member of another nuclear to the second position from said at least one consideration convey of said first material to promote polarization from the polairzed area said first material.The member that is used to guide can be through adjusting and be configured to through greater than T ₂But less than T ₁Time period said first material shifted from the polarization environment pass zone that magnetic field reduces to the second position.If desired, the member that is used to guide preferably through adjust and be configured to (for example) less than 1.0 seconds, less than 0.1 second, less than 0.01 second in or in about 0.001 second, said first material shifted from the polarization environment and passes zone that magnetic field reduces to the second position.

According to more on the one hand, the said second position can comprise the low temperature environment with magnetic field.For example, the said second position can comprise the transfer of cryogenic thermostat that contains magnet, and wherein said magnet applies magnetic field to said first material under low temperature.Preferably, said first material is solid-state after polarization and through make said first material quicken it is directed to the said second position with fluid pressure.In one embodiment, through with Compressed Gas to surpass 10m/s, surpass 100m/s, to surpass the speed of 1000m/s or as required the guiding of first material is passed conduit and it is directed to the said second position.Compressed Gas can comprise helium, and can comprise ³He.As another instance, the said second position can comprise the melting vessel that is used to melt said first material.In one embodiment, the zone of said magnetic field reduction comprises magnetic shield so that the magnetic field intensity in the zone that magnetic field reduces is reduced to the value less than the earth background field.On the other hand, said system can further comprise the member (for example resistance heater) that is used for when the polarization environment, heating said first material.Said heater preferably makes the temperature of said first material from being lower than the T of first material ₁Temperature (T during the experience minima _Min) be increased to the T that is higher than first material ₁Temperature (T during the experience minima _Min) second temperature and said first material melted in fact or distil.According to another aspect, said first material can be the high surface powder type before polarization.In addition; The initial technology that is selected from by the following group that forms capable of using of the nuclear of said first material polarizes: (i) dynamical nuclear polarization; (ii) nuclear Overhauser effect; The (ii) polarization of para-hydrogen induced (iii) makes proton be exposed to the hyperpolarization nuclear of hyperpolarized gas in advance, (iv) makes said first material be exposed to powerful environment and its combination.

The present invention further provides the beneficial agent that comprises the material with at least one methyl, and wherein the nuclear of the carbon in the methyl is solid-state through adjusting and being configured in the outside of polarization cryostat through hyperpolarization and wherein said beneficial agent.Said beneficial agent can be made according to the arbitrary teaching among this paper.

The present invention further provides the method for carrying out the NMR spectral method.Said method comprises to be introduced the hyperpolarization material of making according to the arbitrary teaching among this paper in the target area, and the electromagnetic energy burst transmissions is composed to excite hyperpolarization capsule closure material and to receive NMR from the target area in the target area.Can analyze the NMR spectrum of sample in vitro or in vivo.According on the other hand, another method is provided, it comprises making according to the arbitrary teaching among this paper and is suitable for metabolic material hyperpolarization in bioprocess, and said hyperpolarization material is introduced in the target area; With the metabolic NMR data or the MR image that receive the said hyperpolarization material of indication.

To incorporate in this description and constitute its a part of accompanying drawing and included with graphic extension and the further understanding to institute's revealing method and system is provided.Said accompanying drawing comes together to explain principle of the present invention together with explanation.

Description of drawings

Fig. 1 illustrates for some kinds of different freezing 1- ¹³C enrichment acetic acid through protonated and nuclear polarization the die-away time (" T of deuterate sample in different magnetic field ₁") to temperature.

Fig. 2 illustrates the sketch map according to exemplary methods and the system of announcement embodiment.

The specific embodiment

To at length touch upon the now preferred embodiment of the present invention of the embodiment that discloses, the example is illustrated in the accompanying drawing.With the method and the corresponding step that combine the detailed description of said system is described the embodiment that discloses.

An object of the present invention is to provide exemplary methods, endorsing through hyperpolarization in the various thus molecules do not need to add (or use) toxicity catalyst (for example TA/EPA or other catalyst) or any polarization agent (no matter whether being toxic).According to preferred embodiment, the nuclear in the molecule can make its reaction have having of importance biology with formation through hyperpolarization subsequently ¹³The molecule of C for example is stored in acetate and pyruvate in the solution.

According to preferred embodiment especially, the sodium acetate that comprises hyperpolarization nuclear can be provided.Sodium acetate can be used as reporter molecule and in metabolic process, plays particular importance.Although sodium acetate is not the substrate of in blood, finding with higher level usually, it is easy to absorb and activate into acetyl group-coenzyme A.Acetyl group-coenzyme A circulates oxidized and formation carbon dioxide (C0 through TCA in mitochondrion ₂).In the oxidizing process of acetyl group-coenzyme A, produce NADH, it drives oxidative phosphorylation, the reduction and 0 of oxygen workload (workload) ₂Consume and the flux through TCA circulation acetyl group-coenzyme A is closely connected.Therefore, the needed metabolism of measurement report cardiac function of TCA circulation flux.

According to an exemplary embodiment, can produce the method that is used to make the sodium acetate solution that comprises hyperpolarization nuclear.This can make acetic acid and reaction of sodium bicarbonate reach to produce sodium acetate, water and carbon dioxide through (for example), and the nuclear in the wherein at least a predecessor is through hyperpolarization.Therefore, said reaction produces naturally when randomly making up with buffer, saline or other chemicals and to be fit in vivo to use as tracer and/or as the mixture (for example solution) in the source of metabolic information.Can be in addition or another be chosen as and use for example other acid such as lactic acid, acetone acid and formic acid.

The storage of polarization material and transfer:

Different with radioactive indicator, comprise characteristic nuclear polarization (T die-away time of the material of hyperpolarization nuclear ₁) change with its surrounding.Temperature, magnetic field and the physical state of material (liquid, solid, gas etc.) play an important role in all before the inductive nuclear polarization of decision is decaying to thermal balance, will lasting long.Under appropraite condition, can make T ₁Quite long.Making long die-away time is becoming possibility with HP material (that is the material that, comprises hyperpolarization nuclear) than the interior transportation of big distance.Therefore, the HP material can be supplied as consumable goods subsequently, settles the needs of polarizer and has reduced cost burden in its place thereby eliminated the user.

Remove temperature and outside the venue, the physical state of material and chemical composition also influence its nuclear polarization die-away time.The applicant measured the wide region temperature with in the T of acetic acid and sodium acetate ₁The applicant finds, in the wide region temperature (for example, 4K is to 300K), and the T of the hyperpolarization nuclear in the sodium acetate ₁Very short.This time is too short so that can not the hyperpolarization sodium acetate be transported arbitrary appropriate distance in the reasonable magnetic field at any type under the polar situation of not serious loss.Yet, the T of acetic acid (through deuterate) under T＜15K and in moderate magnetic field (usually, B approximates 0.1T) ₁Can be very long.This discovery is allowed with the big distance of HP acetic acid (that is the acetic acid that, comprises hyperpolarization nuclear) transportation and as consumable materials supply.Since need as reagent in vivo be sodium acetate but not acetic acid, so before being about to use, acetic acid is being changed into sodium acetate.

DNP method mentioned above not too is applicable to the long period transportation or the storage of hyperpolarization material.A reason that causes this situation is that the TA/EPA that is present in the freezing HP material shortens the T when being solid-state ₁Can't remove TA/EPA material not being fused under its liquid situation.Yet, in the material that is in a liquid state ¹³The T of C ₁Be generally about 10-60 second.From this reason, utilize the longer-term storage and/or the transportation and infeasible of the material of DNP hyperpolarization.Therefore, the DNP polarizer is settled very near the NMR/MRI system of the HP material that is used to analyze its generation usually.

Polarizer is placed near the NMR/MRI system because of a plurality of former thereby existing problems.At first, the expensive of these machines applied high cost burden to the terminal use aspect two of capital equipment costs and administrative expenses.In addition, the limited payload measurability of DNP machine means that time per unit only can carry out minority scanning.This has limited again and can use the diagnostic message of utilizing the polar HP material of DNP technology to obtain.The end product that will be liquid form is transported to also elapsed time of patient from the DNP polarizer, and this makes and is not useable for observing desired metabolic process subsequently.

