Contrast medium and method for providing same

Abstract

The invention relates to a method for providing a contrast medium (1), wherein the contrast medium (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), which differs from the molecule type A (2), in at least one polarization solution (7); hyperpolarizing (8) 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-aided evaluation of a nuclear magnetic resonance signal of the molecule type D (5) in the measured NMR spectrum; providing (12) the contrast medium (1) depending on the determined pH value. The invention furthermore relates to a contrast medium (1) provided by a method according to the invention.

Description

[0001] Contrast agent and method for its provision

[0002] The invention relates to a method for providing a contrast agent, wherein the contrast agent contains at least one hyperpolarized molecule species.

[0003] The invention further relates to a contrast agent provided by a method of the type mentioned at the outset.

[0004] Such methods and contrast agents are known from the state of the art. They are used in magnetic resonance methods, particularly in magnetic resonance spectroscopy and magnetic resonance tomography. These are nuclear magnetic resonance methods, which can be referred to as NMR methods (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, tissue with increased metabolic activity, such as tumors, can be detected. In order to clearly visualize this tissue, contrast agents can be administered to the patient.This can be done intravenously, for example. Such a contrast agent can contain contrast agent molecules which, on the one hand, are, for example, a metabolic metabolite, i.e., they participate in the patient's metabolism and accumulate and / or are converted to a greater extent in tissues with increased metabolic activity, and which, on the other hand, can be visualized using the magnetic resonance techniques mentioned. For this purpose, the contrast agent molecules have 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.

[0005] 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.

[0006] 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 describe states in which two or more atoms of the same species jointly occupy a non-equilibrium state, for example, a singlet state.

[0007] 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 can in particular comprise releasing a contrast agent for use on a patient. Providing the contrast agent can 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.

[0008] 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 use on a patient. However, as time goes on, 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 it takes to determine the pH value, which can be several minutes with the previously mentioned 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 already have lost 75% or more of its hyperpolarization and may only be of limited use for subsequent examinations.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:

[0010] In a first step, a first molecule type A and a second molecule type B different from the molecule type A are provided in at least one polarization solution.

[0011] 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 which 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 water or an organic solvent, for example acetone, methanol, ethanol and / or chloroform. The polarization solution can also contain further substances which are required, for example, for the hyperpolarization process (e.g. exchange or hydrogenation catalysts, radicals, excitable radicals) or which 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 respective plurality of molecules of the respective type of molecule by means of hyperpolarization.

[0012] 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.

[0013] 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.

[0014] The hyperpolarization of the polarization solution is therefore the process after at least the molecular types A and B have each been converted into hyperpolarized molecular types C and D. This does not necessarily involve a material transformation of the molecular types. The molecular types A and C or B and D can, for example, only differ in that the hyperpolarizable molecular types A and B are not hyperpolarized and the molecular types C and D are hyperpolarized. Non-hyperpolarized molecular types can be understood in particular to mean that a degree of ordered alignment of nuclear spins of the molecular type corresponds to a thermal equilibrium state. The hyperpolarization process can comprise further steps, for example for purifying the polarization solution, which can lead to material transformations of the molecular types.Thus, it is possible that, within the framework of the hyperpolarization process, molecule type A is first hyperpolarized, whereby only after a further intermediate step, for example, the splitting off of a molecular fragment of molecule type A, is the hyperpolarized molecule type C obtained.

[0015] 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 therefore available. The hyperpolarized polarization solution can be prepared by at least proportionally 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 therefore also be carried out separately, in which case the same or different hyperpolarization processes can be used.Just like the purification or cleavage steps mentioned above, the mixing step mentioned above can be counted as the second step of the process. The mixing step can, for example, take place before or after purification or cleavage steps.

[0016] 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.

[0017] The NMR method can, for example, be a X 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 ( X H or 2 H NMR) can be used to determine 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.

[0018] In a fourth step, the pH value of the polarization solution is determined by computer-assisted evaluation of a nuclear magnetic resonance signal of the molecular type D in the measured NMR spectrum.

[0019] The molecule type D is chosen such that it contains the NMR-active atomic nucleus excited in the NMR process. In order to enable the determination of a pH value, the molecule type D is chosen such that it has 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 the molecule type D. The molecule type D can cause several 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 the molecule type D to be evaluated is known within a certain chemical shift range, so that it can be evaluated in a targeted, preferably automated, computer-aided manner.The pH value of the hyperpolarized polarization solution can be determined by evaluating the position of this nuclear magnetic resonance signal.

