Hyperpolariser, hyperpolarisation arrangement, method for hyperpolarisation and method for producing a contrast agent

Abstract

A hyperpolariser (1) is proposed which has a reactor (2) for treating a polarisation solution (3) with parahydrogen (4), wherein the reactor (2) has an inlet (5, 23) and an outlet (6), wherein the hyperpolariser (1) furthermore has a polarisation chamber (8) with a wall (7), said polarisation chamber being fluidically connected to the reactor (2), wherein in the wall (7) of the polarisation chamber (8) an opening (9) is formed through which a gas (10), which is located in the polarisation chamber (8) and is displaced during a process of filling the polarisation chamber (8) with the polarisation solution (3), can be removed, and wherein the hyperpolariser (1) furthermore has a high-frequency end coil (11) which can be introduced into a magnetic resonance device and is arranged such that a region of maximum homogeneity of a magnetic field generated by the high-frequency end coil (11) can be generated in the polarisation chamber (8). Preferably, the opening (9) of the polarisation chamber (8) opens into a gas compression chamber (15).

Description

[0001] Hyperpolarizer, hyperpolarization arrangement, method for hyperpolarization and method for producing a contrast agent

[0002] The invention relates to a hyperpolarizer.

[0003] The invention further relates to a hyperpolarization arrangement with a hyperpolarizer.

[0004] The invention further relates to a method for polarizing a polarization solution in a hyperpolarization arrangement.

[0005] The invention further relates to a process for producing a contrast agent from a polarization solution which has been hyperpolarized by means of a process mentioned above.

[0006] Such hyperpolarizers, hyperpolarization arrangements, and methods are known. Hyperpolarizers and hyperpolarization arrangements are used to hyperpolarize polarization solutions. The hyperpolarized polarization solutions can be used, for example, as contrast agents in magnetic resonance techniques such as magnetic resonance spectroscopy and / or magnetic resonance imaging.

[0007] These are nuclear magnetic resonance techniques, also known as NMR techniques (NMR: nuclear magnetic resonance, in German referred to as Kernspinresonanz, Nuklearmagnetische Resonanz or kernmagnetische Resonanz). These are measurement methods that can be described as non-destructive or harmless, and can be used in particular to examine living organisms, for example human patients. It can be of interest to observe physiological processes such as metabolism. For example, tissue with increased metabolic activity, such as tumors, can be detected. In order to display this tissue clearly, the patient can be administered contrast media. This can be done intravenously, for example.Such a contrast agent can contain contrast agent molecules that, on the one hand, are, for example, a metabolic metabolite, i.e., they participate in the patient's metabolism and accumulate and / or undergo increased conversion in tissues with increased metabolic activity, and which, on the other hand, can be visualized using the aforementioned magnetic resonance techniques. For this purpose, the contrast agent molecules contain NMR-active atoms, i.e., atoms whose nuclear spin quantum number is not equal to zero, and which can thus be visualized using an NMR technique. These include, for example: X H-, 13 C-, 15 N-, 29 Si-, 31 p- and / or 57 Fe atoms come into question.

[0008] When measuring on the patient, the concentration of contrast agent molecules at the examination site can be comparatively low. This is particularly the case when a metabolic metabolite is used as the contrast agent molecule. In this case, the contrast agent molecule may already be naturally present at the examination site. It may therefore be difficult or impossible, for example, to achieve sufficient resolution with regard to the examination site and / or the nuclear magnetic resonance signal intensity. However, the nuclear magnetic resonance signal can be amplified using hyperpolarization techniques. Hyperpolarization can be understood in particular as an ordered alignment of nuclear spins in a material sample, for example the hyperpolarized contrast agent, beyond thermal equilibrium. A large number of aligned nuclear spins can produce a hyperpolarized contrast agent orwhose contrast agent molecules can be measured and displayed particularly well using magnetic resonance techniques. The term hyperpolarization can be understood in a particularly general way and describes a state in which the eigenstates are unequally occupied by thermal equilibrium. This can, in particular, describe a state in which one or more atomic nuclei of a molecule are in a hyperpolarized state and / or describe states in which two or more atoms of the same species jointly assume a non-equilibrium state, for example, a singlet state.

[0009] Hyperpolarized molecules, for example, in a hyperpolarized polarization solution and / or a contrast agent, lose their hyperpolarization over time. The degree of hyperpolarization and the associated signal enhancement thus decrease over time. This degree is naturally lower at the time the contrast agent is used than immediately after hyperpolarization. As the degree of hyperpolarization of the contrast agent decreases, so does the signal and image quality achievable in magnetic resonance imaging.

[0010] The object of the invention is to improve existing hyperpolarizers, hyperpolarization arrangements, and methods for hyperpolarizing a polarization solution and for producing a contrast agent. In particular, the object of the invention is to increase the degree of hyperpolarization of a contrast agent at the time it is used in a magnetic resonance procedure.

[0011] To achieve the stated object, the invention provides the features of claim 1. In particular, to achieve the stated object, hyperpolarizers of the type described above are provided according to the invention with a reactor for treating a polarization solution with parahydrogen, the reactor having an inlet and an outlet. The reactor can have exactly one inlet or several inlets and exactly one outlet or several outlets.

[0012] A volume can therefore be provided to accommodate a polarization solution in which it can be treated with parahydrogen. The polarization solution can be introduced into the reactor through the inlet and, after treatment with parahydrogen, removed from the reactor through the outlet. The polarization solution can be a liquid, for example water, an organic solvent, a mixture, or an emulsion, with at least one hyperpolarizable molecule dissolved in the liquid. The hyperpolarizable molecule can, for example, contain NMR-active atomic nuclei, i.e., atomic nuclei with a nuclear spin other than zero, for example X H or 13 C atoms .