Therefore, another object of the present invention is set forth the method and system that is used to store and/or transport the HP material.According to preferred embodiment, be provided for storing and/or the method and system of transporting material, said material can be used as predecessor in the chemical reaction comprises hyperpolarization nuclear with manufacturing the material with importance biology (for example, solution).The present invention allows that transportation is more remote, and said thus HP material can be used as in the material the consumed supply of primary importance manufacturing and is transported to the terminal use.

Take out the HP material from cryostat

Many molecules with importance biology contain methyl.Said molecule comprises sodium acetate, Sodium Pyruvate and other.The existence of methyl has profound influence for the processing of HP material.As in Fig. 1, finding out the T of acetic acid ₁Under far below its fusing point, has minima.The position of minima has field dependence slightly.T ₁Minima be to be attached to three of methyl carbon ¹The result of H nuclear rotation.These protons even under low temperature, also continue rotation cause formerly should having very long T ₁Near nuclear on the scene/temperature conditions under relaxation.

Because said minima, low temperature hyperpolarization methods up to now depend on the polarization of heat protocol during taking out from the polarization environment, to preserve various materials very fast.Usually, this relates to makes material in the presence of magnetic field, be exposed to superheated water or methanol so that sample＜＜T ₁Time in reach temperature far above minima.

This approach requires the amount of material to keep less, and it can be by heating apace thus.It means that also polarizer must be very near the NMR/MRI system that is used to analyze.This is extremely unfavorable for the limited many customer sites in space.In addition, when utilizing DNP to make the material hyperpolarization, must make a certain minimum range of DNP device distance objective device (NMR/MRI system).

As indicated above, many metabolism substrates contain methyl, and it is applying T under the temperature between polarization temperature and the fusion temperature ₁Minima.The applicant finds, but still under the temperature far below the fusing of material or sublimation temperature far above minima, and T ₁Long enough once more, thus make that short-term storage/transportation is feasible.This makes places the polarizer transfer of cryogenic thermostat of polarization material (and/or contain) to such an extent that become possibility away from the MR magnet.Suitably utilize this discovery need be with the temperature of polarization material much smaller than relaxation time T ₁Inherent this process of time during any point from changing to far above minima far below minima, and do not make material fusing or distillation.After the material fusing, its T ₁Become very short and it must use immediately.

The applicant finds to have the form (for example powder or sinter) of high surface and volume ratio through treating the material configuration one-tenth of hyperpolarization, can make the thermal relaxation time of material become very short.This allows and very rapidly regulates its temperature.This has following remarkable advantage: make that material can be from longer-term storage/(for example transport needed extremely low temperature; T＜10K) be heated to be suitable for the short-term transportation more moderate temperature (for example; T approximates 200K) and do not melt and/or excessive loss polarization, said polarization loss can be owing to the short T in the temperature curve somewhere of target material ₁And take place.According to some preferred embodiment, can be in the presence of magnetic field increase with the temperature that the speed of falling to the polarization loss of the nuclear in first material makes the hyperpolarization material of giving less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 5%.

The advantage for preparing polarization material in this way is, it can use the cryogenic material (for example, liquid nitrogen or dry ice) of easy acquisition in low relatively magnetic field, to transport than short distance (for example, from the part in user site to another part) subsequently.Another advantage is that the fusing time of material reduces and shortens along with the temperature difference between its starting point and fusion temperature.

To at room temperature become the high surface powder simpler relatively for solid material configuration.For example, if desired, capable of usingly know technology (for example ball milling) particle diameter of solid material is narrowed down to less than one micron.When the material of treating powdered at room temperature is liquid, must use different approaches.Ball milling is unavailable for many frozen liqs, and this is can make particles fuse because grind heat.The applicant has developed the method for the freezing powder of high surface that produces various materials, and said various materials are liquid under the arm's length standard temperature and pressure, and is suitable for the metabolism substrate that HP MR studies purpose inherently or owing to chemical reaction produces.Proper method is set forth in (for example) applicant's No. the 12/193rd, 536, the patent application of 18 days Augusts in 2008 applications.Preceding text mention that patent application case also discloses various other mixture (for example, colloid, suspension etc.) that can reach according to the present invention.

Quantum relaxation switch " QRS " method

Up to now, it is debatable using " brute force " environment in the non-pneumatic material, to produce high-level nuclear polarization always, this be because under the described conditions relaxation times of examining of great majority very long.The applicant finds, becomes high surface powder and powder surface is exposed to through treating polar material configuration ³He can shorten the magnetic relaxation time greatly and make its suitable commercial scale manufacturing.The applicant further finds, can be exposed to through making material ⁴He removes from material surface ³He.This increases the T of material greatly ₁Thereby, make it can be heated to room temperature and can excessive loss polarization.After material returns to room temperature, the nuclear in the material become " hyperpolarization ".Mentioned like preceding text, that is to say that the nuclear polarization of some nuclears in the material is higher than person in thermal balance originally far away.The material that comprises " hyperpolarization " nuclear can be used for multiple NMR/MRI scheme now.The most significantly, material oneself itself can be used as in vivo MR material, or it can be used as predecessor and another material reacts to form the 3rd material that itself can be used as the NMR/MRI material.

United States Patent (USP) the 6th, 651, No. 459 (it is incorporated herein by reference in full) set forth the technology that produces hyperpolarized gas (that is, being the material of gas under standard conditions).This can implement via following example steps:

1) gas configuration is become high surface powder or sinter.As the exemplary limiting examples, this can analyse or or more advantageously implement as high surface " snow " through material is frozen on the aeroge surface.

2) gas cooled is arrived " brute force " (extremely low temperature, high magnetic field) condition, wherein the balance nuclear polarization is very high.

3) frozen gas is exposed to ³The overlying strata of He.Except that the thermal relaxation path is provided, ³The He layer relaxes towards thermal balance in order to make the nuclear magnetism that is arranged in the top layer of frozen gas effectively, its under " brute force " condition by high degree of polarization.On this meaning, ³The peculiar property of He is used as relaxation agent so that nuclear ralaxation accelerates to high polarized state.

4) frozen gas is exposed to ⁴The overlying strata of He. ⁴The He layer is in order to remove from the surface of frozen gas effectively ³He.This effectively isolated nuclei and make it can heat back room temperature and can excessive loss polarization.

The preceding text process is called " quantum relaxation switch " (QRS); This is because it describes a kind of technology; Can " connect " thus and " cut-out " powerful environment in effective nuclear ralaxation producing high degree of polarization nuclear, said high degree of polarization is endorsed and is heated to room temperature and is used for HP precursor material or the HP material that multiple NMR/MRI uses with generation.Importantly, it should be noted that said process need not added any catalyst and said powerful environment can reach highly aseptic.

The applicant finds, can expand said QRS process and operate with the material to wide region, rather than only be the material of gas under standard conditions.This needs to treat that polar material configuration becomes high surface.The applicant further finds, can be with the liquid freezing of wide region and powdered so that its surface area and volume ratio are very high.Specifically, make behind chemical reaction that to be suitable for injection be preferred with the liquid such as for example acetic acid of the metabolism substrate solution of NMR/MRI scheme in vivo.

Each discovery mentioned above is constructed as follows method and system: it can become the freezing powder of high surface with various material configuration fully; Thereby in that being exposed to, material do not make the material polarization under the situation of catalyst; Take out polarization material from low-temperature environment; Its hyperpolarization that becomes (HP) thus, and with said hyperpolarization transport of materials to the terminal use site.It should be understood that in this article and mention that " hyperpolarization material " desire refers to comprise the material of hyperpolarization nuclear.If desired, can make the reaction of said hyperpolarization material and other material can be used for the 3rd HP material that MRI/NMR uses (for example, in vivo MRI uses) with formation.According to preferred embodiment, use to contain the material that is useful on the target molecule that MRI uses biology.Following instance part is based on experience and partly based on insight.

Instance 1:

Through being introduced to be stored among the LN2 in the pulverizing form droplet, deuterate acetic acid make it be frozen into the high surface granule.The surface area of measuring granule through BET is about 5m ²/ g.Granule is placed the sample chamber of dilution refrigeration device, and in the presence of 10T magnetic field, be cooled to T＜100mK.Will ³He adds in the sample chamber to quicken magnetic relaxation.After making sample polarization (said process NMR capable of using monitors), will ⁴He adds in the sample chamber to remove from specimen surface ³He.Sample is heated to T to be approximated 5K and removes helium.The chamber of granule from the polarization cryostat removed, remain in simultaneously under the temperature of T＜10K and in the magnetic field greater than 0.1 tesla.Granule is transferred in the transfer of cryogenic thermostat, wherein kept similarly field/temperature conditions.After the transportation, through (for example) granule is immersed in and makes its temperature be warmed up to T rapidly in the liquid nitrogen to approximate 77K from T＜10K.Can remove and use little magnetic field and suitable cryogenic material to take near the MR system from the transfer of cryogenic thermostat granule subsequently to keep polarization.Can it be melted to produce the hyperpolarization mixture fast through granule is existed in magnetic field, for example be hyperpolarization sodium acetate solution (that is, comprising the sodium acetate solution that hyperpolarization is examined) form.

