Contrast agent for nuclear spin imaging

Abstract

The invention relates to a contrast agent for nuclear spin imaging, comprising a polarizable agent (tracer) having a nuclear spin, tracer molecules being polarizable by polarizing the nuclear spins thereof, and comprising a retarding agent (retarder), a molecular interaction of retarder molecules with tracer molecules resulting in an extension of the T1 relaxation time of the tracer. The invention further relates to a method for producing a hyperpolarized contrast agent, to a retarder for use in a contrast agent for nuclear spin imaging, to a contrast agent for use in an in vivo and / or in vitro diagnostic method, and to the use of a retarder in a contrast agent for nuclear spin imaging in order to extend the T1 relaxation time of the tracer.

Description

[0001] Contrast agents for magnetic resonance imaging

[0002] The invention relates to a contrast agent for magnetic resonance imaging.

[0003] The invention further relates to a method for producing a hyperpolarized contrast agent.

[0004] The invention further relates to a retarder for use in a contrast agent for magnetic resonance imaging.

[0005] The invention further relates to a use of a retarder according to the invention.

[0006] Such a contrast agent comprises at least one polarizable agent exhibiting nuclear spin. This agent consists of molecules and possesses nuclear spin because at least one type of atom from which the agent is composed exhibits nuclear spin. The agent is therefore polarizable by aligning at least a portion of its nuclear spins. Thus, the agent can be used in a manner known per se in nuclear spin-based imaging, in particular magnetic resonance imaging (MRI).

[0007] This agent is referred to as a tracer in this application. The tracer consists of tracer molecules. It is possible that, when applied to the patient, the tracer participates in the patient's metabolism and, for example, accumulates in areas of increased metabolic activity. These areas are then highlighted in magnetic resonance imaging (MRI). However, it is not necessary for the tracer to participate in the patient's metabolism. Therefore, the terms "tracer" or "tracer molecules" as used in this application can also refer to substances or their molecules that do not participate in the patient's metabolism. These substances or molecules, which can be described, for example, as non-metabolic substances or non-metabolic molecules, can be used, for instance, in angiography, the examination of the patient's blood flow, the examination of the blood-brain barrier function, pH measurements, ion mapping, or the investigation of organ function.

[0008] The visibility of tissue structures in magnetic resonance imaging (MRI) depends, among other things, on the concentration of tracer molecules at the site of observation, the degree of polarization of the tracer molecules, and the Tl relaxation time of the tracer. A higher concentration of tracer molecules and / or a higher degree of polarization of the tracer molecules and / or a longer Tl relaxation time leads to a higher signal intensity in the magnetic resonance image.

[0009] The object of the invention is to improve the visibility of tissue structures when using a contrast agent of the type described above.

[0010] To solve the aforementioned problem, the features of claim 1 are provided according to the invention. In particular, to solve the aforementioned problem in contrast agents of the type described above, it is proposed according to the invention that the contrast agent comprises a retarding agent, which is referred to in this application as a retarder and consists of retarder molecules, wherein a molecular interaction of retarder molecules with the tracer molecules results in a prolongation of the Tl relaxation time of the tracer.

[0011] The invention has recognized that a molecular interaction between retarder molecules and tracer molecules can be used to extend the Tl relaxation time of the tracer.

[0012] The tracer and / or the retarder can consist of neutral or ionic molecules. They can also be composed of several molecules and form an adduct. In this case, it is sufficient if one molecular component acts as the tracer and / or the retarder.

[0013] In an advantageous embodiment, it can be provided that the polarizable tracer is hyperpolarizable and that the tracer molecules can be brought into a hyperpolarized state by hyperpolarizing their nuclear spins.

[0014] Hyperpolarization techniques, such as DNP, PHIP, and / or SABRE, can therefore be applied to the contrast agent to increase the signal intensity of the tracer in magnetic resonance imaging (MRI). The tracer's nuclear spins can thus be aligned beyond thermal equilibrium, resulting in a greater degree of tracer polarization than is possible at thermal equilibrium.

[0015] In an advantageous embodiment, the tracer may be dissolved and / or dispersed in a solvent. Alternatively or additionally, the retarder may be dissolved and / or dispersed in a solvent.

[0016] Thus, the tracer and / or the retarder are manageable in a liquid, for example, a liquid contrast medium. The tracer and / or the retarder can be dissolved at the molecular level. The tracer and / or the retarder can also form a dispersion with the solvent, such as a suspension and / or an emulsion. In this case, the solvent constitutes at least part of the dispersion medium. Depending on the properties of the tracer and / or the retarder, they can therefore be injected into a patient as a solution and / or as a dispersion.

[0017] Additionally, it may be specified that the solvent is selected from the group consisting of water, ethanol, methanol, DMSO and their mixtures.

[0018] Therefore, the solvent can be advantageously chosen depending on the tracer and / or retarder used. In addition to the tracer, the retarder, and the solvent, which can constitute a dispersion medium and / or at least partially form one, the contrast agent may also contain further additives, for example, for pH adjustment or stabilization of a dispersion.

