Contrast media and methods for its provision

Abstract

A method for providing a contrast agent (1) is proposed, wherein the contrast agent (1) contains at least one hyperpolarized molecule species C (4), the method comprising at least the following steps: providing (6) a first molecule species A (2) and a second molecule species B (3) different from molecule species A (2) in at least one polarizing solution (7), hyperpolarizing (8) the at least one polarizing solution (7) by hyperpolarizing molecule species A (2) and B (3) using a hyperpolarization method, whereby a hyperpolarized molecule species C (4) is obtained from molecule species A (2) and a hyperpolarized molecule species D (5) is obtained from molecule species B (3), measuring (9) an NMR spectrum of the at least one hyperpolarized polarizing solution (10) using an NMR method.Determining the pH value of at least one hyperpolarized polarization solution (10) by computer-aided evaluation of a nuclear magnetic resonance signal of molecule type D (5) in the measured NMR spectrum, and providing (12) the contrast agent (1) as a function of the determined pH value. Furthermore, a contrast agent (1) is proposed, provided by a method according to the invention.

Description

[0001] The invention relates to a method for providing a contrast agent, wherein the contrast agent contains at least one hyperpolarized molecule species.

[0002] The invention further relates to a contrast agent provided by a method of the type mentioned at the outset.

[0003] Such methods and contrast agents are known from the state of the art. They are used in magnetic resonance techniques, particularly in magnetic resonance spectroscopy and magnetic resonance imaging. These are nuclear magnetic resonance techniques, which can be referred to as NMR techniques (NMR: nuclear magnetic resonance). These are measurement methods that can be described as non-destructive or harmless, and by means of which living organisms, for example human patients, can be examined. In this case, it can be of interest to observe physiological processes such as metabolism. For example, tissues with increased metabolic activity, such as tumors, can be identified. To clearly visualize these tissues, contrast agents can be administered to the patient.This can be administered 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, 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, . 1 H-, 13 C-, 15 N-, 29 Si-, 31 P- and / or 57 Fe atoms come into question.

[0004] 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 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, e.g. 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 or displayed particularly well using magnetic resonance techniques.

[0005] The term hyperpolarization can be understood in a 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 states in which two or more atoms of the same species jointly occupy a non-equilibrium state, for example, a singlet state.

[0006] Such hyperpolarized contrast agents can be used in biological and medical contexts, whereby the contrast agent must comply with certain chemical and / or physical parameters for in vivo application. For example, a condition for providing a contrast agent may be that a certain parameter is within a certain parameter range. Providing the contrast agent may in particular comprise releasing a contrast agent for use on a patient. Providing the contrast agent may further comprise preparing the contrast agent ready for injection. Providing a contrast agent implies that the contrast agent has not yet been injected. Providing the contrast agent may, for example, require the contrast agent to have a pH value that is within a pH range that is harmless to a patient.A pH value can, for example, be determined manually using indicator solutions or test strips.

[0007] If the pH value is determined after the hyperpolarized contrast agent has been prepared, this can lead to a delay before the contrast agent can be made available for application to a patient. However, as time passes, the extent of hyperpolarization of a material decreases. The extent of contrast enhancement that can be achieved with a hyperpolarized contrast agent therefore decreases as time goes on. The time required to determine the pH value, which can be several minutes with the previously mentioned determination methods, therefore influences the extent of contrast enhancement that can be achieved with the hyperpolarized contrast agent. For example, after a pH value has been determined, a hyperpolarized contrast agent may have already lost 75% or more of its hyperpolarization and may only be of limited suitability for subsequent examinations.

[0008] The object of the invention is to improve methods for providing a contrast agent. The contrast agent contains at least one hyperpolarized molecule, hereinafter referred to as molecule type C.

[0009] To achieve the stated object, the features of claim 1 are provided according to the invention. In particular, to achieve the object, a method of the type described above is proposed according to the invention that this method comprises at least the following five steps: In a first step, a first molecule type A and a second molecule type B different from molecule type A are provided in at least one polarization solution.