If desired, when using predecessor to make the hyperpolarization mixture, can use the stray magnetic field of MR system to keep the magnetic field in the hyperpolarization predecessor scope.For example, as illustrating among Fig. 2, can hyperpolarization predecessor (acid or the alkali that for example comprise hyperpolarization nuclear) be transferred to the transfer vessel from polarization cryostat (if nearby) (or transfer of cryogenic thermostat).The temperature that can make the hyperpolarization predecessor subsequently is from being lower than the T of first material ₁First temperature of the temperature during the experience minima is brought up to the T that is higher than first material ₁Second temperature of the temperature during the experience minima.Preferably, the temperature that makes the hyperpolarization predecessor is from being lower than the T of first material in fact ₁First temperature of the temperature during the experience minima is increased to the T that is higher than first material in fact ₁Second temperature (for example, from being lower than about 10K) of the temperature during the experience minima to about 200K.This can be immersed in predecessor in the liquid coolant (for example liquid argon, nitrogen, xenon or krypton) through (for example) reaches, the boiling point of said cryogen far above ¹³The T of C ₁Temperature when being in minima.Perhaps, predecessor can through make be heated to about 200K gas in its surface square tube come the heating.

As illustrating among Fig. 2, the material that is formatted into high surface area forms is polarized in cryostat 1.Preferably, make material between between about 1mK and the 100mk, more preferably under the temperature between about 10mK and the about 40mK, polarize.The temperature of material is increased, thereby reach hyperpolarization (that is, polarization is higher than the polarization when generally being in thermal balance under this state).Take out material subsequently and be stored in the transfer of cryogenic thermostat 2, said transfer of cryogenic thermostat 2 keeps certain temperature and magnetic field environment so that the nuclear polarization depletion of material is slowed down.Can this hyperpolarization material be transported to warehouse or terminal location, for example hospital via transfer of cryogenic thermostat 2 subsequently.Subsequently the hyperpolarization material is taken out from transfer of cryogenic thermostat 2 and place interim cryostat or transfer vessel 3, it remains on the higher temperature that is suitable for the short-term transportation with said hyperpolarization material and than under the downfield.With before the hyperpolarization material transfer is in the transfer vessel 3, during or afterwards, its temperature is raise surpasses the T of material ₁Temperature when being in minima.

For example, said temperature increase is preferably less than 30 seconds, 20 seconds, 10 seconds or most preferably carry out in 5 seconds long time periods.Preferably, the applied field of transfer vessel 3 is no more than 500 Gausses (Gauss), but its safety area is contiguous to the NMR/MRI system thus.Subsequently said hyperpolarization material is discharged the entering mixing arrangement 4 from transfer vessel 3, in mixing arrangement 4, convert it into and preferably be suitable for the in vivo mixture (for example solution) of injection.Hyperpolarised solution is expelled among the patient 6 via aseptic pipeline 5.Use NMR/MRI system 7 to implement various NMR/MRI schemes subsequently.

Transfer vessel 3 comprises the compartment 8 that is used to receive the hyperpolarization precursor material, and comprises the magnet 9 that is used for during transfer process, keeping the magnetic field in the material ranges, for example electromagnet or permanent magnet.Preferably, mixing arrangement 4 and transfer vessel 3 are arranged in the stray magnetic field 10 of MR system 7.It should be noted that the field wire that illustrates only plans graphic extension.Advantageously, this allows that the hyperpolarization material is extremely melting near MR system place, and saving time thus is delivered to individuality with gained solution, and polarization will decay during this period.As further illustrating among Fig. 2, polarization cryostat 1 comprises the magnet 11 that is used for to its applied field, be used to contain and remain hyperpolarization container of material and the material temperature that is used to raise to promote the thermal source of hyperpolarization.Fig. 2 also illustrates the following fact: polarization cryostat 1 with ³14 draws of He source ⁴He source 15 operationally is communicated with.Fig. 2 also illustrates second thermal source 16, just, can be used for the hyperpolarization material is experienced minimum T from being lower than the hyperpolarization material ₁The temperature of temperature be heated to the material source of higher temperature.Fig. 2 also illustrates, and system 7 comprises transmission RF coil 17, detector 18 (for example receiving coil array and supporting hardware) and is used for receiving and handling the data computing machine terminal/processor 19 that receives.

In a preferred embodiment, magnet 9 is electromagnets.This allows that optionally the operation of MR system is disturbed in case spline is moved the field of container 3 in the magnetic field of passivation transfer vessel 3.Perhaps, can said field be shielded so that minimize interference fully.If desired, the hyperpolarization predecessor that is used to make the hyperpolarization mixture can relatively extremely made near MR system place is on-the-spot.

The replacement scheme of relaxation agent

A kind of replacement scheme of outside relaxation agent or polarization agent (person for example mentioned above) is directly to make the material polarization that contains the nuclear that under high B/T condition, has quick relaxation rate inherently.Said nuclear is uncommon, and this is because under these conditions, and is as indicated above, T ₁Usually very long and can be the thoughtful several months of approximate number under extremely low temperature for the temperature that is lower than 100mK.Yet, be tested and appraised the quick relaxation nuclear of one or more classifications, in the rationally short time period, under the situation of the catalyst of any kind of that need not mix or outside agent, under high B/T condition, producing high polarization becomes possibility.

Be low to moderate the quick proton nuclei relaxation rate of observing the molecule (for example potassium acetate) that contains methyl rotor group under the 10K.It is believed that the uncommon quick relaxation rate in the proton is CH ₃The result of quantum tunneling between the rotation attitude of group, and at many CH that contain ₃Observe in the molecule of group.Said tunnelling is relatively freely to be caused around its axis of symmetry rotation by methyl proton.The obstruction potential energy (hindering potential) of rotation is to be caused by the intermolecular and intramolecular interaction between methyl proton and its environment.Therefore, can the methyl rotor be specifically described as and have the three-dimensional quantization harmonic oscillator that depends on the branch subenvironment and the obstruction potential energy of the details that is solid-state crystal structure.

When the obstruction potential energy that separates methyl proton was high, the proton rotor was positioned at the fixed position.Rotor has three degeneracy positions.When the obstruction gesture was low, the quantum tunneling between these positions became possibility.This makes the degeneracy division, exists single ground state (being labeled as A usually) and two excited state (to be labeled as E usually thus _aAnd E _b), it is corresponding to clockwise direction or rotation counterclockwise.(usually, under the T＜10K), this moment, the methyl rotor was in its ground state, and the quantum tunneling between A and E attitude is to be labeled as ω in enough low temperature _0TFixed frequency carry out.

Observe solid ³Quantum tunneling in the He layer is non-temperature dependency effect, and it still continues and cause solid being low to moderate under any low temperature ³Relaxation rate relatively fast among the He; ³Having quantum tunneling among the He is the basis that is set forth in the method in 6,651,459.Similarly, CH ₃Quantum tunneling between group rotation attitude reduces the relaxation rate of methyl proton, and its expection meeting originally becomes extremely high with T → 0.Under the low temperature limit, the T of methyl proton ₁Relaxation time is determined by following formula:

${T_1}^{-1}=C_{\mathrm{EE}}\underset{n=1}{\overset{2}{\mathrm{\&Sigma;}}}\frac{{\mathrm{<figure-callout\; id="2"\; label="n"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">n</figure-callout>}}^2{{\mathrm{\&tau;}}_{\mathrm{<figure-callout\; id="2"\; label="c"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">c</figure-callout>}}}^2}{1+{{\mathrm{\&omega;}}_{0\mathrm{<figure-callout\; id="2"\; label="T"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">T</figure-callout>}}}^2{{\mathrm{\&tau;}}_{\mathrm{<figure-callout\; id="2"\; label="c"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">c</figure-callout>}}}^2}$

τ wherein _c=correlation time and C _EE=constant.This formula demonstration, under the low temperature limit, T ₁Be constant, this is because ω _0TDo not rely on surrounding magnetic field or temperature.