[0019] In an advantageous embodiment, the contrast agent may contain a relaxation source that shortens the Tl relaxation time of the tracer, the effect of which is weakened and / or suppressed by the molecular interaction of the retarder molecules with the tracer molecules.

[0020] Thus, the molecular interaction of the retarder with the tracer can be used to reduce the effect of the relaxation source on the tracer and its relaxation time. The relaxation source can be a substance that is already present in the contrast agent, particularly if it is necessary for its production.

[0021] Additionally, the relaxation source may be the solvent or solvent, preferably selected from the group consisting of water, ethanol, methanol, DMSO and mixtures thereof.

[0022] This can be the solvent in which the tracer and / or retarder are dissolved and / or dispersed. The solvent can thus also act as a dispersion medium and / or at least partially constitute one. Therefore, the retarder can be chosen to at least partially compensate for the effect of a solvent that shortens the tracer's Tl relaxation time.

[0023] Alternatively and / or additionally, the relaxation source may consist of dissolved and / or solid substances, preferably oxygen and / or impurities.

[0024] The retarder can therefore be chosen in such a way that it at least partially compensates for the effect of dissolved and / or solid substances that shorten the TL relaxation time of the tracer.

[0025] In an advantageous design, it can be provided that the interaction of the retarder with the tracer is stronger than an interaction of the relaxation source with the tracer.

[0026] The retarder can therefore be chosen so that its interaction with the tracer is stronger than that of the relaxation source. For example, the retarder can displace the relaxation source and reduce its effect on the tracer.

[0027] Additionally, the interaction of the retarder with the tracer can be stronger than the interaction of solvent molecules, especially water molecules, with the tracer. Alternatively or additionally, the retarder can be designed to reduce the interaction between the relaxation source and the tracer.

[0028] Depending on the chosen tracer and / or retarder, the type of relaxation source may be irrelevant to the interaction of the retarder with the tracer. For example, the retarder may be suitable for reducing the interaction of several different relaxation sources, such as a solvent mixture, dissolved oxygen, and impurities, with the tracer, which would shorten the Tl relaxation time of the tracer.

[0029] In an advantageous embodiment, it can be provided that the interaction of the retarder with the tracer takes place between the respective retarder and tracer molecules.

[0030] Thus, a direct interaction between retarder and tracer is possible. However, it is also possible that the retarder interacts directly with a relaxation source, which consequently can no longer interact with the tracer and cause its relaxation, or can do so to a lesser extent than before.

[0031] Alternatively or additionally, it may be provided that the interaction of the retarder with the tracer is an attractive interaction.

[0032] For example, an attack site of a relaxation source on the tracer can be blocked and / or shielded by the retarder.

[0033] Alternatively or additionally, the retarder may be designed to influence an interaction between the tracer and the solvent. This influence may, in particular, be a weakening of the interaction.

[0034] Therefore, a purely direct interaction between the retarder and the tracer is not necessary to, for example, reduce or prevent an interaction between a relaxation source and the tracer.

[0035] In an advantageous embodiment, it may be provided that the molecular interaction of retarder molecules with the tracer molecules and / or the relaxation source with the tracer and / or the solvent molecules with the tracer is an interaction within the framework of a hydrogen bond, a hydrotropic effect, a molecular collision, a molecular motion, a molecular rotation, electromagnetic interactions and / or dipolar interactions.

[0036] The interaction can originate, for example, from a single atom of a molecule. In this case, the interaction can be primarily attributed to a lone pair of electrons. The interaction can also originate from delocalized electrons. The same interaction can thus be attributed to several atoms of the same molecule. For the purposes of this application, the origin of an interaction can be understood to mean, in particular, that the structure from which the interaction originates participates in the interaction. In this context, a resultant force of the interaction can be exerted on the structure, i.e., on an atom and / or delocalized electrons and / or the atoms associated with the delocalized electrons.

[0037] Additionally, it may be provided that the molecular interaction of the relaxation source with the tracer and / or the solvent molecules with the tracer shortens the Tl-relaxation time of the tracer.

[0038] In this context, it is particularly advantageous if this interaction, which shortens the Tl relaxation time of the tracer, is reduced or prevented by the retarder.

[0039] In an advantageous embodiment, the retarder can be designed to spatially shield a binding site, or in particular several binding sites, of the tracer. This is a binding site through which the relaxation source can interact with the tracer, and / or a binding site through which the relaxation source can shorten the Tl relaxation time of the tracer. The relaxation source can be, for example, a solvent molecule.

[0040] Thus, the tracer can be shielded from a relaxation source by the retarder, for example by steric hindrance, in order to reduce or prevent the shortening of the Tl relaxation time caused by the relaxation source.

[0041] In an advantageous design, it may be provided that the average duration of an interaction between the retarder and the tracer exceeds 10 ms.

[0042] Thus, the interaction between the retarder and the tracer can prevent relaxation sources from shortening the Tl relaxation time of the tracer long enough to achieve sufficient signal strength and image quality in nuclear spin-based imaging.