[0013] For the purposes of this application, the treatment of the polarization solution with parahydrogen can be understood in particular to mean that a chemical reaction, i.e. a synthesis, takes place. This can be a hydrogenation reaction, for example. In order to carry this out, the reactor can be pressurized with parahydrogen. This is necessary, for example, if the contact of the polarization solution with parahydrogen at normal pressure alone is not sufficient to carry out the hydrogenation reaction. A catalyst can be used alternatively or additionally to carry out the hydrogenation reaction. The carrying out of a chemical conversion can thus be spatially separated from a hyperpolarization of the resulting reaction product.Thus, the synthesis of the substance to be hyperpolarized, particularly by hydrogenation, can take place in a first chamber, for example referred to as a reactor, and the hyperpolarization in a second chamber, for example referred to as a polarization chamber. This makes it possible to create favorable conditions for the synthesis outside the polarization chamber, which then only needs to be adapted to the hyperpolarization, but not to the synthesis. Any properties of a first chamber adapted to the synthesis that might inhibit hyperpolarization therefore do not interfere with the hyperpolarization in the second chamber.

[0014] The hydrogenation of a molecule can be characterized by the addition of hydrogen to an unsaturated compound of the molecule.

[0015] A pre-chamber can be arranged upstream of the reactor. For this purpose, the pre-chamber can have an outlet and the reactor an inlet, the outlet and the inlet being connected to one another via a line. The pre-chamber can have an inlet for parahydrogen. For this purpose, the pre-chamber can be connected to a parahydrogen source, such as a container filled with parahydrogen. A liquid which may contain water can be located in the pre-chamber. By introducing the parahydrogen into the pre-chamber, a hydrogen solution, in particular the hydrogen solution already mentioned, can be produced. The hydrogen solution can in particular be pre-saturated in the pre-chamber. The hydrogen solution can then be passed into the reactor via the line. The aforementioned chemical reaction, in particular the hydrogenation reaction, can then be carried out in the reactor.For this purpose, the reactor can already be filled with polarization solution. A catalyst to accelerate the hydrogenation reaction can also be present in the reactor. Alternatively, the hydrogen solution can be fed into the reactor first, followed by the polarization solution. It is also possible to first prepare the polarization solution with the hydrogen solution, then add a catalyst, or initiate the hydrogenation reaction in another way.

[0016] If no prechamber is provided, the parahydrogen gas can also be introduced directly into the reactor. For this purpose, a container filled with parahydrogen can be connected to a reactor inlet. The reactor can be filled with the substances described above, necessary for carrying out the chemical reaction, in particular the hydrogenation reaction.

[0017] Whether with or without a pre-chamber, the polarization solution treated in the reactor can then be fed into the polarization chamber, in which the hyperpolarization is then carried out.

[0018] It may therefore be provided that a prechamber is installed upstream of the reactor. A container filled with parahydrogen may be connected to the prechamber.

[0019] As described, it can be provided in particular that the hyperpolarizer is designed such that a chemical reaction, in particular a hydrogenation reaction, takes place in the reactor during operation and that the polarization solution is hyperpolarized in the polarization chamber when subjected to a spin-order transfer sequence. For this purpose, it can be provided that the reactor is filled with the substances required to carry out the chemical reaction or that sources for these substances are connected to the reactor, wherein the sources can be containers filled with the substances, for example. Furthermore, the hyperpolaristor can have a control unit with which a supply of the substances required to carry out the chemical reaction can be controlled. For this purpose, valves can be formed in supply lines, for example, which can be regulated with the control unit.The control unit can also be connected for control purposes to a valve formed between the polarization chamber and the reactor, for example, the valve arranged in the pressure line. The valve control can be configured to direct the polarization solution treated in the reactor into the polarization chamber for hyperpolarization.

[0020] Accordingly, in a method for hyperpolarizing a polarization solution mentioned above, a chemical reaction, in particular a hydrogenation reaction, can take place in the reactor, and the polarization solution can be subjected to a spin-order transfer sequence in the polarization chamber, thereby hyperpolarizing it. The supply of the required substances and / or valves can be controlled in such a method in order to control the chemical reaction in the reactor and the subsequent hyperpolarization in the polarization chamber.

[0021] Furthermore, the invention provides that the hyperpolarizer has a polarization chamber having a wall which is fluidically connected to the reactor, wherein an opening is formed in the wall of the polarization chamber through which a gas located in the polarization chamber and displaced during a filling process of the polarization chamber with the polarization solution can be removed.

[0022] The unfilled polarization chamber contains a gas with finite density, for example air or nitrogen at room pressure. The term "gas" can therefore also be understood to mean a gas mixture. Because this gas can be removed from the polarization chamber through an opening, trouble-free filling of the polarization chamber with the polarization solution is possible. This can in particular prevent a build-up of excess pressure resulting from the compression of the gas in the polarization chamber from counteracting further, in particular complete, filling of the polarization chamber.

[0023] Furthermore, the invention provides that the hyperpolarizer has a radio-frequency transmitting coil that can be introduced into a magnetic resonance device and is arranged such that a region of maximum homogeneity of a magnetic field generated by the radio-frequency transmitting coil can be generated in the polarization chamber.