[0010] The molecule types can be provided in the same polarization solution or separately, each in its own polarization solution. A solution can be understood in this context as a liquid or solid phase that contains more than one substance, namely at least molecule type A and / or molecule type B and also a solvent, where the solvent can be, for example, water or an organic solvent, for example acetone, methanol, ethanol and / or chloroform. The polarization solution can also contain other substances that are required, for example, for the hyperpolarization process (for example, exchange or hydrogenation catalysts, radicals, excitable radicals) or that serve to adapt the contrast agent to physiological environments. In this case, molecule type A and molecule type B are hyperpolarizable, i.e.The molecules of both types of molecules can be converted into a hyperpolarized state. In this case, the molecules of types A and B can each have at least one NMR-active nucleus, whose nuclear spin can be aligned in an orderly manner across a plurality of molecules of the respective type of molecule by means of hyperpolarization.

[0011] In a second step, the at least one polarization solution is hyperpolarized by hyperpolarizing the molecule types A and B by means of a hyperpolarization process, whereby a hyperpolarized molecule type C is obtained from the molecule type A and a hyperpolarized molecule type D is obtained from the molecule type B.

[0012] If the molecule types A and B are provided in a common polarization solution, they can be hyperpolarized simultaneously, as provided in an advantageous embodiment of the method.

[0013] Hyperpolarization of the polarization solution is therefore understood to be the process after at least molecule types A and B have been converted into hyperpolarized molecule types C and D, respectively. This does not necessarily involve a material transformation of the molecule types. The molecule types A and C, or B and D, can, for example, only differ in that the hyperpolarizable molecule types A and B are not hyperpolarized and the molecule types C and D are hyperpolarized. Non-hyperpolarized molecule types can be understood, in particular, that a degree of ordered alignment of nuclear spins of the molecule type corresponds to a thermal equilibrium state. The hyperpolarization process can include further steps, for example, for purifying the polarization solution, which can lead to material transformations of the molecule types.Thus, it is possible that, within the hyperpolarization process, molecule type A is first hyperpolarized, with the hyperpolarized molecule type C being obtained only after a further intermediate step, for example, the cleavage of a molecular fragment of molecule type A. Purification steps can include, for example, the extraction of a molecule type into a biocompatible aqueous solution, the removal of solvents and / or reaction by-products, the adjustment of the pH value, and / or the filtration of a solution. After the second step, a hyperpolarized polarization solution is thus obtained. The hyperpolarized polarization solution can be prepared by at least partially mixing the polarization solutions containing the hyperpolarized molecule type C and the hyperpolarized molecule type D, as is the case in an advantageous embodiment of the invention.The hyperpolarization of molecule type A and molecule type B can thus also be performed separately, using the same or different hyperpolarization methods. Just like the aforementioned purification or cleavage steps, the mixing step can be counted as the second step of the process. The mixing step can, for example, be performed before or after purification or cleavage steps.

[0014] In a third step, an NMR spectrum of the at least one hyperpolarized polarization solution or a sample from the at least one hyperpolarized polarization solution is measured by means of an NMR method.

[0015] The NMR method can, for example, be a 1 H-NMR and / or a 13 C-NMR and / or a 15N-NMR method. If both molecule type C and molecule type D, or other substances in the polarization solution, contain the corresponding NMR-active nuclei, their nuclear magnetic resonance signals are displayed together in the measured NMR spectrum. For example, the shift of the water resonance ( 1 H or 2 H NMR) can be used to determine the temperature. The NMR spectrum can be determined as a plot of nuclear magnetic resonance signals versus chemical shift. The chemical shift can be determined from the difference between the resonance frequencies of the polarization solution and a standard, or as the quotient of the difference between the resonance frequencies of the polarization solution and a standard, and the resonance frequency of the standard.

[0016] In a fourth step, the pH value of the polarization solution is determined by computer-assisted evaluation of a nuclear magnetic resonance signal of molecular type D in the measured NMR spectrum.