[0043] Alternatively or additionally, the contrast agent may be introduced in a magnetic field, and the average duration of an interaction between the retarder and the tracer may exceed a multiple of a Larmorf frequency of a hyperpolarized atomic nucleus of the tracer triggered by the magnetic field. This multiple is at least 100 times, preferably 1000 times, 10,000 times, 100,000 times, 300,000 times, or 1,000,000 times.

[0044] In an advantageous design, it can be provided that several interactions originate from atoms of a retarder molecule.

[0045] The multiple interactions are preferably of the same type. For example, each of the multiple interactions can be ionic interactions and / or hydrogen bonds. Preferably, the multiple interactions originate from different atoms of the retarder molecule. However, the multiple interactions can also originate, for example, from delocalized electrons.

[0046] Alternatively or additionally, it can be provided that several interactions attack atoms of one or more tracer molecules.

[0047] These are preferably similar interactions. The multiple interactions can preferably act on different atoms of the tracer molecule(s). An interaction acting on the structure, for example the atom, can be understood to mean in particular that the structure is involved in the interaction. A resultant force of the interaction can be exerted on the structure.

[0048] For example, two interactions in the form of hydrogen bonds can exist between a tracer molecule and a retarder molecule, with one of the hydrogen atoms involved being provided by the tracer molecule and one by the retarder molecule, and each interacting with a nitrogen atom on the other molecule. In this case, within the meaning of this application, several similar interactions originate from different atoms of the retarder molecule and act on different atoms of the tracer molecule.

[0049] In an advantageous embodiment, it can be provided that the tracer is a preferably water-soluble biomolecule.

[0050] Thus, the invention can also be used with biomolecules as tracers. The water solubility of the tracer improves its handling in biocompatible solutions, its distribution in the patient's body, and its degradation or excretion from the body. These advantages can already be realized if the tracer is merely water-soluble but not a biomolecule. This, too, is part of this invention.

[0051] Alternatively or additionally, it may be provided that the tracer selects a structure from the group consisting of 13 Carbon atom, 15 N atom, 29 Si atom, 31 P-atom, 13 C-carbonyl group , 15 has an N-pyridine ring.

[0052] Thus, the tracer can provide different atomic nuclei for polarization or hyperpolarization to enable diverse nuclear spin-based imaging.

[0053] In an advantageous embodiment, it may be provided that the tracer and / or the retarder is a substance selected from the group consisting of nicotinamide, nicotinic acid and succinates.

[0054] Thus, a range of biomolecules can be used with the invention or in magnetic resonance imaging (MRI). In particular, the biomolecules can participate in the patient's metabolism to indicate areas of increased metabolic activity. The biomolecules can also serve to ensure the biocompatibility of the contrast agent.

[0055] Additionally, it may be provided that the tracer is materially identical to the retarder.

[0056] The tracer and the retarder can nevertheless differ atomically, namely by having different isotopes of the same element. It is therefore not necessary for both the tracer and the retarder to have a nuclear spin. For example, only the tracer, but not the retarder, may be detectable in nuclear spin-based imaging. In an advantageous embodiment, the retarder may be a substance selected from the group consisting of urea, thiourea, sulfates, cysteine, cystine, amides, glycerols, dendrimers of preferably a second generation, triphenylborane, Lewis acids, especially with boron as the Lewis acidic center, metals, and hydrogen bridge donors. Particularly when using boron, it is advantageous to select the quadrupole moment of the naturally occurring isotopes. 10 B and X1 B to be noted.

[0057] Thus, the retarder can be selected from a range of molecules, such as biomolecules and / or metabolic metabolites. The retarder can, for example, be chosen to bind to the tracer with a desired strength, resulting in a desired prolongation of the TL relaxation time.

[0058] In an advantageous embodiment, it may be provided that the solvent is water and the retarder is nicotinamide, and that the tracer is selected from the group consisting of nicotinamide, pyridine and pyrimidine.

[0059] The contrast agent can therefore contain water as a solvent and, in particular, can be injected into a patient without separation. The contrast agent may contain other solvents. Nicotinamide as a retarder has proven particularly suitable in aqueous solutions for prolonging the thrombolysis time of nicotinamide, pyridine, and / or pyrimidine.

[0060] In an advantageous embodiment, the solvent may be water and the tracer and retarder may be selected from the following tracer / retarder pairs: nicotinamide / urea, pyrimidine / urea or metronidazole / urea, thiourea / pyridine, glucose / pyridine, ascorbic acid / pyridine, lactic acid / pyridine, pyridine / triphenylborane, pyruvate / phosphate buffer, pyruvate / tris buffer, pyruvate / HEPES buffer, succinate / phosphate buffer, succinate / glycerol, nicotinamide / glycerol, nicotinamide / dendrimer, pyridine / glycerol.

[0061] The contrast agent can therefore contain water as a solvent and, in particular, can be injected into a patient without separation. The contrast agent may contain other solvents. The selected tracer / retarder pairs exhibit a particularly advantageous interaction between tracer and retarder and / or between retarder and relaxation sources, so that the tracer's relaxation time is advantageously prolonged. The use of ascorbic acid can reduce the oxygen content in the solvent, so that it can only act to a reduced extent as a relaxation source.