[0024] The radio-frequency transmission coil can in particular be constructed such that it can be introduced into a magnetic resonance scanner through an opening. The radio-frequency transmission coil can, for example, delimit the hyperpolarizer on the outside, so that the hyperpolarizer as a whole can be introduced into a magnetic resonance scanner. The hyperpolarizer can therefore be used in hyperpolarization methods that are carried out using a magnetic resonance scanner, for example a magnetic resonance spectroscope and / or a magnetic resonance tomograph. This can, for example, be SAMBADENA (Synthesis Amid the Magnet Bore Allows a Dramatically Enhanced Nuclear Alignment). This method has advantages over other known hyperpolarization methods such as dDNP (dissolution dynamic nuclear polarization) or PHIP (parahydrogen induced polarization).Thus, only minimal additional hardware is required, as essentially an existing magnetic resonance scanner can be used. This can deliver a pulsed spin-order transfer sequence (SOT sequence) to the polarization solution, resulting in a polarization transfer from parahydrogen atoms to other atoms, for example, carbon atoms. 13 C atoms. In this context, parahydrogen atoms can be understood to mean, in particular, those hydrogen atoms of other molecules that have been added to other molecules by means of a hydrogenation reaction using parahydrogen, for example, to obtain a contrast molecule or a precursor of the contrast molecule.

[0025] Shim coils or static shim elements can be provided here, which are designed and adjusted to increase the homogeneity of the magnetic field provided by the magnetic resonance scanner. The position and / or control of the shim coils must be adapted to the object located in the magnetic field. The object can be, for example, a reactor, a polarization solution or a gas such as air or nitrogen. Depending on the object, a more or less homogeneous magnetic field can be achieved by shimming. The radio-frequency transmission coil can, for example, be introduced into the magnetic resonance scanner separately from the polarization chamber, if necessary with additional shim coils. The radio-frequency transmission coil can, for example, be operated via an amplifier of a radio-frequency output of the magnetic resonance scanner.The radio-frequency transmitting coil can also preferably be inductively connected or coupled to another coil, for example, a volume resonator of the magnetic resonance scanner. The radio-frequency transmitting coil can, for example, be tuned to one or more specific resonance frequencies or emit one or more narrow- or broadband electromagnetic frequencies.

[0026] The radio-frequency transmit coil can be used to create a particularly homogeneous and strong magnetic field in the polarization chamber, which significantly improves polarization transfer. The radio-frequency transmit coil is a separate coil from the magnetic resonance scanner and any transmit coils installed in it. This allows the radio-frequency coil to be brought particularly close to the polarization chamber. The radio-frequency transmit coil therefore enables the delivery of pulses with a broad frequency spectrum and high pulse power, for example as a spin-order transfer (SOT) sequence. The loss of significant portions of the polarization associated with lower electrical and / or magnetic field strengths, such as those provided by the magnetic resonance scanner, can thus be reduced or avoided. This applies particularly when using clinical magnetic resonance scanners.The advantages of the SAMBADENA procedure can therefore be combined with those of a separate radiofrequency transmit coil to achieve a greater degree of hyperpolarization. This also results in a greater degree of hyperpolarization remaining at the time of contrast agent application.

[0027] In an advantageous embodiment, the fluidic connection between the polarization chamber and the reactor can be established via a polarization chamber inlet. Alternatively or additionally, the fluidic connection between the polarization chamber and the reactor can be established via a pressure line.

[0028] In this way, the fluidic connection can be designed, for example, in such a way that increased pressures can be generated in the polarization chamber and / or are harmless for other components of the hyperpolarizer. The polarization chamber inlet is different from the already described opening in the wall of the polarization chamber. The polarization chamber inlet can, for example, be guided through the wall of the polarization chamber in a lower region and / or at a lower end thereof. The polarization chamber inlet can also be provided at a preferably lower and / or bottom-near end of a tube and / or hose provided in the polarization chamber. The tube can, for example, be guided through one of the openings in the wall of the polarization chamber or the opening already described.

[0029] In an advantageous embodiment, it can be provided that the reactor has a catalyst so that a chemical reaction, in particular a hydrogenation, of a polarization solution introduced into the reactor can be catalysed.

[0030] Thus, the chemical reaction, which may be a hydrogenation, for example using parahydrogen, with which the reactor may be charged, can already be carried out in the reactor.

[0031] In an advantageous embodiment, a valve can be arranged in the pressure line. Alternatively or additionally, the pressure line can be connected to a valve.

[0032] It is thus possible to build up an overpressure in the polarization chamber and to avoid a spontaneous reduction in pressure, for example due to the drainage of liquid and / or the escape of gas.

[0033] In an advantageous embodiment, it can be provided that the opening of the polarization chamber opens into a gas compression chamber.

[0034] The gas compression chamber can be a volume sealed off from the environment of the polarization chamber, which adjoins the opening of the polarization chamber and serves to absorb the displaced gas. The gas compression chamber can have a single opening, which can be adjacent to the opening of the polarization chamber. The hyperpolarizer can therefore be designed so that the opening of the polarization chamber does not lead to the outside, but into the gas compression chamber. The accumulated pressure in the compression chamber can thus be used, for example, to transport the polarization solution further, for example back into the reactor, into another chamber that is or can be used to prepare the polarization solution, and / or into a syringe for in vivo application.

[0035] Alternatively or additionally, it can be provided that the diameter of the opening of the polarization chamber is narrower by at least a factor of 3, preferably by a factor of at least 6, than a maximum diameter of the polarization chamber.

[0036] The sizes of the polarization chamber and its opening can thus be advantageously matched. For example, it can be provided that the diameter of the gas compression chamber matches the diameter of the opening of the polarization chamber. The volume of the gas compression chamber can, for example, be selected such that it is adapted to the volume of a gas quantity expected at a certain elevated pressure and / or corresponds to this if the gas quantity fills the polarization chamber and preferably also the gas compression chamber at normal pressure.

[0037] Because the gas present in the polarization chamber prior to filling can be removed from the polarization chamber and, in particular, displaced into the gas compression chamber and compressed there, and because the diameter of the polarization chamber opening can be selected to be comparatively small, it is possible to reduce the interface between the polarization liquid and the gas. Due to differences in susceptibility, this interface causes only limited shimable inhomogeneities. Because this interface can be kept small, the homogeneity of the magnetic field in the region of the polarization chamber can be increased.