[0017] Molecule type D is chosen such that it contains the NMR-active atomic nucleus excited in the NMR method. To enable the determination of a pH value, molecule type D is selected such that it exhibits a pH-dependent nuclear magnetic resonance signal in at least one pH range, for example, the expected pH range. In this context, one can also speak of a pH-sensitive NMR spectrum of molecule type D. Molecule type D can cause multiple nuclear magnetic resonance signals in the measured NMR spectrum, with at least one nuclear magnetic resonance signal being evaluated. The position of the nuclear magnetic resonance signal of molecule type D to be evaluated is known within a specific chemical shift range, so that it can be evaluated specifically, preferably automatically, with computer support. The pH of the hyperpolarized polarization solution can be determined from the evaluation of the position of this nuclear magnetic resonance signal.

[0018] In a fifth step, the contrast agent is provided depending on the determined pH value.

[0019] A pH range can be specified within which the pH of the hyperpolarized polarization solution must lie so that it can be provided. The pH is preferably between 6.5 and 8.0, particularly preferably between 7.0 and 7.7. The provision can be made for injection into a patient. However, provision will not take place in this case if the pH lies outside the specified pH range. For example, the contrast agent can then be disposed of instead of being prepared for injection. The provided contrast agent is not necessarily chemically different from the hyperpolarized, possibly purified, polarization solution on which the NMR spectrum was measured. The NMR spectrum can therefore be measured on a solution that is identical to the solution injected into a patient as a contrast agent.For the purposes of this invention, the hyperpolarized polarization solution can be referred to as a contrast agent, for example, if it has been determined that the pH value of the hyperpolarized polarization solution lies within a predetermined pH range.

[0020] In an advantageous embodiment, it can be provided that molecule types A and C are identical in their chemical structure. Alternatively or additionally, it can be provided that molecule types B and D are identical in their chemical structure.

[0021] The respective hyperpolarized molecule types C and D can thus represent the chemically identical substance as the respective hyperpolarizable molecule types A and B. In this case, the molecule types A and C, or B and D, differ only in the degree of ordered alignment of their nuclear spins. Thus, it can be provided, in particular, that the molecule type A already serves as the contrast agent molecule for the subsequent magnetic resonance procedure, in particular magnetic resonance spectroscopy and / or magnetic resonance imaging, preferably on a patient.

[0022] In an advantageous embodiment, it can be provided that molecule type A is a precursor of molecule type C. Alternatively or additionally, it can be provided that molecule type B is a precursor of molecule type D.

[0023] Thus, within the scope of the process according to the invention, material transformations of molecule type A and / or molecule type B can occur. This can be the case in particular if the hyperpolarization process comprises further intermediate steps, cleavage processes, for example, ester cleavage processes, purification processes, and / or chemical conversion steps. For example, a hyperpolarized molecule type A* and / or B* can first be generated from molecule type A and / or B, from which the hyperpolarized molecule type C and / or D arises, for example, through a cleavage reaction.

[0024] In an advantageous embodiment, it can be provided that the hyperpolarization method is dDNP (dissolution dynamic nuclear polarization). Alternatively or additionally, it can be provided that the hyperpolarization method is PHIP (parahydrogen induced polarization) or parahydrogen-based hyperpolarization methods based thereon. Alternatively or additionally, it can be provided that the hyperpolarization method is PHIP-SAH (parahydrogen induced polarization-side arm hydrogenation). Alternatively or additionally, it can be provided that the hyperpolarization method is SABRE (signal amplification by reversible exchange). Alternatively or additionally, it can be provided that the hyperpolarization method is brute force.

[0025] Thus, various hyperpolarization methods known to those skilled in the art can be selected. For example, dDNP is a method that can eliminate the use of parahydrogen. In this method, after the addition of free radicals to the polarization solution, the hyperpolarizable molecules A and B are exposed to electromagnetic radiation in a strong magnetic field of, for example, 5 Tesla at temperatures around 1 Kelvin. This transfers the pronounced electron polarization to the molecules A and B, thus resulting in hyperpolarization of the molecules A and B. In this method, the polarization solution is present, at least temporarily, as a solid phase.