[0062] In an advantageous design, it can be provided that at least the tracer is hyperpolarized.

[0063] This makes it possible to provide a hyperpolarized contrast agent and achieve an even higher signal intensity and thus better quality in nuclear magnetic resonance imaging.

[0064] Additionally, it may be provided that at least the tracer is hyperpolarized using DNP, PHI P and / or SABRE.

[0065] The tracer of the contrast agent can be hyperpolarized using various established methods.

[0066] Alternatively or additionally, it may be provided that the concentration of the retarder is greater than the concentration of the tracer.

[0067] The concentration of the retarder can be adjusted to that of the tracer. This concentration can be, for example, a mass concentration and / or a concentration by volume. A higher, especially several times higher, concentration of the retarder than that of the tracer can ensure, for instance, that at least one retarder molecule is available for every tracer molecule.

[0068] Alternatively or additionally, it can be provided that the concentration of the retarder binding sites is greater than the concentration of the tracer binding sites.

[0069] The binding sites can be, for example, hydrogen bond donor and / or acceptor atoms. The concentration of the binding sites can be expressed, for example, analogously to a substance concentration in mol / L. A higher, especially several times higher, concentration of the retarder binding sites can ensure, for example, that the tracer binding sites are saturated with those of the retarder. In this context, one could speak of a kind of competitive inhibition of the tracer binding sites by those of the retarder. Relaxation sources attacking the tracer binding sites are thus prevented from influencing the tracer, and the Tl relaxation time of the tracer can be prolonged. Advantageously, a concentration of the tracer and / or retarder binding sites can be in the range between 1 mM and 1 M.

[0070] Alternatively or additionally, it may be stipulated that the concentration of the retarder is greater than 100 mM.

[0071] Thus, the concentration of the retarder can be set such that it exceeds 100 mM. If the concentration of the tracer is chosen to be lower, especially several times lower, than that of the retarder, the tracer can be competitively shielded from relaxation sources. In this case, the concentration of the retarder can be, in particular, between 125 mM and 250 mM.

[0072] The effect of the retarder in a solution of this concentration on the T1 relaxation time of the tracer has proven particularly advantageous. This can also lead to a beneficial prolongation of the T2 relaxation time. It is also possible that a prolongation of the T1 relaxation time and / or the T2 relaxation time occurs at retarder concentrations below 100 mM.

[0073] The concentration of the retarder can also be determined by finding and adjusting a balance between the shielding of the tracer from relaxation sources by the retarder, which can prolong the Tl relaxation time of the tracer, and an excessively high concentration of the retarder, which shortens the Tl relaxation time of the tracer.

[0074] Alternatively or additionally, to solve the aforementioned problem, the features of the dependent claim, which relates to a method for producing a hyperpolarized contrast agent, are provided according to the invention. In particular, to solve the aforementioned problem in methods of the type described at the outset, it is proposed according to the invention that the hyperpolarized contrast agent is a contrast agent according to one of the preceding claims, at least with a hyperpolarized tracer, wherein the hyperpolarization is carried out using DNP, PHIP and / or SABRE, and wherein the retarder is added before, during and / or after the hyperpolarization.

[0075] Thus, a contrast agent according to the invention can be provided as a hyperpolarized contrast agent. Compared to a non-hyperpolarized contrast agent, this exhibits a larger proportion of aligned nuclear spins, exceeding thermal equilibrium, and therefore greater polarization. The hyperpolarized contrast agent leads to a stronger signal and thus better image quality in nuclear spin-based imaging.

[0076] Alternatively or additionally, to solve the aforementioned problem, the features of the dependent claim, which relates to a retarder for use in a hyperpolarized contrast agent for imaging a metabolic process, are provided according to the invention. The contrast agent may, in particular, be a contrast agent according to the invention. The contrast agent may also, in particular, be a contrast agent produced by a method according to the invention. In particular, to solve the aforementioned problem, it is thus proposed according to the invention that, in the case of retarders of the type described above, the retarder interacts with the hyperpolarized tracer of the contrast agent, thereby prolonging the Tl relaxation time of the hyperpolarized tracer.

[0077] Thus, a retarder can be manufactured that can be used in a contrast agent. For example, the contrast agent can be industrially prepared, and the retarder can then be added to prolong the T1-relaxation time of a component of the contrast agent. For example, a retarder can be used with different types of contrast agents.

[0078] In an advantageous design, the retarder may be intended for use in in vivo and / or in vitro diagnostic procedures. In particular, the retarder may be intended for the detection of diseases, monitoring of disease progression and / or therapeutic response, especially in the case of tumor diseases and / or metabolic disorders.

[0079] Thus, the advantages of the invention can be utilized in such a process. Alternatively or additionally, to solve the aforementioned problem, the features of the dependent claim, which relates to a contrast agent for use in a diagnostic procedure in vivo and / or in vitro, are provided according to the invention. In particular, to solve the aforementioned problem, it is proposed according to the invention that, with regard to contrast agents of the type described above, the contrast agent is a contrast agent according to the invention as described above and / or that the contrast agent is a contrast agent produced according to a process according to the invention.