[0038] In an advantageous embodiment, the opening of the polarization chamber can be arranged in an upper region of the polarization chamber. This can be an uppermost location of the polarization chamber. Alternatively or additionally, the gas compression chamber can extend upwards from the opening.

[0039] An upper region or uppermost location or an upward direction can be determined in particular based on the direction of the gravitational force when the hyperpolarizer is in use. By arranging the opening of the polarization chamber in an upper region, in particular at an uppermost location in the polarization chamber, gas displaced during a filling process of the polarization chamber is guided or pressed in the direction of the opening and / or through the opening. By arranging the gas compression chamber so that it extends upwards from the opening, gas displaced during a filling process of the polarization chamber can be guided in such a way that it collects in the gas compression chamber and is compressed under the pressure of the inflowing polarization solution. In the region of the uppermost location or opening, for example, a valve can be arranged with which a vacuum, i.e. a negative pressure, can be applied to the polarization chamber.

[0040] In an advantageous embodiment, it can be provided that the polarization chamber is spherically shaped.

[0041] In this way, it can be ensured that gas in the polarization chamber collects in an upper area or at a top location in the polarization chamber and from there can, for example, reach the gas compression chamber.

[0042] Alternatively or additionally, it can be provided that the polarization chamber is formed by at least one molded part. Alternatively or additionally, it can be provided that the wall of the polarization chamber is a surface of a molded part.

[0043] In this way, the polarization chamber can be easily manufactured in a defined shape.

[0044] In an advantageous embodiment, the wall of the polarization chamber may be coated. Additionally, the wall of the polarization chamber may be coated to be liquid-repellent and / or solvent-resistant and / or solvent-repellent.

[0045] A liquid-repellent coating can ensure that no liquid, or as little liquid as possible, remains in the polarization chamber when it is emptied, for example by reducing or preventing adhesion processes. This can be the case in particular with a solvent-repellent coating, particularly if the coating is repellent to the solvent in the polarization solution. Solvent-resistant and / or solvent-repellent can be understood in particular to mean resistant and / or repellent with respect to organic solvents. These solvents are not necessarily the solvents in the polarization solution, which can be an aqueous solution, for example. The organic solvents can be, in particular, acetone, chloroform and / or ethanol.The polarization chamber can therefore also be cleaned using a solvent without damaging the polarization chamber.

[0046] Alternatively or additionally, the coating can be provided to be acid and / or base resistant. The hyperpolarizer can therefore be cleaned in a simple manner by filling the polarization chamber once or several times with a cleaning agent, for example one of the solvents mentioned and / or an acid and / or a base or a mixture of the substances mentioned or other substances. Residues of the polarization solution and / or the contrast agent can be removed in this way. All components of the hyperpolarizer that come into contact with fluid can be provided with a corresponding resistance. This can result from the choice of material and / or the selection of a coating. Individual components of the hyperpolarizer can also be provided as replaceable parts. This means that they can be replaced after a stress that exceeds a desired level, for example due to the cleaning agents mentioned.The cleaning agent can, for example, be selected so that it can be removed by applying a vacuum—for example, to the valve mentioned above. The cleaning agent can also be selected so that it can be removed by rinsing with a solvent, after which it can additionally be provided that any remaining solvent residues can be removed by applying a vacuum.

[0047] In an advantageous embodiment, the high-frequency transmitting coil can be designed to emit electromagnetic waves with a frequency between 10 kHz and 500 MHz. The high-frequency transmitting coil can, in particular, be designed to emit electromagnetic waves with a frequency of more than 5 MHz.

[0048] Alternatively or additionally, it can be provided that the polarization chamber is located in a geometric and / or electromagnetic isocenter of the radio-frequency transmitting coil.

[0049] In this way, a particularly homogeneous static magnetic field and / or a sufficiently powerful, for example pulsed, electric field can be provided within the polarization chamber, which enables a particularly efficient hyperpolarization of the polarization solution.

[0050] In the advantageous embodiment, it can be provided that the high-frequency transmitting coil is adjacent to one or the molded part and / or is fastened to it.

[0051] In this way, a position of the high-frequency transmitting coil relative to the polarization chamber can be advantageously selected and determined.

[0052] In an advantageous embodiment, it can be provided that the distance between the radio-frequency transmitting coil and a center of the polarization chamber is less than five times the maximum diameter of the polarization chamber. In addition, it can be provided that the distance between the radio-frequency transmitting coil and a center of the polarization chamber is less than three times the maximum diameter of the polarization chamber.

[0053] In this way, the radio-frequency transmitting coil can be advantageously positioned near the polarization chamber in such a way that a region of maximum homogeneity of the magnetic field generated by the radio-frequency transmitting coil is created in the polarization chamber. This allows for particularly efficient polarization transfer.

[0054] Alternatively or additionally, the features of the independent claim directed to a hyperpolarization arrangement with a hyperpolarizer according to the invention are provided to achieve the stated object.

[0055] In particular, to achieve the stated object in hyperpolarization arrangements of the type described at the outset, the invention proposes that a parahydrogen reservoir is connected to the inlet or to an inlet of the reactor, that the reactor and the pressure line can be subjected to an overpressure via a fluidic control system, and that a valve is arranged in the pressure line. In addition, it can be provided that this is an overpressure of parahydrogen. The parahydrogen reservoir can, for example, be in the form of a container for parahydrogen. However, it can also be designed as a prechamber to which such a container is connected. The prechamber can be designed in the manner described above.