Therefore, under enough low temperatures and for ω _0T＞ω _L(for proton, ω _L=Larmor frequency (Larmor frequency)=42.6MHz/ tesla) magnetic field, the T of proton in the methyl rotor ₁Neither temperature dependent does not rely on the field yet.Itself and the T that does not show the molecule of quantum tunneling ₁Very different, wherein expect the T of said molecule ₁Can in this scope, reduce with temperature and be the index increase.The wonderful result of this situation is CH ₃The saturated polarization of the proton in the group even under high B/T condition, also can produce fast.This is as CH ₃The result of the non-temperature dependency quantum tunneling of proton in the group and taking place, and for example do not add polarization agent or outside relaxation agent of adding such as triphenylmethyl radical.

Being used in vivo, many target molecules of MR contain methyl.These especially comprise (for example) acetate and pyruvate.In other molecule, methyl can be included in through well-known chemical method in the industry, so that at least one or an above methyl can be attached to molecule.

One aspect of the present invention relates to one group of nuclear making in the molecule (CH for example ₃Proton in the group) method of quick saturated polarization.Directly come polarized nucleus than using outside relaxation agent or polarization agent to have many advantages to target molecule.At first, as indicated above, many relaxation agent and polarization agent have toxicity.It is much easier that material processed becomes, and this is because this does not relate to the suitable dispersion of outside agent.Because use ³He is as effective relaxation agent, so the material that also do not need a person with the qualifications of a general is configured to the high surface form.

For MR in vivo, methyl proton itself has very little interest, this be because at room temperature in solution its relaxation rate too quick usually.What have big interest is near methyl and carbonyl carbon.These often have long T ₁(especially carbonyl).In addition, compare with proton, the chemical shift of carbon is much wide, and this makes it in spectral method research, be easier to differentiate.From this reason, another aspect of the present invention relates to the polar method of effective transfer between the nuclear in molecule; Specifically,, study near methyl and/or carbonyl carbon from methyl proton so that it is used for MR.

Exist in the industry and shift polar method between the some kinds of nuclears in molecule.For example, can use pulse train between nuclear, to shift polarization.Yet these are not suitable for the bi-directional scaling manufacturing of hyperpolarization material, and this is that said resonator only can be handled small quantity of material usually at every turn because it needs magnet and NMR resonator highly uniformly.A kind of method that is easier to and has more scalability is to make material be exposed to low.Polarization can be shifted between the nuclear in molecule through making molecule be exposed to downfield.This is called low heat and mixes (" LFTM ").In the method, molecule is exposed to enough low magnetic field, so that near the given localized dipole fields of examining another of checking surpasses surround.In these cases, " spin temperature " of two nuclears will be to equal following rate equation:

$\frac{1}{\mathrm{\&tau;}}=\frac{1}{{\mathrm{<figure-callout\; id="2"\; label="T"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">T</figure-callout>}}_2}\exp \frac{{({\mathrm{\&gamma;}}_1-{\mathrm{\&gamma;}}_2)}^2{B}^2}{{({\mathrm{\&gamma;}}_1+{\mathrm{\&gamma;}}_2)}^2{{\mathrm{<figure-callout\; id="2"\; label="B\; L"\; filenames="HDA0000154950430000011.png"\; state="\{\{state\}\}">B</figure-callout>}}_L}^2}$

Wherein B is a surrounding magnetic field, B _LBe the localized dipole fields of 1 pair of nuclear 2 of nuclear, and γ _1,2It is respectively the gyromagnetic ratio of nuclear 1,2.For the contiguous nuclear in the molecule, B _LBe generally about 1-5G, so B also must be with quick transfer polarization on this order of magnitude.Find out easily, for B＜B _L, τ → T ₂T when solid-state ₂Be generally tens of approximately microseconds, therefore for B＜B _L, the polarization exchange takes place very fastly.

Used LFTM to produce the polarization material that is solid-state.For example, at United States Patent (USP) the 6th, 466, in No. 814, with solid 2-1 ^3C-2, two (the three deuterium acute pyogenic infection of nails bases)-1,1,3 of 2-, 3-four deuteriums are for propane-1, and 3-glycol sample is polarised under 6.65T and 2.5K ¹³The C thermodynamical equilibrium, this is to reach about 1 second through the stray magnetic field that it is repeated draw in and pull out polarized magnets and move about 70G to reach.These and the explanation of other instance can use a low hot mixing will polarize from proton translocation to for example ¹³Heteronuclears such as C.

Yet, making material be exposed to low and also can cause rapid depolarization, this is because T when solid-state ₁Usually with the surround strong variations.For example, at United States Patent (USP) the 6th, 466, in No. 814, use LFTM to make solid 2- ¹³C-2, two (the three deuterium acute pyogenic infection of nails bases)-1,1,3 of 2-, 3-four deuteriums are for propane-1, and the polarization of 3-glycol take out through pull it the polarization cryostat at the test rod end, and last dissolving is to form solution.With respect to ¹³C, the gained enhancer is about 12 through measuring in solution.Total potential gain or enhancer are for making an appointment with＞100, and therefore the inductive polarization loss under high B/T greater than 90% is fallen during taking out.

By convention, " enhancer " being regarded as is the ratio of the hyperpolarization NMR signal intensity (itself being defined as the integration of Fourier transformation line (Fourier Transform line)) of the molecule NMR signal intensity during divided by thermal balance.When measuring this amount in practice,, the hyperpolarization sample use radio-frequency tuner (rf tuning set) to collect a series of delay (Free Induction Delay) (" FID ") signals of freely inducing after being placed NMR magnet inside at once at a series of NMR impulse durations usually.After sample reaches thermal balance, repeat this test subsequently, put into practice purpose from all, it is about 5T ₁, or for example, for acetic acid, it is about 4-5 minute.Enhancer is the ratio of two kinds of FID signals.Should be appreciated that the rapid degree that enhancer will receive to measure sample at first naturally influences.Enhancer is that 12 (for example mentioned above) mean, and is 12 times that contain in the identical spectrometer without the signal intensity of the same solution that strengthens sample from the signal intensity of hyperpolarised solution.

From the reason that preceding text are discussed, most of hyperpolarization schemes depend on polarization material directly are dissolved in the polarization cryostat, so that material never is exposed to low.After being in a liquid state, can promptly remove outside agent, and the T of HP material ₁More insensitive to an outside relaxation agent and/or a variation.United States Patent (USP) the 7th, 102, the method for this incident is implemented in No. 354 elaborations, wherein makes material dissolves through injection hot water.

Yet as indicated above, the negativity result of this scheme is that the hyperpolarization material can not be stored the long period section or transportation is more remote; Except that rare gas, this only can realize under material can keep solid-state situation.Therefore, need be solid-state polarization material and the polar method of non-excessive loss from the taking-up of polarization cryostat in the industry.Hereinafter of the present invention sets forth how to reach this purpose.

According to an embodiment, in vivo MR application, the hyperpolarization material is can be with its form of in vivo introducing.Look application and material and decide, it can take the form of solution, suspension, colloid or other types of mixtures.Suspension can comprise the capsule envelope of the solid granule that is suspended in the liquid that can tolerate on the physiology or solid or liquid hyperpolarization material in addition.

United States Patent (USP) the 6th, 466 is set forth through the hyperpolarization solid being dissolved in the method for making HP solution in the liquid that can tolerate on the physiology with No. the 6th, 278,893, United States Patent (USP) for No. 814.But it is teaching use liquid and/or predissolve solution not.For many application, if the hyperpolarization material is liquid or is predissolve solution that it will be preponderated so under STP.A reason of this situation is that liquid can directly be granulated through it is for example splashed in the cryogenic liquid such as liquid nitrogen.With solid (especially powder solid) but granulate and can binding agent or other additive of its total payload of participant reduction hyperpolarization material in granule be mixed.In addition, liquid melts and mixes faster, during forming solution phase, preserves polarization thus better.United States Patent (USP) the 6th, 6466, No. 814 with No. the 6th, 278,893, United States Patent (USP) not teaching how to form suspension, colloid or other types of mixtures, also set forth how to make the polarization of capsule closure material.Another aspect of the present invention teaching is used the method for the mixture of these types of hyperpolarization material production.