[0080] Additionally, the contrast agent may be intended for use in a diagnostic procedure in vivo and / or in vitro for the detection of diseases, monitoring of disease progression and / or therapy response, particularly in tumor diseases and / or metabolic diseases.

[0081] Thus, the advantages of the inventive and the contrast media produced according to the invention can be utilized in such processes.

[0082] A preferred application of the invention provides that in a hyperpolarizable contrast agent a retarder according to the invention is used to prolong the Tl relaxation time of the tracer.

[0083] Thus, the advantages of the retarder according to the invention can be used when applying, for example, separately produced contrast agents.

[0084] The invention will now be described in more detail using an exemplary embodiment, but is not limited to this embodiment. Further exemplary embodiments result from combining the features of one or more claims with each other and / or with one or more features of the exemplary embodiment.

[0085] They show:

[0086] Figure 1 shows the polarization or degree of polarization and the Tl relaxation time of various atoms from 1-1 5 N-Nicotinamide depending on a retarder concentration,

[0087] Figure 2 shows the polarization or degree of polarization as well as a Tl-relaxation time of 15 N atoms of different tracers in different environments with and without retarder,

[0088] Figure 3 shows the influence of pH and retarder on the TL relaxation time from 1- 15 N-NAM as a function of magnetic field strength ,

[0089] Figure 4 shows the TL relaxation time of TL. 13 C-pyruvate as a function of magnetic field strength ,

[0090] Figure 5 shows the TL relaxation time of TL. 13 C-pyruvate in the presence of Tris (hydroxymethyl)aminomethane as a function of magnetic field strength.

[0091] To demonstrate the effect of the invention, samples for hyperpolarization using dDNP were prepared by mixing a substrate with a triphenylmethyl radical (trityl radical) in deionized water with trehalose. The substrate used was 1- 15 N-Nicotinamide (NAM) , 15 N-pyridine, metronidazole (MTZ), 15 N2-urea or pyrimidine is used. Examples of this are as follows:

[0092] 130 mg water and 60 mg trehalose, 100 mg 1- 15 N-NAM, and

[0093] 10.5 mg trityl radical, wherein a sample volume of 225 pL contains approximately 29 mM trityl radical and 3.6 M 1- 15N-NAM is obtained as follows: 100 mg water and 48 mg trehalose, 68 mg 15 N-pyridine, and 8.1 mg trityl radical, wherein a sample volume of 185 pL with approximately 27 mM trityl radical and 4.6 M 15 N-pyridine is obtained.

[0094] 300 mg DMSO, 77 mg MTZ, and 11.4 mg trityl radical, yielding a sample volume of 335 pL containing approximately 21.3 mM trityl radical and 1.34 M MTZ.

[0095] 49 mg trehalose, 108 mg pyrimidine, and 5.8 mg trityl radical, yielding a sample volume of 144 gL containing approximately 25 mM trityl radical and 9.3 M pyrimidine.

[0096] After preparation, the solution was stored at -24°C. Before use, the vial was warmed (in the hands) and mixed for 2 minutes using a vortex mixer. The typical sample size was 30 mg for pyridine and 50 mg for the other substances. 1- 15N-NAM was synthesized in a two-step reaction from NAM (72340, CAS: 98-92-0, Sigma-Aldrich) via the Zincke salt, followed by a nitrogen exchange with 15 NH4C1 (299251, CAS: 39466-62-1, Sigma-Aldrich). In the first step, the Zincke salt of NAM was formed with l-chloro-2,4-dinitrobenzene (237329, CAS: 97-00-7, Sigma-Aldrich) in DMSO. The resulting compound was a slightly yellowish powder, which was subsequently treated with 15 NH4C1 was implemented to produce 1- 15 N-NAM is obtained as a white powder. In some cases, a yellow coloration was observed after chromatographic workup due to the presence of 2,4-dinitroaniline, which could not be separated chromatographically. In these cases, for example, an additional purification step with activated carbon can be performed before column chromatographic workup, or additional recrystallization in ethyl acetate can be performed after column chromatography.

[0097] The dissolution medium with a pH of 7.5 was prepared by mixing 300 mg of Trizma pre-set crystals (pH 7.6, average M = 149.0 g / mol, T7943, Sigma-Aldrich) and 50 mg of ethylenediaminetetraacetic acid (EDTA, 11280, CAS: 9002-07-7, SERVA) in 50 mL of deionized water or 99.9% D2O (151882, Sigma-Aldrich) and stored at room temperature. For example, naturally occurring sodium isotope (na) (72340, CAS: 98-92-0, Sigma-Aldrich), bipyridine (CDS018251, Sigma-Aldrich), and urea (2317, CAS: 57-13-6, Carl Roth) can be added to the medium. To obtain a dissolving medium with a pH of 8.5, approximately 50 mg of NaOH (1355, CAS: 1310-73-2, ChemSolute) was added.