[0026] However, hyperpolarization methods that utilize parahydrogen can also be selected. PHIP and PHIP-SAH are available, which can involve hydrogenation of molecule type A and / or B using parahydrogen. This allows a spin order of 1 H atoms of parahydrogen are introduced into the molecule type A and / or B, which are transferred to another NMR-active atomic nucleus, for example 13C. The SOT sequence consists of a specific sequence of electromagnetic pulses, and / or passage through a variable magnetic field, and / or pulses of a static magnetic field. In the case of PHIP, the hyperpolarized molecule type C and / or D can be obtained directly from this, whereas in the case of PHIP-SAH this occurs directly or after cleavage of a molecular fragment of a hyperpolarized molecule type A* and / or B*. With SABRE, a hyperpolarization process using parahydrogen can also be used, which does not involve hydrogenation of the molecule type A and / or B. Here, a catalyst is used to which parahydrogen and molecule types A and B bind simultaneously and reversibly, which serves to transfer the spin order from the parahydrogen molecules to the molecule type A and / or B.

[0027] In an advantageous embodiment, it can be provided that a molar ratio of molecule type B to molecule type A is at least 1%. Alternatively or additionally, it can be provided that a molar ratio of molecule type D to molecule type C is at least 1%. In particular, it can be provided that the respective molar ratios are at least 2% or at least 5%.

[0028] In this way, it can be ensured that a sufficiently strong nuclear magnetic resonance signal of molecule type D can be obtained in the further course of the process to enable a sufficiently accurate determination of the pH value of the hyperpolarized polarization solution.

[0029] In an advantageous embodiment, it can be provided that the molecule type A and / or the molecule type C is a 13 C-labeled and / or a 15 N-labeled compound.

[0030] Therefore, organic compounds can be used that contain a number of NMR-active atoms and / or NMR-active atoms at defined positions that exceed the natural isotopic distribution. The NMR-active atoms can be, for example, the atoms mentioned above, such as 1 H-, 13 C-, 15 N-, 29 Si-, 31 P- and / or 57 Fe atoms. For example, NMR spectra of preferably high quality can be generated, especially at comparatively low molecular concentrations, and / or contrasts related to these atoms can be analyzed in magnetic resonance imaging.

[0031] Alternatively or additionally, it may be provided that molecule type A and / or molecule type C is a metabolic metabolite. It is also possible that a metabolic metabolite can be released from molecule types A and / or C, particularly after their possible hydrogenation during the hyperpolarization process, for example during a further intermediate step of the hyperpolarization process.

[0032] In this way, a metabolic metabolite can be used as a contrast molecule in the contrast agent. This allows metabolic processes in organisms, for example, human patients, to be reconstructed. For example, the metabolic metabolite can be a metabolic metabolite from glycolysis and / or cellular respiration and / or fatty acid synthesis. Molecule type A and / or molecule type C can also be a substance selected from the group consisting of glucose, glucolactone, pyruvate, alanine, lactate, citrate, α-ketoglutarate, glutamine, glutamate, succinate, bicarbonate, fumarates, acetates, acetoacetates, vitamins, vitamin C, and dehydroascorbic acid. Furthermore, they can be (metabolically active) active ingredients such as azomycin and / or substances from the nitroimidazole group.

[0033] In an advantageous embodiment, it can be provided that the molecule type B and / or the molecule type D is a 13 C-labelled compound. Alternatively or additionally, it may be a substance selected from the group consisting of zymonic acid, 13 C-labeled Z-OMPD ([1,5- 13 C2]Z-4-methyl-2-oxopent-3-enedioic acid), bicarbonate, azomycin and metronidazole.

[0034] In this way, NMR-active carbon in the form of 13 C atoms and / or NMR-active nitrogen in the form of 15N atoms are used to amplify the nuclear magnetic resonance signal of molecule type D. This ensures that the NMR spectrum has sufficient signal intensity for computer-assisted analysis of the nuclear magnetic resonance signal of molecule type D. Molecule type B and / or molecule type D can, for example, also be bicarbonate and / or Z-OMPD and / or azomycin, if molecule type A and / or molecule type C are not already bicarbonate and / or Z-OMPD and / or azomycin.

[0035] In an advantageous embodiment, it can be provided that the molecule type C has hyperpolarized atomic nuclei of an element different from the hyperpolarized atomic nuclei of the molecule type D.

[0036] For example, the molecule type C can produce hyperpolarized 13 C atoms and the molecule type D hyperpolarized 15 have N atoms.