Therefore, the present invention sets forth the method for making hyperpolarised solution with novel manner; In addition, the manufacturing of its teaching hyperpolarization suspension and/or other mixture.Institute's revealing method need not use adulterated catalyst, and this has eliminated the existence of genotoxic potential material and has allowed in addition material is taken out from polarizer with solid-state.If desired, but stored hyperpolarization material, thus its can through with said material dissolves be scattered in suitable liquid or liquid combination or solution in and using away from the site of polarization cryostat.

What therefore, the applicant had proposed not include in catalyst such as triphenylmethyl radical for example makes the polar method of material.Said method allows that material still takes out from the polarization environment with solid-state, and it can be in stored under the polar situation of excessive loss not thus.Said method allows that further the hyperpolarization material is forms such as solution, suspension, capsule envelope, uses in its MR research in vivo thus.

When will (for example examining by spin 1/2 ¹³C, ¹²⁹Xe, ¹⁵N, ¹H etc.) the spin assemblage of forming (spin ensemble) is when placing the external magnetic field, and the quantization magnetic moment of nuclear (m=± 1/2) makes said system have two kinds of possibility energy states with the interaction of field.Usually, be that " upwards (up) " (m=-1/2), is parallel or antiparallel with magnetic moment and the surrounding magnetic field that refers to nuclear with " (down) downwards " (m=1/2) with these status indications.

In non-zero magnetic field, " making progress " state is more low-yield arranging with " downwards " compared.From this reason, the spin colony that in thermodynamical equilibrium, is " making progress " state will be above " downwards " state.The nuclear spin that will be " making progress " state and the ratio that is the nuclear spin of " downwards " state are called " the Zeeman polarization (Zeeman polarization) " or " Boltzmann polarize (Boltzmann polarization) " of said system; For arbitrary temperature T, it can calculate by formula P=tanh μ B/kT, wherein the gyromagnetic ratio of μ=spin and k=Boltzmann constant (Boltzmann ' s constant)." hyperpolarization " as herein described is meant and produces the nuclear polarization that surpasses thermodynamical equilibrium.

Spin assemblage through " hyperpolarization " will be attempted the mechanical balance of relaxation backheat.Usually, relaxation and time are exponential relationship, the time constant of its generation " T that is called in the field of business ₁".In the NMR term, T ₁Be z component (that is M, of nuclear magnetisation _z, it is parallel with surrounding magnetic field) and the time constant recovered and set forth the interaction between spin assemblage and the lattice.Note T ₁Not only change, and change with temperature, field, molecular structure or combination that all are above-mentioned with nuclear type through hyperpolarization.

Another feature property time constant of NMR experiment is T ₂It formally is called the M of nuclear magnetisation _{X, y}The time constant that component (that is, vertical with surrounding magnetic field) recovers.More not formally, it is a time constant of setting forth spin-spin interaction, and usually with Fourier space (Fourier space) in the live width of NMR signal relevant.With T ₁The same, T ₂Also can change with temperature, field, molecular structure etc.It should be noted that when being solid T ₂All the time less than T ₁, and when being liquid, T ₂Approximate T ₁In low hot combined experiments, be polarized in and shift the time that is consumed between the nuclear and approximate T usually ₂The time that the polarization complete attenuation of lattice is consumed approximates T ₁Therefore, importantly, the time that the hyperpolarization material is exposed to downfield (mixing with another nuclear (the for example carbon of methyl nuclear) heat to allow the proton in the methyl) meets T ₂＞t＞T ₁

According to first exemplary embodiment, the method that is provided at first comprises the step that disposes material.Said material preferably contains and has at least one CH ₃The molecule of methyl and nonzero spin nuclear.Preferably, nuclear belongs to and under STP, has high T ₁Material.Said method randomly specifies the granulation of sample subsequently, is arranged in the inner high B/T environment of polarization cryostat and from wherein taking out so that can said sample be introduced apace.

How the applicant makes liquid splash into freezing and granulation with it among the LN2 through (for example) if formerly setting forth in the application case (for example, PCT/US2009/39696, on April 6th, 2009 filed an application).For example, utilized this to produce the freezing granule of glacial acetic acid.Similar procedure can be used for solution, emulsion, suspension etc.Also can gas be granulated; As the nonexcludability instance, this can be through freezingly implementing it to powder surface.

Having set forth the molecule that is used for MRI research that will at room temperature be liquid in the industry granulates.For example, United States Patent (USP) the 5th, 617, No. 859 elaborations are used can be polar through granulation liquid through standing the highfield.Yet said teaching does not disclose to be used the methyl rotor or makes one group of nuclear relaxation fast in high B/T environment based on the phenomenon of quantum tunneling.It is not set forth a consideration convey that uses low field will polarize from molecule yet and moves on to another nuclear.At last, its overrelaxation does not lose during granule is taken out from the polarization environment to avoid temperature/field of teaching control granule.Utilize these steps disclosed herein to make polar molecule, especially contain CH ₃The molecule of methyl, and it is at room temperature merged to form solution, suspension or other types of mixtures with fluid.

According on the other hand, said exemplary methods further provides to make and granule is exposed to high B/T environment (for example can use high field super magnet and low temperature cryostat to produce), and reaching the long enough time (especially is CH with at least a nuclear matter in material ₃Methyl proton in the group) produces the high level polarization in.Said method also provides granule from magnet High-Field regional guidance, so that be exposed to downfield (for example by Earth Week enveloping field supplier (about 0.5G)) or cask flask (for example Mumetal (mu-metal)) reaches blink.Said discharge method preferably uses helium to implement as propellant, and the speed of granule preferably makes the time t that is exposed to low meet T ₂＜t＜T ₁

The applicant finds that under some temperature, the relaxation time of containing the molecule of methyl can be very quick.If make molecule under said ambient conditions, continue to retain the long time, these temperature (are called T _Min) unpolarized path can be provided, and this can become more obvious in low.Therefore, said exemplary methods further provides randomly the temperature of control granule, with during being exposed to a low environment fully away from making its nuclear relaxation time temperature very fast.For example, can granule be heated to far above T _MinAnd guide from high B/T environment subsequently.

In another aspect, said method also can be provided at after high field magnet is discharged and make material still be solid-state.After being positioned at polarization cryostat outside, granule is remained under the uniform temperature so that the T of target heteronuclear ₁Has expected time length.For example, this can implement down and in the magnetic field (magnetic field that is for example provided by permanent magnet) greater than 0.1 tesla through granule being stored in 4K.Said hyperpolarization material subsequently can be immediately or sometime in the future/and the position uses; To form solution, suspension, colloid or other mixture, it can be used for producing image, kinetics flow-data, diffusion data, data perfusion, physiological data or metabolite data subsequently.Below the same part of other instance based on experience and part based on insight.

Instance 2

Through making liquid 1- ¹³The acetic acid of C labelling splashes in the liquid nitrogen (" LN2 ") and it is frozen into granule.The collection granule is also introduced in the high B/T environment (the for example low temperature environment in the ambient field of 8-10 tesla under about 150mK).Make it remain in the high B/T environment methyl (" CH in acetic acid ₃") in proton relaxation fully, this can use NMR or through measuring proton T under the described conditions in advance ₁Observe.Use the high pressure helium granule to be guided/ejects from high B/T environment subsequently through conduit.Should be appreciated that for example, refrigerated hydrogen granule is being introduced in the field in the fusion tokamak (fusion tokamak) with the speed of about 1000m/ second, the practice of quickening freezing of light is well-known usually.Along with granule is discharged from, it sends out and is sent to the extremely low field from polarization field, and polarizing thus flow to neighbouring from proton ¹³C labelling carbonyl.Granule is collected in the volume that is arranged in high B/T environmental externality, and wherein environment temperature/field the environment of granule can be controlled independently.As the nonexcludability instance, can volume be maintained at about under the 200K through using dry ice.Can use little permanent magnet to keep the field of granule.Under the described conditions, in the acetic acid ¹³The T of C ₁Be about several minutes; Its long enough makes can be with the transportation of polarization acetic acid than short distance.Subsequently can with granule be melted in the volume and make its with buffer solution reaction of heating to produce the sodium acetate solution of high degree of polarization.