[0056] In this way, the reactor, particularly after filling with a polarization solution, can be placed under an overpressure, particularly caused by parahydrogen, and this overpressure can be maintained for a certain time by keeping the valve closed. In this way, the polarization solution can be treated with parahydrogen. The reactor can be filled with parahydrogen through the same inlet as the filling with the polarization solution, or through a separate inlet. In an advantageous embodiment, it can be provided that the parahydrogen reservoir is a gas reservoir and / or a reservoir of a liquid enriched with parahydrogen.

[0057] In this way, the reactor can be supplied with parahydrogen via a fluid, in particular a gaseous and / or liquid fluid.

[0058] In an advantageous embodiment, it can be provided that a purification chamber is provided for purifying the polarization solution which can be removed from the polarization chamber via a fluidic connection.

[0059] The hyperpolarization arrangement can thus comprise a further chamber in which post-treatment of the hyperpolarized polarization solution is possible. Depending on the hyperpolarization process selected, the purification can serve to obtain the molecule ultimately used as the contrast molecule from the hyperpolarized molecules, for example by splitting it off. The purification can, for example, comprise processes for extracting the contrast molecule into a biocompatible aqueous solution, removing solvents and / or reaction by-products, adjusting the pH value and / or filtering the solution. The purification chamber can have an outlet through which a finished contrast agent can be dispensed and / or removed, for example for or by drawing it into a syringe, preferably for direct administration to a patient.

[0060] Alternatively or additionally, in order to achieve the stated object, the features of the independent claim directed to a method for hyperpolarizing a polarization solution in a hyperpolarization arrangement according to the invention are provided according to the invention.In particular, in order to achieve the stated object in methods for hyperpolarizing a polarization solution of the type described at the outset, it is proposed according to the invention that the reactor is filled with the polarization solution through its inlet, wherein, with the valve closed, parahydrogen is introduced from the parahydrogen reservoir into the reactor filled with the polarization solution, wherein the reactor and at least part of the pressure line are subjected to an overpressure, wherein the valve is opened so that the liquid flows into the polarization chamber and gas located in the polarization chamber is displaced from the polarization chamber through the opening, and wherein the polarization solution located in the polarization chamber is subjected to a spin-order transfer sequence (SOT sequence) so that molecules of the polarization solution change into a hyperpolarized state.

[0061] Thus, the hyperpolarizer according to the invention or the hyperpolarization arrangement according to the invention can be advantageously used for hyperpolarizing a polarization solution. A particular advantage here is that a region of maximum homogeneity of a magnetic field generated by the radio-frequency transmitting coil can be created in the polarization chamber. It is particularly advantageous to use a separate coil in hyperpolarization methods using existing magnetic resonance scanners, as this separate coil is crucial to achieving the high homogeneity of the magnetic field. Polarization losses can thus be reduced or avoided. The reactor can be filled with the polarization solution through its inlet, for example, from a reservoir.

[0062] In addition, it may be provided that a

[0063] Polarization solution containing substance a chemical

[0064] reaction, preferably a hydrogenation. The hydrogenation can be carried out, for example, using a catalyst.

[0065] Thus, applying an excess pressure of parahydrogen to the reactor can be used, for example, to hydrogenate a substance contained in the polarization solution. A chemical reaction can therefore already take place in the reactor. Compared to simply bringing the polarization solution into contact with parahydrogen in the reactor, followed by a chemical reaction in the polarization chamber, this has the advantage that the polarization chamber can be adapted not to carry out a chemical reaction, but solely to the hyperpolarization of the reaction product. The chemical substance is chosen depending on the selected hyperpolarization process and the area of ​​application of the hyperpolarized product.

[0066] In an advantageous embodiment, it can be provided that the polarization solution is pressed out of the polarization chamber after being subjected to the spin-order transfer sequence (SOT sequence) due to an expansion of the gas fed into the gas compression chamber during the filling process of the polarization chamber with the liquid.

[0067] In this way, the gas compressed in the gas compression chamber during the filling process, and its resulting increased energy, can be used to empty the polarization chamber and transfer the polarization solution. This can eliminate the need for separate pumps and / or additional valves.

[0068] In an advantageous embodiment, it can be provided that the polarization solution and / or molecules of the polarization solution after exposure to the spin order transfer sequence (SOT sequence) in the

[0069] Polarization chamber and / or the purification chamber.

[0070] The contrast agent can be obtained from the hyperpolarized polarization solution, if necessary, by purification. If no purification is required, the hyperpolarized polarization solution itself can serve as the contrast agent. The purification can take place before or after the expansion of the gas introduced into the gas compression chamber. The purification can also involve a material conversion, whereby the contrast molecule can be generated from hyperpolarized molecules in the polarization solution.

[0071] Alternatively or additionally, to achieve the stated object, the invention provides the features of the independent claim directed to a method for producing a contrast agent from a polarization solution that has been hyperpolarized by a method according to the invention. In particular, to achieve the stated object, in methods for producing a contrast agent of the type described above, the invention proposes that the hyperpolarized polarization solution be purified.

[0072] The contrast agent is obtained through purification, whereby a substance conversion can take place.

[0073] In an advantageous embodiment, it can be provided that a hyperpolarized molecule of the hyperpolarized polarization solution is a contrast molecule for a magnetic resonance method. Alternatively or additionally, it can be provided that a hyperpolarized molecule of the hyperpolarized polarization solution is a precursor of a contrast molecule for a magnetic resonance method.

[0074] For example, the hyperpolarized polarization solution may already contain the contrast molecule. However, further steps, such as purification, may be necessary to obtain the contrast molecule from one of its precursors.

[0075] In an advantageous embodiment, it can be provided that the or a hyperpolarized molecule type of the hyperpolarized polarization solution is chemically converted during the purification.