[0037] In an advantageous embodiment, it can be provided that further chemical and / or physical parameters of the hyperpolarized polarization solution and / or the contrast agent are determined. This determination can preferably be carried out using sensors. In this case, it can be provided that the provision of the contrast agent is additionally dependent on the determined parameter.

[0038] The parameters can include, for example, the signal intensity to determine the concentration or degree of polarization of the contrast agent, the chemical shift to determine solvent purity, or the temperature of the hyperpolarized polarization solution and / or the contrast agent. In this context, a pH control measurement with a sensor, a determination of the sample volume, or an optical transparency or transmission measurement, for example, to examine the sample for particle and / or catalyst residues, can also be performed.

[0039] Alternatively or additionally, the features of the independent claim directed to a contrast agent are provided according to the invention to achieve the stated object. In particular, to achieve the stated object, it is proposed in the invention for contrast agents of the type described above that they be prepared by a method according to the invention.

[0040] Thus, the advantages of the method according to the invention can be utilized for the provision of contrast agents as well as with the contrast agents provided.

[0041] In an advantageous embodiment, it can be provided that a molar ratio of the molecule type D to the molecule type C is at least 1%, in particular at least 2% or at least 5%.

[0042] In this way, it can be ensured that the contrast agent has a sufficiently strong nuclear magnetic resonance signal of molecular type D in the measured NMR spectrum and that the computer-assisted evaluation for determining the pH value can be carried out.

[0043] The invention will now be described in more detail using exemplary embodiments, but is not limited to the exemplary embodiments. Further exemplary embodiments arise from combining the features of one or more claims with one another and / or with one or more features of the exemplary embodiments.

[0044] They show: Fig. 1 a flow diagram of a method according to the invention for providing a contrast agent and Fig. 2 a schematic representation of different states of the polarization solution during two inventive processes of the inventive method for providing a contrast agent.

[0045] Fig. 1 shows a schematic representation of five steps of a method according to the invention for providing a contrast agent 1, wherein the contrast agent 1 contains at least one hyperpolarized molecule type C 4.

[0046] Step 1 involves providing 6 a polarization solution 7 containing a first molecule type A 2 and a second molecule type B 3 that differs from molecule type A 2 . In an embodiment of the method not shown, molecule type A 2 and molecule type B 3 can be provided in separate polarization solutions 7. The second step comprises hyperpolarizing 8 the polarization solution 7 by simultaneously hyperpolarizing molecule types A 2 and B 3 using a hyperpolarization process, whereby a polarized molecule type C 4 is obtained from molecule type A 2 and a hyperpolarized molecule type D 5 is obtained from molecule type B 3 . In an embodiment not shown, molecule type A 2 and molecule type B 3 can be hyperpolarized separately from one another. The second step can comprise purification, cleavage, and / or mixing steps.For example, the hyperpolarized polarization solution 10 can be prepared by at least partially mixing the polarization solutions containing the hyperpolarized molecule type C 4 and the hyperpolarized molecule type D 5 . The third step comprises measuring 9 an NMR spectrum of the hyperpolarized polarization solution 10 using an NMR method. The fourth step comprises determining 11 a pH value of the hyperpolarized polarization solution 10 by computer-assisted evaluation of a nuclear magnetic resonance signal of the molecule type D 5 in the measured NMR spectrum. The fifth step comprises providing 12 the contrast agent 1 depending on the determined pH value. In the method shown in . Fig. In the process according to the invention schematically illustrated in Figure 1, the molecule types A 2 and C 4 as well as the molecule types B 3 and D 5 can have the same chemical structure.

[0047] In Fig. Figure 2 schematically shows the changes a polarization solution 7 containing molecules of type A 2 and B 3 can undergo during various processes according to the invention. The horizontally guided sequence represents a process according to the invention, wherein molecule type A 2 is a precursor of molecule type C 4 and molecule type B 3 is a precursor of molecule type D 5. The conversion of molecule types A 2 and B 3 into molecule types C 4 and D 5 occurs during hyperpolarization 8 of the polarization solution 7, resulting in a hyperpolarized polarization solution 10. Hyperpolarization 8 can be carried out by means of PHIP, in which hydrogenation of molecule types A 2 and B 3 occurs, which are therefore precursors of molecule types C 4 and D 5.