Instance 3

Described in embodiment 1, make liquid 1- ¹³C acetic acid granule also is cooled to high B/T condition.Work as CH ₃When the proton in the group has polarized, granule is heated to above T _MinBut still far below its fusion temperature temperature of (the T fusing of acetic acid is about 17 ℃), simultaneously still in polarization field.Subsequently, can it guided/eject from the polarization cryostat, it can be used for stored or melt thirty years of age promptly using through collection thus.

Instance 4

Anhydrous 1-with powdered ¹³C labelling sodium acetate mixes with suitable solvent (for example through buffered water or saline) to be used in vivo MR application.Through (for example) solution is splashed among the LN2 subsequently and it is frozen into granule.Make granule be exposed to high B/T environment subsequently.Make it remain in the high B/T environment CH in sodium acetate ₃Proton in the group is relaxation fully.Use the high pressure helium that granule is guided/ejects from high B/T environment subsequently.Can granule be mixed with hot water or saline solution through (for example) subsequently and make its fusing, to produce the sodium acetate solution of high degree of polarization.

Instance 5

With pulverous anhydrous 1- ¹³The sodium acetate of C labelling mixes with the solvent (for example through buffered water or saline) that is suitable in vivo MR application.Subsequently solution is encapsulated in the thin polymer shell to form enough little indivedual beadlet to be used in vivo using.Said granule can be chosen wantonly through functionalized to produce the in vivo function of expectation; For example, be bonded to the in vivo structure of expectation, for example fibrid tumor or tumor.Remain in the high B/T environment CH in sodium acetate through functionalized capsule with optional ₃Proton in the group is relaxation fully.Use high-pressure helium that granule is guided/ejects from high B/T environment subsequently, and with the physiology on the solution that can tolerate mix to form the hyperpolarization suspension.

The present invention further provides a kind of method of the NMR of execution spectral method.Said method comprises to be introduced the hyperpolarization material of making according to the arbitrary teaching among this paper in the target area, with the electromagnetic energy burst transmissions in the target area exciting hyperpolarization capsule closure material, and receive the NMR spectrum from the target area.Therefore, the material that this paper provided can be used for analyzing in vitro or the NMR spectrum of sample in vivo.In addition,, might make according to the arbitrary teaching among this paper to be suitable for metabolic material hyperpolarization in bioprocess, said hyperpolarization material is introduced in the target area according on the other hand; And the metabolic NMR data or the MR image of the said hyperpolarization material of reception indication.Said technology can be used for diagnosing the existence of specific type of tissue, and described in No. the 12/193rd, 536, the patent application of filing an application on August 18th, 2008, the full text of said case is incorporated herein by reference.

The those skilled in the art should also be clear that; Proton in the methyl as described herein can polarize according to multiple technologies; For example (i) via quantum relaxation switch, (ii) dynamical nuclear polarization, (iii) nuclear Overhauser effect, (iv) para-hydrogen induced polarization, (v) make the nuclear of first material be exposed to hyperpolarized gas in advance hyperpolarization nuclear, (vi) make first material be exposed to powerful environment and its combination.

Dynamical nuclear polarization (" DNP ") is usually directed to polarization is transferred near nuclear spin from electron spin; Usually (but nonexcludability), use microwave exposure to realize via the saturated of electron resonance line.The instance of DNP comprises United States Patent (USP) the 6th, 008 in the patent documentation, and No. 644, the full text of said case is incorporated herein by reference.In the context of certain embodiments of the invention, for example, can use DNP to make the proton hyperpolarization in the methyl of material.

Nuclear Overhauser effect is usually directed to nuclear polarization is transferred near the nuclear spin of another group from one group of nuclear spin; Usually (but nonexcludability), saturated through first group of self-rotating nuclear resonance line.The instance of nuclear Overhauser effect is set forth in Si Qieliqiete (Schlichter) in the document, magnetic resonance principle (Principles of Magnetic Resonance), the 2nd edition; Springer Verlag (Springer Velas); Berlin (Berlin), 1978, it is incorporated herein by reference in full.In the context of certain embodiments of the invention, can be higher than common polarization through the polarization that makes the proton in the methyl and use nuclear Overhauser effect.

The polarization of para-hydrogen induced (" PHIP ") can be used for making the hydrogen atom hyperpolarization in the methyl.PHIP is usually directed to shift polarization via the catalytic hydrogenation of p-H2, and target nuclear is transferred in spin subsequently (spin-order) in order.The instance of PHIP comprises (for example) United States Patent (USP) the 6th, 574, No. 495 in the patent documentation, and the full text of said case is incorporated herein by reference.

Powerful hyperpolarization preferably uses quantum relaxation switch (being called " QRS " in this article) to can be used for making hydrogen atom (or other material) hyperpolarization in the methyl.As term in the industry, brute force is to instigate the material of treating hyperpolarization to be exposed to extremely low temperature, highfield condition.Material in " brute force " environment tends to nature and relaxes towards high nuclear polarization state.Yet under the situation of not using additional mechanism, it is oversize usually so that can't actually utilize to reach the time that hyperpolarization consumes.Through (for example using hyperpolarization promoter ³He), ³Quantum relaxation switch that He provides promote material under powerful condition relaxation with induced material hyperpolarization apace.Utilize subsequently and apply ⁴The hydrogen atom of He from methyl removes ³He is so that it can be heated to room temperature and non-excessive loss hyperpolarization.The instance of QRS comprises United States Patent (USP) the 6th, 651 in the patent documentation, and No. 459, the full text of said case is incorporated herein by reference.

Hydrogen atom in the methyl also can examine hyperpolarization through making it be exposed in advance the hyperpolarization of hyperpolarized gas.This can implement in every way, for example through first material being immersed in the hyperpolarization of liquefaction ¹²⁹Among the Xe, or through making polar gaseous xenon bubbling pass through material.Examining the instance that hyperpolarization shifts from gas in the patent documentation can be referring to United States Patent (USP) the 6th, 426, and No. 058, the full text of said case is incorporated herein by reference.

" overhauser effect " is considered to polarization from the electron transfer to nuclear.Further said like this paper, " nuclear Overhauser effect " is similar phenomenon, and just shifting is to examine another nuclear from one.Under each situation, polarization all is to shift (under " overhauser effect " situation, electronics-nuclear, under " nuclear Overhauser effect " situation, nuclear-nuclear) since one group of spin.Whether relative to each other whether said technology is capable of using applies radio frequency (" RF ") pulse to material, apply to depend on two groups of spins (that is, (i) electronics-nuclear or (ii) nuclear-nuclear) motion.

The inventive method of being shown provides good hyperpolarization material and its manufacturing approach with system among as indicated above and the figure.The full text of mentioned all patents, patent application case and list of references all is incorporated herein by reference among this paper.It will be apparent to those skilled in the art that, under the situation of the spirit of the embodiment that discloses and scope, can make various modifications and change the apparatus and method of announcement embodiment not deviating from.Therefore, the present invention plans to be included in modification and the change in disclosure of the present invention and the equivalent scope.

Claims (115)

1. method that is used to make the hyperpolarization material, it comprises:

A) provide and treat that polar first material, said first material comprise methyl rotor (methyl rotor) group;

B) polarization of at least one proton in the said methyl of said first material is increased;

C) with the polarization transfer of the said increase of said at least one proton in said first material to another nuclear.

2. method according to claim 1, wherein said first material is through using ¹²⁹Xe, ¹³C, ¹⁵N, ¹H, ²H, ³¹P, ¹⁹F with ²⁹An alternative one of which of among the Si at least one or an above atom site and strengthen through isotope.

3. method according to claim 1, wherein said first material had been disposed paramagnetic agent and polarization agent in fact before polarization.

4. method according to claim 1; Wherein said polarization step comprises is exposed to said first material to comprise following at least one polarization environment: the temperature that (i) reduces said first material; The magnetic field that (ii) makes said first material stand to increase, wherein said first material are exposed to said polarization environment is enough to for one section make at least one the proton polarization that is contained in said first material to reach the time of thermodynamical equilibrium.

5. method according to claim 1, wherein said first material is a gas under STP.

6. method according to claim 1, wherein said first material is a liquid under STP.

7. method according to claim 1, wherein said first material is a solid under STP.

8. method according to claim 4; It further comprises said first material is passed zone that magnetic field reduces to the second position from the guiding of said polarization environment, transfers to another nuclear after said polarization step, to promote polarization said at least one proton from said first material.