[0098] All dDNP experiments were performed using a cryogen-free dDNP system (SpinAligner) at ~1.4 K and 6.7 T. A microwave frequency (MW) between 187.07 and 187.19 GHz with a power of 10 to 45 mW was used for polarization. The optimal MW frequency was calibrated for each sample batch by varying the microwave frequency. For each DNP experiment, the specified amount of concentrate (usually 50 mg) was taken from the supply, placed in the sample beaker, and lowered into the microwave cavity at ~1.3 K. DNP was initiated by continuous wave irradiation at the optimized frequency and power. The setup of the 15 N-polarization in the solid state was measured every 15 minutes with a 15 N-HF pulse of 3° was monitored. The flipping angle of the built-in NMR was set to before the experiments. 15 N calibrated.

[0099] 15 N-MR signals were acquired using two 1-T- 13 C and 15N-benchtop NMR devices (Spinsolve Nitrogen, Magritek), a 9, 4-T wide-bore NMR device (WB400, Avance NEC, Bruker) with a 5-mm BBFO probe and a 0, 57-T 10-mm table MRI system (magnet unit "magspec", console unit "drive L", Pure Devices GmbH) were recorded.

[0100] A 0.5–1 T Halbach magnet was used for transport to the measurement positions at 0.57 T and 9.4 T in a known manner. The NMR spectra were quantified by manual integration after manual phase correction, line broadening, and baseline correction (MestReNova 14.2.2, Mestrelab Research SL). The MRI images were evaluated using the manufacturer's software (Paravision 360, Bruker).

[0101] The signal amplification was quantified using (Eq. 1) with respect to the accumulated signal of the same sample at thermal equilibrium: where P TP the polarization in thermal equilibrium, S xthe integral of the respective signal, N a C q the number of accumulated spectra, a x the excitation angle and RG X the linear receiver gain for hyperpolarized (x = HP) and thermally polarized (x = TP) NMR spectra.

[0102] Thermally polarized liquid-state NMR spectra were recorded using high-resolution NMR at 9.4 T, ^-decoupling, and the following acquisition parameters: number of accumulations = 64, Flip angle a TP = 90°, repetition time TR = 170 s. A typical signal-to-noise ratio of 20 was achieved.

[0103] The 15 N-signal intensities were quantified using quantification methods, with the selected integration range around the hyperpolarized signal being ±3 ppm. Polarization was only quantified at 9.4 T.

[0104] The waning hyperpolarization was detected with a <z HP= 5°-10° pulse sampled every 3-6 s. To quantify the lifetime of hyperpolarization T P A monoexponential decay function was fitted to the data, which represents the apparent / observed constant T°. bs This results in (Eq. 2):

[0105] To obtain the longitudinal relaxation time TI, T° was used. bs In all cases, unless otherwise specified, corrected, whereby the repeated HF excitations at the angle cr HP The polarization consumed was taken into account:

[0106] Ti = Ti bs [l + ^-ln(cos(cr HP ))] (Eq. 3)

[0107] Figure 1 shows the polarization or degree of polarization (polarization in %) and the T1 relaxation time (T2 in seconds) of the atoms represented in the structural formula. 15 N, C a, C4 and NI (nitrogen of the amino group) as a function of the concentration of the retarders in their natural isotopic distribution: NAM (A), urea (B), glycerol (C) and a dendrimer (D). The data presented are particularly relevant for 15 N, which is part of the tracer and is to be detected in the imaging. The remaining data serve as a control. Also shown are the concentrations of 15 N-NAM and the pH of the respective sample. It is evident that the addition of the retarder leads to significantly improved signal retention. The polarization, or Tl relaxation time, is considerably increased. This increase can be maintained over several cycles of the experiment even without further addition of the retarder (see (C) , first (0 lst ) , second (0 2nd ) and eighth (0 8th ) Repetition) .

[0108] Figure 2 shows the polarization or degree of polarization (polarization in %) and the T1 relaxation time (T2 in seconds) of the structures represented in structural formulas a to e. 15 N- atoms of various tracers in different environments with and without retarder. For 1- 15 N-NAM (A) , 15 N-Pyridine (B) , 15 NO2- Metronidazole and 15 N3-Metronidazole (C) , 15 N-Pyrimidine (D) and 15 N-urea is shown to be suitable for basic and neutral environments in water or heavy water and with or without retarder in the form of urea or NAM, in that both polarization and Tl-relaxation time can be significantly increased.

[0109] Figure 3 shows the influence of pH and retarder on the TL relaxation time of 1- 15N-NAM as a function of magnetic field strength. This is shown for four samples: three without retarder with pH values ​​of 12.05, 10.34 and 8.27, and one sample with retarder (1 M NAM) with a pH value of 8.24.

[0110] The maximum Tl relaxation times achieved at a magnetic field strength of approximately 1 T were 62.3 s, 30.1 s, 20.6 s, and 29.6 s for the respective samples, in the order listed above. The addition of 1 M NAM thus resulted in a 9-second increase in the maximum Tl relaxation time.