[0048] The hyperpolarization 8 of the polarization solution 7 may include further sub-steps. This is shown in the lower part of the Fig. 2. Here, the hyperpolarization 8 is divided into a first intermediate step, in which the hyperpolarization 13 of the polarization solution 7 takes place, resulting in a hyperpolarized polarization solution 14 with the molecular types A* 15 and B* 16. These are not yet the molecular types later present in the provided contrast agent 1, in particular not the hyperpolarized molecular type C 4. This case occurs when using the PHIP-SAH hyperpolarization method, in which the molecular types C 4 and D 5 are only obtained after a purification step 17.

[0049] In embodiments of the method according to the invention not shown, other parahydrogen-based methods (for example, SABRE and / or SABRE-Relay and / or PHIP-X) and / or the hyperpolarization methods dDNP and / or brute force can also be used. Furthermore, it is possible that not every molecule type is subject to material changes. For example, molecule type A 2 can represent a precursor of the hyperpolarized molecule type C 4 , with molecule type B 3 and molecule type D 5 having the same chemical structure.

[0050] In both cases, ie with differently designed hyperpolarization 8 of the polarization solution 7, the procedure with the hyperpolarized polarization solution 10 can basically be continued in the same way. Fig.The steps explained in Figure 2 include measuring 9 an NMR spectrum of the hyperpolarized polarization solution 10 using an NMR method and determining 11 a pH value of the hyperpolarized polarization solution 10 by computer-assisted evaluation of a nuclear magnetic resonance signal of the molecule type D 5 in the measured NMR spectrum. Subsequently, the provision 12 of the contrast agent 1 can take place depending on the determined pH value.

[0051] In the processes described, a molar ratio of molecule type B 3 to molecule type A 2 and of molecule type D 5 to molecule type C 4 is at least 1%, namely at least 5%.

[0052] Molecule type A 2 and molecule type C 3 are each a 13C-labeled compound, namely a metabolic metabolite. This can be a metabolic metabolite from glycolysis and / or cellular respiration and / or fatty acid synthesis, or a substance selected from the group consisting of glucose, glucolactone, pyruvate, alanine, lactate, citrate, α-ketoglutarate, glutamine, glutamate, succinate, bicarbonate, fumarates, acetates, acetoacetates, vitamins, vitamin C, and dehydroascorbic acid. Molecule type B 3 and molecule type D 5 are also 13C-labeled compound, namely zymonic acid. This can also be bicarbonate, metronidazole, and / or Z-OMPD, if molecule type A 2 and / or molecule type C 3 are not already bicarbonate, metronidazole, and / or Z-OMPD. It is possible that molecule type C 4 contains hyperpolarized nuclei of an element that differs from the hyperpolarized nuclei of molecule type D.

[0053] In an embodiment of the method not shown, further chemical and / or physical parameters of the hyperpolarized polarization solution 10 and / or the contrast agent 1 can be determined. This can preferably be done using sensors. The provision 12 of the contrast agent 1 can additionally depend on the determined parameters. Finally, the contrast agent 1 is a contrast agent 1 provided by a method according to the invention.

[0054] A method for providing a contrast agent 1 is thus proposed, wherein the contrast agent 1 contains at least one hyperpolarized molecule type C 4 , wherein the method comprises at least the following steps: providing 6 a first molecule type A 2 and a second molecule type B 3 different from the molecule type A 2 in at least one polarization solution 7, hyperpolarization 8 of the at least one polarization solution 7 by hyperpolarizing the molecule types A 2 and B 3 by means of a hyperpolarization method, wherein a hyperpolarized molecule type C 4 is obtained from the molecule type A 2 and a hyperpolarized molecule type D 5 is obtained from the molecule type B 3, measuring 9 an NMR spectrum of the at least one hyperpolarized polarization solution 10 by means of an NMR method,Determining a pH value of the at least one hyperpolarized polarization solution 10 by computer-assisted evaluation of a nuclear magnetic resonance signal of the molecule type D 5 in the measured NMR spectrum, providing 12 the contrast agent 1 depending on the determined pH value. Furthermore, a contrast agent 1 provided by a method according to the invention is proposed. List of reference symbols 1 contrast agent 2 Molecule type A 3 Molecule type B 4 Molecule type C 5 Molecule type D 6 Provision 7 Polarization solution 8 Hyperpolarization 9 trade fairs 10 hyperpolarized polarization solution 11 Determine 12 Provision 13 Hyperpolarization 14 hyperpolarized polarization solution 15 Molecule Type A* 16 Molecule type B* 17 Purification step