9. method according to claim 8, wherein with said first material through greater than T ₂But less than T ₁Time period shift from said polarization environment and pass zone that said magnetic field reduces to the said second position.

10. method according to claim 9 is wherein transferred to the said second position from said polarization environment with said first material in less than 1.0 seconds.

11. method according to claim 9 is wherein transferred to the said second position from said polarization environment with said first material in less than 0.1 second.

12. method according to claim 9 is wherein transferred to the said second position from said polarization environment with said first material in less than 0.01 second.

13. method according to claim 9 was wherein transferred to the said second position from said polarization environment with said first material in about 0.001 second.

14. method according to claim 4, the wherein said polarization time is enough to make the said proton polarization in the said methyl.

15. method according to claim 8, the wherein said second position comprises the low temperature environment with magnetic field.

16. method according to claim 15, the wherein said second position comprise the transfer of cryogenic thermostat that contains magnet, wherein said magnet applies magnetic field to said first material at low temperatures.

17. method according to claim 8, wherein said first material are solid-state after said polarization step and through make said first material quicken it is directed to the said second position with fluid pressure.

18. method according to claim 17 wherein is directed to the said second position through with Compressed Gas conduit being passed in said first material guiding with it.

19. method according to claim 18 is wherein passed said conduit with the speed that surpasses 10m/s with said first material guiding with said Compressed Gas.

20. method according to claim 18 is wherein passed said conduit with the speed that surpasses 100m/s with said first material guiding with said Compressed Gas.

21. method according to claim 18 is wherein passed said conduit with the speed that surpasses 1000m/s with said first material guiding with said Compressed Gas.

22. method according to claim 18, wherein said Compressed Gas comprises helium.

23. method according to claim 22, wherein said Compressed Gas comprises ³He.

24. method according to claim 8, the wherein said second position comprises the melting vessel that is used to melt said first material.

The intensity in magnetic field is reduced to the value less than the earth background field in the zone that said magnetic field reduces 25. method according to claim 8, the zone that wherein said magnetic field reduces comprise magnetic shield.

26. method according to claim 8, it further comprises when said first material is in said polarization environment heated said first material before discharging.

27. method according to claim 26, the wherein said step of heating make the temperature of said first material from being lower than the said T of said first material ₁Temperature (T during the experience minima _Min) be increased to the said T that is higher than said first material ₁Said temperature (T during the experience minima _Min) second temperature, and said first material melted in fact or distil.

28. a method that is used to make the hyperpolarization material, it comprises:

A) polar first material of treating that is the high surface powder type is provided;

B) in container, in the polarization environment, the polarization of at least one nuclear that is contained in said first material is increased: the temperature that (i) reduces said first material through carrying out following at least one; The magnetic field that (ii) makes said first material stand to increase, wherein said first material are exposed to said polarization environment is enough to for one section make at least one nuclear polarization that is contained in said first material to reach the time of thermodynamical equilibrium; With

C) with the polarization transfer of the said increase of said at least one nuclear in said first material to another nuclear, simultaneously will said first material from zone that the magnetic field reduction is passed in said polarization environment guiding to the second position.

29. method according to claim 28 wherein makes formative first material of said high surface be exposed to ³One period that is enough to make at least one nuclear polarization that is contained in the said material of He.

30. method according to claim 28 wherein exists ³He is exposed to said high surface first material after exposing ⁴He is said to remove ³He.

31. method according to claim 28 wherein is being exposed to ⁴After the He, said first material is heated and said first material is melted in fact or distil, thereby make nuclear in the said material hyperpolarization that becomes.

32. method according to claim 28, wherein heat make said first material temperature from being lower than the T of said first material ₁Temperature (T during the experience minima _Min) be increased to the said T that is higher than said first material ₁Said temperature (T during the experience minima _Min) second temperature, and said first material melted in fact or distil.

33. method according to claim 28 wherein remains in said material in the magnetic field during the said step of heating.

34. method according to claim 28, wherein with said first material greater than T ₂And less than T ₁Time in be directed to the second position from said polarization environment.

35. method according to claim 34, the wherein said second position comprises the low temperature environment with magnetic field.

36. method according to claim 35, the wherein said second position comprise the transfer of cryogenic thermostat that contains magnet, wherein said magnet applies magnetic field to said first material at low temperatures.

37. method according to claim 1; Wherein use the technology be selected from by the following group that forms to make said first material polarization: (i) dynamical nuclear polarization, (ii) nuclear Overhauser effect (Nuclear Overhauser effect), (ii) para-hydrogen induced polarization, (iii) make the said nuclear of said first material be exposed to hyperpolarized gas in advance hyperpolarization nuclear, (iv) make said first material be exposed to powerful environment and its combination.

38. a method that forms hyperpolarised solution, it comprises according to claim 1 makes the first material hyperpolarization that under STP, is liquid, and with the said first hyperpolarization material and second material mixing to form solution.

39., wherein make the reaction of said first material and said second material to form said solution according to the described method of claim 38.

40. according to the described method of claim 38, wherein said first material comprises that acid and said second material comprise alkali.

41. according to the described method of claim 38, wherein said first material comprises that alkali and said second material comprise acid.

42. according to the described method of claim 40, wherein said acid comprises acetic acid.

43. according to the described method of claim 40, wherein said acid comprises lactic acid.

44. according to the described method of claim 40, wherein said acid comprises acetone acid.

45. according to the described method of claim 40, wherein said acid comprises formic acid.

46. according to the described method of claim 40, wherein said acid one of which or above atom site through be selected from by ¹³C, ¹⁵N, ¹H, ²H, ³¹P, ¹⁹F with ²⁹One or more isotopes of the group that Si forms substitute and strengthen through isotope.

47. according to the described method of claim 40, wherein said second material comprises sodium.

48. according to the described method of claim 47, wherein said second material comprises sodium hydroxide.

49. according to the described method of claim 47, wherein said second material comprises sodium bicarbonate.

50. method according to claim 1, wherein said first material is a solution under STP, and said method further comprises and makes said first material and second material mixing to form second solution.

51. method according to claim 1, wherein said first material is a solid under STP, and said method further comprises and makes said first material and second material mixing to form solution.

52. method according to claim 1, wherein said first material is a solid under STP, and said method further comprises and makes said first material and second material mixing to form suspension.

53. method according to claim 1, wherein said first material is a solid under STP, and said method further comprises and makes said first material and second material mixing to form colloid.

54. method according to claim 1, wherein said first material is a solid under STP, and said method further comprises and makes said first material and second material mixing to form emulsion.

55. method according to claim 1, wherein said first material is a solid under STP, and said method further comprises and makes said first material and second material mixing to form composite.

56. method according to claim 1, it further comprises said first material is encapsulated in the capsule envelope medium.

57. according to the described method of claim 56, wherein said capsule envelope medium is porous.

58. method according to claim 16; It further comprises said first material that is the hyperpolarization state is stored in the said transfer of cryogenic thermostat, and will be stored in said first transport of materials in the said transfer of cryogenic thermostat to the place away from its hyperpolarization position.

59. according to the described method of claim 58, it further comprises the step of said first transport of materials to the position of the fringing field that is positioned at the MR system.

60. according to the described method of claim 59, its further comprise make said first material temperature from being lower than T _MinFirst temperature be increased to and be higher than T _MinSecond temperature.

61. according to the described method of claim 60, it further comprises the step that said first material is placed in the mixing arrangement of the said fringing field that is arranged in said MR system.

62. according to the described method of claim 61, wherein said first material and second material are at said mixing arrangement internal reaction.

63., wherein before carrying out the operation of MR system, the magnet of said transfer vessel is closed according to the described method of claim 62.

64. method according to claim 36; It further comprises said first material that is the hyperpolarization state is stored in the said transfer of cryogenic thermostat, and will be stored in said first transport of materials in the said transfer of cryogenic thermostat to the place away from its hyperpolarization position.

65. according to the described method of claim 64, it further comprises the step of said first transport of materials to the position of the fringing field that is positioned at the MR system.

66. according to the described method of claim 65, its further comprise make said first material temperature from being lower than T _MinFirst temperature be increased to and be higher than T _MinSecond temperature.

67. according to the described method of claim 66, it further comprises the step that said first material is placed in the mixing arrangement of the said fringing field that is arranged in said MR system.

68. according to the described method of claim 67, wherein said first material and second material are at said mixing arrangement internal reaction.