[0111] At magnetic field strengths in the range of 7.8 pT to 120 pT, the Tl relaxation times were approximately 6.9 ± 0.5 s, 2.0 ± 0.1 s, 1.8 ± 0.2 s and 4.7 ± 0.3 s in the above.

[0112] Sequence. The addition of 1 M NAM also led to a prolonged TL relaxation time here.

[0113] At a magnetic field strength of 9.4 T, the respective T1 relaxation times were 19.9 s, 14.3 s, 14.4 s, and 8.1 s, in the order listed above. The T2 relaxation times were 1952 ms, 1063 ms, 442 ms, and 1345 ms, in the order listed above.

[0114] Therefore, the use of the invention can lead to a prolonged T2 relaxation time. The invention can be advantageously used to extend the T2 relaxation time.

[0115] A shortening of the Tl relaxation time at high magnetic field strengths can generally indicate an interaction between the retarder and the tracer. At high magnetic field strengths, rapid relaxation due to chemical exchange or paramagnetic impurities may be inefficient. Therefore, an increase in the Tl relaxation time can occur even without a retarder. Conversely, at higher retarder concentrations, a slowed movement and / or accelerated relaxation of the tracer at high magnetic field strengths can occur due to an interaction between the retarder and the tracer, for example, due to steric factors. This follows the classical nuclear relaxation theory.

[0116] Figure 4 shows the tl-relaxation time of l- 13 C-pyruvate as a function of magnetic field strength on a sample of 91 mM l- 13C-pyruvate in 90% H2O and 10% D2O. A significant decrease in the tidal relaxation time to about 30 seconds can occur in fields with low magnetic field strength (approximately between 10⁻⁶). 5 T and 10" 2 T) can be observed.

[0117] Figure 5, in contrast, shows the TL relaxation time from 1- 13 C-Pyruvate in the presence of Tris(hydroxymethyl)aminomethane as a function of magnetic field strength on a 90 mM l sample 13 C-pyruvate and 43 mM Tris buffer in 90% H₂O and 10% D₂O. An optimal retarder concentration is below 100 mM. The decrease in the tl relaxation time in fields with low magnetic field strength (approximately between 10⁻¹⁰°F and 10⁻¹⁰°F) is observed. 5 T and 10" 2 T) is significantly weakened. The TL relaxation time is in the range of 50 seconds and is therefore prolonged by approximately 67%. The previously used 15The effect described for N-nuclei of prolonging the TL relaxation time due to the presence of the retarder is therefore also true in N-nuclei. 13 observable in carbon nuclei. This applies, for example, to 13 C-Pyruvate .

[0118] A contrast agent for magnetic resonance imaging (MRI) is proposed, comprising a polarizable agent (tracer) possessing a nuclear spin, wherein tracer molecules can be brought into a polarized state by polarizing their nuclear spins, and a retarder, wherein a molecular interaction of retarder molecules with the tracer molecules results in a prolongation of the Tl relaxation time of the tracer. Furthermore, a method for the production of a hyperpolarized contrast agent, a retarder for use in a contrast agent for MRI, a contrast agent for use in a diagnostic procedure in vivo and / or in vitro, and the use of a retarder in a contrast agent for MRI to prolong the Tl relaxation time of the tracer are proposed.

[0119] / Claims

Claims

Claims 1. Contrast agent for nuclear spin-based imaging, comprising a nuclear spin-possessing, polarizable agent (tracer), wherein tracer molecules can be brought into a polarized state by polarization of their nuclear spins, and comprising a retarding agent (retarder), wherein a molecular interaction of retarder molecules with the tracer molecules results in an extension of the Tl relaxation time of the tracer.

2. Contrast agent according to the preceding claim, characterized in that the polarizable tracer is hyperpolarizable and that the tracer molecules can be brought into a hyperpolarized state by hyperpolarization of their nuclear spins.

3. Contrast agent according to one of the preceding claims, characterized in that the tracer and / or the retarder are dissolved and / or dispersed in a solvent, in particular wherein the solvent is selected from the group consisting of water, ethanol, methanol, DMSO and mixtures thereof.

4. Contrast agent according to one of the preceding claims, characterized in that the contrast agent contains a relaxation source that shortens the Tl relaxation time of the tracer, the effect of which is weakened and / or suppressed by the molecular interaction of the retarder molecules with the tracer molecules, in particular wherein the relaxation source is the solvent or a solvent, preferably selected from the group consisting of water, ethanol, methanol, DMSO and mixtures thereof, and / or wherein the relaxation source is dissolved and / or solid substances, preferably oxygen and / or impurities.

5. Contrast agent according to one of the preceding claims, characterized in that the interaction of the retarder with the tracer is stronger than an interaction of the relaxation source with the tracer, in particular wherein the interaction of the retarder with the tracer is stronger than an interaction of solvent molecules, in particular water molecules, with the tracer, and / or that the retarder reduces an interaction between the relaxation source and the tracer.