[0020] In a fifth step, the contrast agent is provided depending on the determined pH value.

[0021] A pH range can be specified here, 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 take place for injection into a patient. In this case, however, provision will not take place if the pH is outside the specified pH range. For example, the contrast agent can then be disposed of instead of being prepared for injection. The contrast agent provided does not necessarily differ chemically 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.The hyperpolarized polarization solution can be referred to as a contrast agent in the sense of this invention, for example, if it has been determined that the pH value of the hyperpolarized polarization solution lies in a predetermined pH range.

[0022] In an advantageous embodiment, it can be provided that molecule types A and C correspond in their chemical structure. Alternatively or additionally, it can be provided that molecule types B and D correspond in their chemical structure.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] Thus, a choice can be made between various hyperpolarization processes known to those skilled in the art. For example, dDNP can be used as a process in which the use of parahydrogen can be dispensed with. In this process, 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 after free radicals have been added to the polarization solution. This transfers the pronounced electron polarization to the molecules A and B, thus resulting in hyperpolarization of the molecules A and B. In this process, the polarization solution is present, at least temporarily, as a solid phase.

[0028] However, hyperpolarization methods that utilize parahydrogen can also be selected. PHIP and PHIP-SAH are available methods that can include hydrogenation of molecule type A and / or B using parahydrogen. In this way, 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 nucleus, for example 13C, can be transferred. The SOT sequence consists of a specific sequence of electromagnetic pulses, and / or passage through a changing 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 splitting off 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 parahydrogen molecules to the molecule type A and / or B.

[0029] 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%.

[0030] In this way, it can be ensured that a sufficiently strong nuclear magnetic resonance signal of the molecule type D can be obtained in the further course of the process in order to enable a sufficiently accurate determination of the pH value of the hyperpolarized polarization solution.

[0031] 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.

[0032] 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 X 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.

[0033] 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.

[0034] In this way, a metabolic metabolite can be used as a contrast molecule in the contrast agent. Thus, metabolic processes in organisms, for example, human patients, can 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, a-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 group of nitroimidazoles. In an advantageous embodiment, it can be provided that molecule type B and / or molecule type D is a 13C-labelled compound. Alternatively or additionally, it may be a substance selected from the group consisting of zymonic acid, demarcated Z-OMPD ([ 1 , 5- 13 C2] Z-4-methyl-2-oxopent-3-enedioic acid), bicarbonate, azomycin and metronidazole.

[0035] In this way, NMR-active carbon can be produced 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 is not already bicarbonate and / or Z-OMPD and / or azomycin.

[0036] In an advantageous embodiment, it can be provided that the molecule type 0 has hyperpolarized atomic nuclei of an element different from the hyperpolarized atomic nuclei of the molecule type D.

[0037] For example, the molecule type 0 can be hyperpolarized 13 C atoms and the molecule type D hyperpolarized 15 have N atoms.

[0038] 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.

[0039] The parameters can be, for example, the signal intensity to determine the concentration or degree of polarization of the contrast agent, the chemical shift to determine the 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 residues such as particles and / or catalyst residues, can also be performed.

[0040] 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 according to the invention that contrast agents of the type described above be prepared by a method according to the invention.

[0041] Thus, the advantages of the method according to the invention for the provision of contrast agents and with the contrast agents provided can be utilized.

[0042] In an advantageous embodiment, it can be provided that a quantitative ratio of the molecule type D to the molecule type C is at least 1%, in particular at least 2% or at least 5%.

[0043] 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.

[0044] The invention will now be described in more detail with reference to exemplary embodiments, but is not limited to the exemplary embodiments. 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 embodiments.

[0045] It shows :

[0046] Figure 1 is a flow diagram of a method according to the invention for providing a contrast agent and

[0047] Figure 2 is a schematic representation of different states of the polarization solution during two inventive sequences of the inventive method for providing a contrast agent.

[0048] Figure 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 .

[0049] 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 the molecule type A 2 . In a not shown

[0050] In one embodiment of the method, molecule type A 2 and molecule type B 3 can be provided in separate polarization solutions 7. The second step comprises the hyperpolarization 8 of the polarization solution 7 by simultaneous hyperpolarization of molecule types A 2 and B 3 by means of a hyperpolarization process, wherein 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, splitting and / or mixing steps. For example, the hyperpolarized polarization solution 10 can be produced by at least proportionally 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 molecular 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 according to the invention schematically shown in Figure 1, the molecular types A 2 and C 4 as well as the molecular types B 3 and D 5 can have the same chemical structure.