69., wherein before carrying out the operation of MR system, the magnet of said transfer vessel is closed according to the described method of claim 68.

70. according to the described method of claim 58, its further comprise make said first material temperature from being lower than T _MinFirst temperature be increased to and be higher than T _MinSecond temperature, make said first material be arranged in said transfer of cryogenic thermostat simultaneously or be directed into transfer vessel simultaneously.

71. according to the described method of claim 70; It further comprises said first material is directed in the said transfer vessel, wherein said transfer vessel through adjust and configuration so that said first material remain under the temperature of magnetic field of increasing and the fusing point that is lower than said first material.

72. according to the described method of claim 71, wherein said transfer vessel comprises magnet and in said transfer vessel, at least partly keeps the said temperature of said first material by means of dry ice.

73. according to the described method of claim 71, it further comprises makes said first material and second material mixing to form mixture.

74. according to the described method of claim 73, wherein said blend step is included in and makes said first material fusing under the magnetic field existence of increasing.

75. according to the described method of claim 73, wherein said blend step is when said first material is arranged in said transfer vessel or takes place when being arranged in another container of said fringing field of said MR system.

76. according to the described method of claim 73, wherein said first material and second material are at said transfer vessel internal reaction.

77., wherein before carrying out the operation of MR system, the magnet of said transfer vessel is closed according to the described method of claim 73.

78. method according to claim 1, wherein said first material is through deuterate.

79. according to the described method of claim 78, wherein said first material part is through deuterate.

80. according to the described method of claim 78, wherein said first material is fully through deuterate.

81. a system that is used to make the hyperpolarization material, it comprises:

A) be used for treating the polar member that comprises first material delivery of methyl rotor group to the polairzed area;

B) member that is used for when in said polairzed area, making the polarization of at least one proton that is contained in the said methyl rotor group of said first material to increase; With

C) be used for the polarization transfer of the said increase of said at least one proton of said first material member to another nuclear.

82. 1 described system according to Claim 8, wherein said first material had been disposed paramagnetic agent and polarization agent in fact before polarization.

83. 1 described system according to Claim 8, the wherein said member that is used for shifting comprises that being used for that said first material is passed the zone that magnetic field reduces from the guiding of said polairzed area moves on to the member of another nuclear to the second position to promote polarization from said at least one consideration convey of said first material.

84. 3 described systems according to Claim 8, the wherein said member that is used to guide is through adjusting and be configured to through greater than T ₂But less than T ₁Time period said first material shifted from said polarization environment pass zone that said magnetic field reduces to the said second position.

85. 4 described systems according to Claim 8, the wherein said member that is used to guide passes zone that said magnetic field reduces to the said second position through adjusting and be configured in less than 1.0 seconds said first material shifted from said polarization environment.

86. 4 described systems according to Claim 8, the wherein said member that is used to guide passes zone that said magnetic field reduces to the said second position through adjusting and be configured in less than 0.1 second said first material shifted from said polarization environment.

87. 4 described systems according to Claim 8, the wherein said member that is used to guide passes zone that said magnetic field reduces to the said second position through adjusting and be configured in less than 0.01 second said first material shifted from said polarization environment.

88. 4 described systems according to Claim 8, the wherein said member that is used to guide passes zone that said magnetic field reduces to the said second position through adjusting and be configured in about 0.001 second said first material shifted from said polarization environment.

89. 3 described systems according to Claim 8, the wherein said second position comprises the low temperature environment with magnetic field.

90. 9 described systems according to Claim 8, the wherein said second position comprises the transfer of cryogenic thermostat that contains magnet, and wherein said magnet applies magnetic field to said first material at low temperatures.

91. 3 described systems according to Claim 8, wherein said first material is solid-state after polarization and through make said first material quicken it is directed to the said second position with fluid pressure.

92., wherein it is directed to the said second position through conduit being passed in said first material guiding with Compressed Gas according to the described system of claim 91.

93., wherein with the speed that surpasses 10m/s said conduit is passed in said first material guiding with said Compressed Gas according to the described system of claim 92.

94., wherein with the speed that surpasses 100m/s said conduit is passed in said first material guiding with said Compressed Gas according to the described system of claim 92.

95., wherein with the speed that surpasses 1000m/s said conduit is passed in said first material guiding with said Compressed Gas according to the described system of claim 92.

96. according to the described system of claim 92, wherein said Compressed Gas comprises helium.

97. according to the described system of claim 96, wherein said Compressed Gas comprises ³He.

98. 3 described systems according to Claim 8, the wherein said second position comprises the melting vessel that is used to melt said first material.

99. 3 described systems according to Claim 8, the zone that wherein said magnetic field reduces comprise magnetic shield so that in the zone that said magnetic field reduces the intensity in magnetic field be reduced to value less than the earth background field.

100. 3 described systems according to Claim 8, it further comprises and is used for the member that said first material heated during at said polarization environment when said first material.

101. according to the described system of claim 100, wherein said warming element makes the temperature of said first material from being lower than the said T of said first material ₁Temperature (T during the experience minima _Min) be increased to the said T that is higher than said first material ₁Said temperature (T during the experience minima _Min) second temperature, and said first material melted in fact or distil.

102. a system that is used to make the hyperpolarization material, it comprises:

A) be used to provide the member of treating polar first material that is the high surface powder type;

B) be used in container, making the member of the polarization increase of at least one nuclear that is contained in said first material through carrying out following at least one: (i) reduce the temperature of said first material and the magnetic field that (ii) makes said first material stand to increase in the polarization environment; With

C) be used for the polarization transfer of the said increase of said at least one nuclear of said first material is passed the member of the zone of magnetic field reduction to the second position with said first material from said polarization environment guiding simultaneously to another nuclear.

103. 1 described system according to Claim 8; Wherein utilize and be selected from the said nuclear polarization that makes said first material by the technology of the following group that forms: (i) dynamical nuclear polarization, (ii) nuclear Overhauser effect, (ii) para-hydrogen induced polarization, (iii) make said proton be exposed to hyperpolarized gas in advance hyperpolarization nuclear, (iv) make said first material be exposed to powerful environment and its combination.

104. method according to claim 1 wherein makes said first material in container, polarize, and said first material is taken out from said container when being solid phase.

105. a method that is used to make the hyperpolarization material, it comprises:

A) provide and treat polar first material;

B) polarization of at least one nuclear that is contained in said first material is increased;

C) with the polarization transfer of the said increase of said at least one nuclear in said first material to another nuclear; With

D) said first material is taken out from said container when being solid phase.

106. according to the described method of claim 105, wherein:

A) said first material comprises methyl rotor group;

B) polarization of at least one proton in the said methyl rotor group is increased; And

C) in said transfer step with the polarization transfer of the said increase of said at least one proton in said first material to another nuclear.

107., wherein before said transfer step, said first material is taken out from said container according to the described method of claim 105.

108. method according to claim 3, wherein said first material had been disposed TA and EPA in fact before polarization.

109. a method of carrying out the NMR spectral method, it comprises:

A) will introduce in the target area according to the hyperpolarization material that arbitrary claim in claim 1 to 80 or 104 to 108 is made;

B) with the electromagnetic energy burst transmissions in the said target area to excite said hyperpolarization through the capsule closure material; With

C) receive the NMR spectrum from said target area.

110., wherein the NMR spectrum of sample is in vitro analyzed according to the described method of claim 109.

111., wherein the NMR spectrum of sample is in vivo analyzed according to the described method of claim 109.

112. a method, it comprises:

A) make according to arbitrary claim in claim 1 to 80 or 104 to 108 and be suitable for metabolic material hyperpolarization in bioprocess;

B) said hyperpolarization material is introduced in the target area; With

C) receive the metabolic NMR data or the MR image of indicating said hyperpolarization material.

113. according to claim 104 or 105 described methods, wherein said first material is through using ¹²⁹Xe, ¹³C, ¹⁵N, ¹H, ²H, ³¹P, ¹⁹F with ²⁹An alternative one of which of among the Si at least one or an above atom site and strengthen through isotope.

114. a beneficial agent, it comprises the hyperpolarization material that forms according to the described method of arbitrary claim in claim 1 to 80 or 104 to 108.

115. a beneficial agent, it comprises the material with at least one methyl, and the carbon nuclear in the wherein said methyl is solid-state through adjusting and being configured in the outside of polarization cryostat through hyperpolarization and wherein said beneficial agent.

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