6. Contrast agent according to one of the preceding claims, characterized in that the interaction of the retarder with the tracer takes place between the respective retarder and tracer molecules and / or is an attractive interaction, and / or that the retarder influences, in particular weakens, an interaction between the tracer and the solvent.

7. Contrast agent according to one of the preceding claims, characterized in that the molecular interaction of retarder molecules with the tracer molecules and / or the relaxation source with the tracer and / or the solvent molecules with the tracer is an interaction in the context of hydrogen bonding, a hydrotropic effect, a molecular collision, a molecular motion, a molecular rotation, electromagnetic interactions and / or dipolar interactions, preferably wherein the interaction of the relaxation source with the tracer and / or the solvent molecules with the tracer shortens the Tl relaxation time of the tracer.

8. Contrast agent according to one of the preceding claims, characterized in that the retarder has a binding site, in particular several binding sites, of the Spatially shields tracers through which the relaxation source can interact with the tracer and / or cause a shortening of its Tl relaxation time.

9. Contrast agent according to one of the preceding claims, characterized in that an average duration of an interaction between the retarder and the tracer exceeds 10 ms and / or that the contrast agent is introduced in a magnetic field and that an average duration of an interaction between the retarder and the tracer exceeds a period of a Larmorf frequency of a hyperpolarized atomic nucleus of the tracer triggered by the magnetic field.

10. Contrast agent according to one of the preceding claims, characterized in that several preferably similar interactions originate from preferably different atoms of a retarder molecule and / or attack preferably different atoms of one or more tracer molecules.

11. Contrast agent according to one of the preceding claims, characterized in that the tracer is a preferably water-soluble biomolecule and / or a structure selected from the group consisting of 13 Carbon atom, 15 N atom, 2 9 Si atom, 31 P-atom, 13 C-carbonyl group , 15 It has an N-pyridine ring.

12. Contrast medium according to one of the preceding claims, characterized in that the tracer and / or the retarder is a substance selected from the group consisting of nicotinamide, nicotinic acid and succinates, in particular wherein the tracer is chemically equivalent to the retarder.

13. Contrast agent according to one of the preceding claims, characterized in that the retarder is a substance selected from the group consisting of urea, thiourea, sulfates, cysteine, cystine, amides, glycerols, dendrimers of preferably a second generation, triphenylborane, Lewis acids, in particular with boron as the Lewis acidic center, metals and hydrogen bond donors.

14. Contrast medium according to one of the preceding claims, characterized in that the solvent is water and the retarder is nicotinamide, and that the tracer is selected from the group consisting of nicotinamide, pyridine and pyrimidine.

15. Contrast medium according to one of the preceding claims, characterized in that the solvent is water and the tracer and retarder are selected from the following tracer / retarder pairs: Nicotinamide / urea, pyridine / urine, pyrimidine / urea or metronidazole / urea, thiourea / pyridine, glucose / pyridine, ascorbic acid / pyridine, lactic acid / pyridine, pyridine / triphenylboron, pyruvate / phosphate buffer, pyruvate / Tris buffer er, pyruvate / HEPES buffer, succinate / phosphate buffer, succinate / glycerin, nicotinamide / glycerin, nicotinamide / dendrimers, pyridine / glycerin.

16. Contrast medium according to one of the preceding claims, characterized in that at least the tracer is hyperpolarized, in particular by means of DNP, PHIP and / or SABRE.

17. Contrast agent according to any of the preceding claims , characterized by the fact that a concentration of Retarders and / or their binding sites are greater than the concentration of the tracer and / or its binding sites.

18. Contrast agent according to one of the preceding claims, characterized in that the concentration of the retarder is greater than 100 mM, in particular between 125 mM and 250 mM.

19. Method for producing a hyperpolarized contrast agent for nuclear magnetic resonance imaging, characterized in that the hyperpolarized contrast agent is a contrast agent according to one of the preceding claims, at least with a hyperpolarized tracer, wherein the hyperpolarization is carried out using DNP, PHIP and / or SABRE, and wherein the retarder is added before, during and / or after the hyperpolarization.

20. Retarder for use in a contrast agent for magnetic resonance imaging, in particular a contrast agent according to any one of claims 1 to 18 and / or produced by a method according to claim 19, for imaging a metabolic process, wherein the retarder interacts with the or a tracer of the contrast agent, thereby prolonging a Tl relaxation time of the tracer.

21. Retarder according to the preceding claim for use in a diagnostic procedure in vivo and / or in vitro, in particular for the detection of diseases, monitoring of disease progression and / or the response to therapy, especially in tumor diseases and / or metabolic diseases.

22. Contrast medium according to any one of claims 1 to 18 and / or produced by a method according to claim 19 for use in a diagnostic procedure in vivo and / or in vitro, in particular for the detection of diseases, monitoring of disease progression and / or the response to therapy, especially in tumor diseases and / or metabolic diseases.

23. Use of a retarder according to one of claims 20 or 21 in a preferably hyperpolarizable contrast agent for magnetic resonance imaging for Prolongation of the TL relaxation time of the tracer. / Summary

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