[0076] This is especially the case when the hyperpolarized molecule of the hyperpolarized polarization solution is a precursor of the contrast molecule. For example, the contrast molecule can then be produced during purification, for example, by cleaving off a molecular fragment of the hyperpolarized molecule, with the molecular fragment constituting the contrast molecule.

[0077] The invention will now be described in more detail using an exemplary embodiment, but is not limited to the exemplary embodiment. Further exemplary embodiments result from combining the features of one or more claims with one another and / or with one or more features of the exemplary embodiment.

[0078] It shows :

[0079] Figure 1 is a schematic representation of a hyperpolarization arrangement according to the invention with a hyperpolarizer according to the invention.

[0080] Figure 1 shows a schematic representation of a hyperpolarizer 1 according to the invention, which has a reactor 2 for treating a polarization solution 3 with parahydrogen 4, the reactor 2 having two inlets 5 and one outlet 6. A polarization solution reservoir 30 is connected to one of the inlets 5. The further inlet 5 in the upper region of the reactor 2 can be used, for example, to supply gases. Instead of a further inlet 5 or in addition to this, the reactor 2 can, for example, have a further outlet through which, for example, a gas can be discharged and / or a vacuum can be applied. The inlets 5 and outlets 6 can, in principle, be positioned flexibly depending on requirements.The hyperpolarizer 1 according to the invention further comprises a polarization chamber 8 having a wall 7, which is fluidically connected to the reactor 2, wherein an opening 9 is formed in the wall 7 of the polarization chamber 8, through which opening a gas 10 located in the polarization chamber 8 and displaced during a filling process of the polarization chamber 8 with the polarization solution 3 can be removed. The hyperpolarizer 1 according to the invention further comprises a radio-frequency transmission coil 11 which can be introduced into a magnetic resonance apparatus (not shown in detail), which is arranged such that a region of maximum homogeneity of a magnetic field generated by the radio-frequency transmission coil 11 can be generated in the polarization chamber 8. In the hyperpolarizer 1 shown, the fluidic connection between the polarization chamber 8 and the reactor 2 is furthermore established via a polarization chamber inlet 12 and a pressure line 13.A valve 14 is arranged in the pressure line 13. In an embodiment not shown, the pressure line 13 can be connected to a valve 14. The reactor 2 has a catalyst so that a chemical reaction, in particular a hydrogenation, of a polarization solution introduced into the reactor 2 can be catalyzed. The opening 9 of the polarization chamber 8 opens into a gas compression chamber 15 and the diameter 16 of the opening 9 of the polarization chamber 8 is at least a factor of three narrower than a maximum diameter 17 of the polarization chamber 8. The opening 9 of the polarization chamber 8 is arranged in an upper region, namely at an uppermost location 18 of the polarization chamber 8 and the gas compression chamber 15 extends upwards from the opening 9. In the region of the uppermost location 18 or. A valve 27 is arranged in the opening 9 through which, for example, a vacuum can be applied to the polarization chamber 8.This vacuum can be used, for example, to remove solvents from the polarization chamber 8. The polarization chamber 8 is spherically shaped and formed by a molded part (not shown in detail). The wall 7 of the polarization chamber 8 is a surface of the molded part (not shown in detail). The wall 7 of the polarization chamber 8 is coated and therefore has a coating 19. The coating 19 is designed to be liquid-repellent. In embodiments not shown, the coating 19 can also be solvent-resistant and / or solvent-repellent. In the exemplary embodiment, the high-frequency transmitting coil 11 is designed to emit electromagnetic waves with a frequency between 10 kHz and 500 MHz. The polarization chamber 8 is located in a geometric and electromagnetic isocenter 20 of the high-frequency transmitting coil 11.In an embodiment not shown, the high-frequency transmission coil 11 can be adjacent to and / or attached to one or the aforementioned molded part. Furthermore, in the exemplary embodiment, the distance 21 of the high-frequency transmission coil 11 from a center 22 of the polarization chamber 8 is less than five times, and even less than three times, a maximum diameter 17 of the polarization chamber 8.

[0081] The inventive and shown in Figure 1

[0082] In the exemplary embodiment, hyperpolarizer 1 is part of a hyperpolarization arrangement 100 according to the invention, wherein a parahydrogen reservoir 24 is connected to a further inlet 23 of reactor 2, wherein the reactor 2 and the pressure line 13 can be pressurized with an excess pressure of parahydrogen 4 via a fluidic control (not shown in detail), and wherein a valve 14 is arranged in the pressure line 13. In the exemplary embodiment, the parahydrogen reservoir 24 is a gas reservoir. In an embodiment not shown, the parahydrogen reservoir 24 can also be a reservoir of a liquid enriched with parahydrogen 4. The hyperpolarization arrangement 100 further comprises a purification chamber 25, which is provided for purifying the polarization solution 3, which can be removed from the polarization chamber 8 via a fluidic connection 26. A valve 14 is also provided in the fluidic connection 26.In an alternative embodiment, the purification chamber 25 is provided by the reactor 2. The purification chamber 25 has an outlet 28 through which a finished contrast agent can be dispensed and / or removed, for example for or by drawing it into a syringe, preferably for direct administration to a patient. The purification chamber 25 also has a further outlet 29, which is connected via a further valve 14. Via the outlet 29, for example, an overpressure in the purification chamber 25 can be reduced or a negative pressure or vacuum can be applied.