[0051] Figure 2 shows a schematic representation of the changes that a polarization solution 7 containing molecules of type A 2 and B 3 can undergo in the course of various processes according to the invention. The horizontal 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 takes place during the hyperpolarization 8 of the polarization solution 7, whereby a hyperpolarized polarization solution 10 is obtained. The hyperpolarization 8 can take place by means of PHIP, in which hydrogenation of molecule types A 2 and B 3 takes place, which are therefore precursors of molecule types C 4 and D 5 .

[0052] The hyperpolarization 8 of the polarization solution 7 can comprise further sub-steps. This is shown in the lower part of Figure 2. Here, the hyperpolarization 8 is divided into a first intermediate step, in which the hyperpolarization 13 of the polarization solution 7 takes place, whereby a hyperpolarized polarization solution 14 with the molecular types A* 15 and B* 16 is obtained. 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.

[0053] 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 , wherein molecule type B 3 and molecule type D 5 have the same chemical structure.

[0054] In both cases, i.e., with differently configured hyperpolarization 8 of the polarization solution 7, the hyperpolarized polarization solution 10 can be further processed in basically the same way. Thus, the steps explained with reference to Figure 2 are followed by the measurement 9 of an NMR spectrum of the hyperpolarized polarization solution 10 using an NMR method and the determination 11 of 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.

[0055] 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%.

[0056] 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 also a substance selected from the group consisting of glucose, glucolactone, pyruvate, alanine, lactate, citrate, a-ketoglutarate, glutamine, glutamate, succinate, bicarbonate, fumarate, acetate, acetoacetate, vitamins, vitamin C and dehydroascorbic acid. Molecule type B 3 and molecule type D 5 are also demarcated compounds, namely zymonic acid. This may 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 the molecule type C has 4 hyperpolarized nuclei of an element that is different from the hyperpolarized nuclei of the molecule type D.

[0057] 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.

[0058] 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 as a function of the determined pH value. Furthermore, a contrast agent 1 provided by a method according to the invention is proposed.

[0059] List of reference symbols

[0060] 1 contrast agent

[0061] 2 Molecule type A

[0062] 3 Molecule type B 4 Molecule type C

[0063] 5 Molecule type D

[0064] 6 Provision

[0065] 7 Polarization solution

[0066] 8 Hyperpolarization 9 Measuring

[0067] 10 hyperpolarized polarization solution

[0068] 11 Determine

[0069] 12 Provision

[0070] 13 Hyperpolarization 14 hyperpolarized polarization solution

[0071] 15 Molecule Type A*

[0072] 16 Molecule type B*

[0073] 17 On cleaning step

Claims

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, wherein from the molecule type A (2) a hyperpolarized molecule type C (4) is formed and from the Molecule type B (3) a hyperpolarized molecule type D (5) be obtained, - 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 in that the molecule types A (2) and B (3) are provided in a common polarization solution (7) and are hyperpolarized simultaneously.

3. Method according to one of the preceding claims, characterized in that the hyperpolarized polarization solution (10) is prepared by at least partial mixing of the hyperpolarized molecule type C (4) and the polarization solutions containing hyperpolarized molecule type D (5).

4. Method according to one of the preceding claims, characterized in that 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 in that the molecule type A (2) is a precursor of the molecule type C (4) and / or that the molecule type B (3) is a precursor of the molecule type D (5).

6. Method according to one of the preceding claims, characterized in that the hyperpolarization method is dDNP, PHIP, PHIP-SAH, SABRE and / or brute force.

7. Method according to one of the preceding claims, characterized in 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 in that the molecule type A (2) and / or the molecule type C (4) is a 13 C-labeled compound and / or a 15 N-labelled 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, a-ketoglutarate, glutamine, glutamate, succinate, bicarbonate, fumarates, acetates, acetoacetates, vitamins, vitamin C and dehydroascorbic acid is .

9. Method according to one of the preceding claims, characterized in 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 in that the molecular type C (4) has hyperpolarized atomic nuclei of an element different from the hyperpolarized atomic nuclei of the molecular type D (5).

11. Method according to one of the preceding claims, characterized in that further chemical and / or physical parameters of the hyperpolarized polarization solution (10) and / or of 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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