Claims

[1] A method for providing a contrast agent (1), wherein the contrast agent (1) contains at least one hyperpolarized molecule type C (4), comprising: - Providing (6) a first molecule type A (2) and a second molecule type B (3) different from the molecule type A (2) in at least one polarization solution (7), - hyperpolarization (8) of the at least one polarization solution (7) by hyperpolarization of the molecule types A (2) and B (3) by means of a hyperpolarization process, whereby a hyperpolarized molecule type C (4) is obtained from the molecule type A (2) and a hyperpolarized molecule type D (5) is obtained from the molecule type B (3), - measuring (9) an NMR spectrum of the at least one hyperpolarized polarization solution (10) by means of an NMR method, - determining a pH value of the at least one hyperpolarized polarization solution (10) by computer-assisted evaluation of a nuclear magnetic resonance signal of the molecular type D (5) in the measured NMR spectrum, - Providing (12) the contrast agent (1) depending on the determined pH value. [2] Method according to the preceding claim, characterized by that the molecule types A (2) and B (3) are provided in a common polarization solution (7) and hyperpolarized simultaneously. [3] Method according to one of the preceding claims, characterized by that the hyperpolarized polarization solution (10) is prepared by at least partially mixing the polarization solutions containing the hyperpolarized molecule type C (4) and the hyperpolarized molecule type D (5). [4] Method according to one of the preceding claims, characterized bythat the molecule types A (2) and C (4) and / or that the molecule types B (3) and D (5) are identical in their chemical structure. [5] Method according to one of the preceding claims, characterized by that the molecular type A (2) is a precursor of the molecular type C (4) and / or that the molecular type B (3) is a precursor of the molecular type D (5). [6] Method according to one of the preceding claims, characterized by that the hyperpolarization method is dDNP, PHIP, PHIP-SAH, SABRE and / or brute force. [7] Method according to one of the preceding claims, characterized by that a molar ratio of the molecule type B (3) to the molecule type A (2) and / or the molecule type D (5) to the molecule type C (4) is at least 1%, in particular at least 5%. [8] Method according to one of the preceding claims, characterized by that the molecule type A (2) and / or the molecule type C (4) is a 13C-labeled compound and / or a 15 N-labeled compound and / or a metabolic metabolite, in particular from glycolysis and / or cellular respiration and / or fatty acid synthesis, and / or a substance selected from the group consisting of glucose, glucolactone, pyruvate, alanine, lactate, citrate, α-ketoglutarate, glutamine, glutamate, succinate, bicarbonate, fumarate, acetate, acetoacetate, vitamins, vitamin C and dehydroascorbic acid. [9] Method according to one of the preceding claims, characterized by that the molecule type B (3) and / or the molecule type D (5) is a 13 C-labeled compound and / or a substance selected from the group consisting of zymonic acid, Z-OMPD, azomycin, bicarbonate and metronidazole. [10] Method according to one of the preceding claims, characterized bythat the molecule type C (4) has hyperpolarized nuclei of an element different from the hyperpolarized nuclei of the molecule type D (5). [11] Method according to one of the preceding claims, characterized by that further chemical and / or physical parameters of the hyperpolarized polarization solution (10) and / or the contrast agent (1) are preferably determined by sensors, in particular wherein the provision (12) of the contrast agent (1) is additionally dependent on the determined parameters. [12] Contrast agent (1) provided by a method according to any one of the preceding claims. [13] Contrast agent (1) according to the preceding claim, wherein a molar ratio of the molecule type D (5) to the molecule type C (4) is at least 1%, in particular at least 5%.

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