[0083] With the hyperpolarizer 1 according to the invention shown and the hyperpolarization arrangement 100 according to the invention shown, a method according to the invention for hyperpolarizing a polarization solution 3 in a hyperpolarization arrangement 100 according to the invention can be carried out, wherein the reactor 2 is filled with the polarization solution 3 from the polarization solution reservoir 30 through its inlet 5, wherein with the valve 14 closed, parahydrogen 4 is introduced from the parahydrogen reservoir 24 into the reactor 2 filled with the polarization solution 3, wherein the reactor 2 and at least a part of the pressure line 13 is subjected to an overpressure, wherein the valve 14 is opened so that the liquid, namely the polarization solution 3,flows into the polarization chamber 8 and gas 10 located in the polarization chamber 8 is displaced through the opening 9 of the polarization chamber 8 and wherein the polarization solution 3 located in the polarization chamber 8 is subjected to a spin-order transfer sequence (SOT sequence) so that molecules of the polarization solution 3 enter a hyperpolarized state. In this method, the then hyperpolarized polarization solution 3 is pressed out of the polarization chamber 8 after being subjected to the spin-order transfer sequence (SOT sequence) due to an expansion of the gas 10 that was fed into the gas compression chamber 15 during the filling process of the polarization chamber 8 with the liquid, in this case the polarization solution 3. Furthermore, the polarization solution 3 , and thus molecules of the polarization solution 3 , after being subjected to the spin order transfer sequence (SOT sequence) in the,

[0084] The sample is cleaned in the cleaning chamber 25. It is also possible to perform the cleaning in the polarization chamber 8.

[0085] With the hyperpolarizer 1 shown and the hyperpolarization arrangement 100, the method according to the invention for producing a contrast agent from a polarization solution 3 that has been hyperpolarized by means of a method according to the invention can also be carried out, wherein the hyperpolarized polarization solution 3 is purified. In this case, a hyperpolarized molecule type of the hyperpolarized polarization solution 3 is a contrast molecule for a magnetic resonance method. In an alternative

[0086] In one embodiment, a hyperpolarized molecule of the hyperpolarized polarization solution 3 can be a precursor of a contrast molecule for magnetic resonance imaging. In this process, it is possible that a hyperpolarized molecule of the hyperpolarized polarization solution 3, in particular the one just described, is chemically converted during purification.

[0087] A hyperpolarizer 1 is proposed which has a reactor 2 for treating a polarization solution 3 with parahydrogen 4, wherein the reactor 2 has an inlet 5, 23 and an outlet 6, wherein the hyperpolarizer 1 further has a polarization chamber 8 having a wall 7, which is fluidly connected to the reactor 2, wherein an opening 9 is formed in the wall 7 of the polarization chamber 8, through which opening a gas 10 located in the polarization chamber 8 and displaced during a filling process of the polarization chamber 8 with the polarization solution 3 can be removed, and wherein the hyperpolarizer 1 further has a radio-frequency transmission coil 11 which can be introduced into a magnetic resonance apparatus and which is arranged such that a region of maximum homogeneity and intensity of a magnetic field generated by the radio-frequency transmission coil 11 can be generated in the polarization chamber 8. .

[0088] Furthermore, a hyperpolarization arrangement 100 with a hyperpolarizer 1 according to the invention is proposed, wherein a parahydrogen reservoir 24 is connected to the or an inlet 5, 23 of the reactor 2, wherein the reactor 2 and the pressure line 13 can be subjected to an overpressure, in particular of parahydrogen 4, via a fluidic control and wherein a valve 14 is arranged in the pressure line 13.Furthermore, a method for hyperpolarizing a polarization solution 3 in a hyperpolarization arrangement 100 according to the invention is proposed, wherein the reactor 2 is filled with the polarization solution 3 through its inlet 5, 23, wherein, with the valve 14 closed, parahydrogen 4 is introduced from the parahydrogen reservoir 24 into the reactor 2 filled with the polarization solution 3, wherein the reactor 2 and at least a part of the pressure line 13 are subjected to an overpressure, wherein the valve 14 is opened so that the liquid flows into the polarization chamber 8 and gas 10 located in the polarization chamber 8 is displaced from the polarization chamber 8 through the opening 9, and wherein the polarization solution 3 located in the polarization chamber 8 is subjected to a spin-order transfer sequence (SOT sequence) so that molecules of the polarization solution 3 transition to a hyperpolarized state. .

[0089] Finally, a method is proposed for producing a contrast agent from a polarization solution 3 which has been hyperpolarized by means of a method according to the invention, wherein the hyperpolarized polarization solution 3 is purified.

[0090] List of reference symbols

[0091] 1 Hype rpo lari sator

[0092] 2 reactors

[0093] 3 Polar isat Ions solution

[0094] 4 Parahydrogen

[0095] 5 Entrance

[0096] 6 Outlet

[0097] 7 Wall

[0098] 8 Polar isat ions combs

[0099] 9 Opening

[0100] 10 Gas

[0101] 11 High frequency transmitting coil

[0102] 12 Polarization chamber inlet

[0103] 13 Pressure line

[0104] 14 Valve

[0105] 15 Gas compression combs

[0106] 16 diameters

[0107] 17 maximum diameter

[0108] 18 highest place

[0109] 19 Coating

[0110] 20 I sozentrum

[0111] 21 distance

[0112] 22 Center

[0113] 23 Entrance

[0114] 24 Parahydrogen reservoir

[0115] 25 On cleaning combs

[0116] 26 fluidic connection

[0117] 27 Valve

[0118] 28 Outlet

[0119] 29 Outlet

[0120] 30 Polarization solution reservoir

[0121] 100 hyperpolarization array

Claims

Claims 1. Hyperpolarizer (1) comprising: - a reactor (2) for treating a polarization solution (3) with parahydrogen (4), the reactor (2) having an inlet (5, 23) and an outlet (6), - a polarization chamber having a wall (7) (8) which is fluidically connected to the reactor (2), wherein in the wall (7) of the polarization chamber (8) an opening (9) is designed such that a gas (10) located in the polarization chamber (8) and displaced during a filling process of the polarization chamber (8) with the polarization solution (3) can be removed, - a radio-frequency transmitting coil (11) which can be introduced into a magnetic resonance apparatus and which is arranged such that a region of maximum homogeneity of a magnetic field generated by the radio-frequency transmitting coil (11) can be generated in the polarization chamber (8).

2. Hyperpolarizer (1) according to the preceding claim, characterized in that the fluidic connection between the polarization chamber (8) and the reactor (2) is established via a polarization chamber inlet (12) and / or a pressure line (13).

3. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the reactor (2) has a catalyst so that a chemical reaction, in particular a hydrogenation, of a polarization solution introduced into the reactor (2) can be catalyzed.

4. Hyperpolarizer (1) according to one of the preceding Claims, characterized in that in the pressure line (13) a valve (14) is arranged and / or that the pressure line (13) is connected to a valve (14).

5. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the opening (9) of the polarization chamber (8) opens into a gas compression chamber (15) and / or that the diameter (16) of the opening (9) of the polarization chamber (8) is narrower by at least a factor of 3 than a maximum diameter (17) of the polarization chamber (8).

6. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the opening (9) of the polarization chamber (8) is arranged in an upper region, in particular at an uppermost location (18), of the polarization chamber (8) and / or that the gas compression chamber (15) extends upwards from the opening (9).

7. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the polarization chamber (8) is spherically shaped and / or is formed by at least one molded part and / or that the wall (7) of the polarization chamber (8) is a surface of a molded part.

8. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the wall (7) of the polarization chamber (8) is coated in particular to be liquid-repellent and / or solvent-resistant and / or solvent-repellent.

9. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the High-frequency transmitting coil (11) is designed to emit electromagnetic waves with a frequency between 10 kHz and 500 MHz and / or that the polarization chamber (8) is located in a geometric and / or electromagnetic isocenter (20) of the high-frequency transmitting coil (11).

10. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the high-frequency transmitting coil (11) is adjacent to one or the molded part and / or is attached to it.

11. Hyperpolarizer (1) according to one of the preceding claims, characterized in that the distance (21) of the high-frequency transmitting coil (11) to a center (22) of the polarization chamber (8) is less than five times, in particular less than three times, a maximum diameter (17) of the polarization chamber (8).

12. Hyperpolaristor (1) according to one of the preceding claims, characterized in that a prechamber is connected upstream of the reactor (2), in particular wherein a container filled with parahydrogen is connected to the prechamber.

13. Hyperpolarizer (1) according to one of the preceding claims, characterized in that it is designed such that during operation a chemical reaction, in particular a hydrogenation reaction, takes place in the reactor (2) and that in the polarization chamber (8) the polarization solution (3) is hyperpolarized when subjected to a spin-order transfer sequence.

14. Hyperpolarization arrangement (100) with a hyperpolarizer (1) according to one of the preceding claims, characterized in that at the or one Inlet (5, 23) of the reactor (2) Parahydrogen reservoir (24) is connected so that the Reactor (2) and the pressure line (13) via a fluidic Control can be subjected to an overpressure, in particular parahydrogen (4), and that a valve (14) is arranged in the pressure line (13).

15. Hyperpolarization arrangement (100) according to the preceding claim, characterized in that the parahydrogen reservoir (24) is a gas reservoir and / or a reservoir of a liquid enriched with parahydrogen (4).

16. Hyperpolarization arrangement (100) according to one of the preceding claims, characterized in that a purification chamber (25) is provided for purifying the polarization solution (3) which can be removed from the polarization chamber (8) via a fluidic connection (26).

17. Method for hyperpolarizing a polarization solution (3) in a hyperpolarization arrangement (100) according to one of the preceding claims, wherein the reactor (2) is filled with the polarization solution (3) through its inlet (5, 23), wherein, with the valve (14) closed, parahydrogen (4) is introduced from the parahydrogen reservoir (24) into the reactor (2) filled with the polarization solution (3), wherein the reactor (2) and at least a part of the pressure line (13) are subjected to an overpressure, in particular wherein a substance contained in the polarization solution undergoes a chemical reaction, preferably a hydrogenation, wherein the valve (14) is opened so that the liquid flows into the polarization chamber (8) and gas (10) present in the polarization chamber (8) is displaced from the polarization chamber (8) through the opening (9). and wherein the polarization solution (3) located in the polarization chamber (8) is subjected to a spin-order transfer sequence (SOT sequence) so that molecules of the polarization solution (3) change into a hyperpolarized state.

18. Method according to the preceding claim, characterized in that the polarization solution (3) is pressed out of the polarization chamber (8) after being subjected to the spin-order transfer sequence (SOT sequence) due to an expansion of the gas (10) fed into the gas compression chamber (15) during the filling process of the polarization chamber (8) with the liquid.

19. Method according to one of the two preceding claims, characterized in that the polarization solution (3) and / or molecules of the polarization solution (3) are purified in the polarization chamber (8) and / or the purification chamber (25) after being subjected to the spin-order transfer sequence (SOT sequence).

20. A method for producing a contrast agent from a polarization solution (3) which has been hyperpolarized by a method according to one of the three preceding claims, wherein the hyperpolarized polarization solution (3) is purified.

21. The method according to the preceding claim, wherein a hyperpolarized molecule species of the hyperpolarized polarization solution (3) is a contrast molecule for a magnetic resonance method or a precursor of a contrast molecule for a magnetic resonance method.

22. Method according to one of the two preceding claims, characterized in that the or a hyperpolarized molecule of the hyperpolarized Polarization solution (3) is chemically converted during purification.

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