Method of producing liquid composition, containing hyperpolarised 13c-pyruvate, composition containing hyperpolarised 13c-pyruvate (versions), use thereof (versions), radical and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a liquid composition which contains hyperpolarised 13C-pyruvate, involving: a) formation of a liquid mixture containing a radical of formula (I) , where M is hydrogen or one equivalent cation; and R1, which are identical or different, each represents hydroxylated and/or alkoxolated C1-C4-hydrocarbon group with a straight or branched chain, 13C-pyroracemic acid and/or 13C-pyruvate, and freezing this mixture; b) increasing polarisation of 13C nuclei of pyroracemic acid and/or pyruvate in this mixture through dynamic nuclear polarisation c) addition of a physiologically transferable buffer, which provides for pH in the range from 7 to 8, and a base to the frozen mixture for its dissolution and for converting 13C-pyroracemic acid to 13C-pyruvate, obtaining a liquid composition or, when at stage (a) only 13C-pyruvate is used, addition of a buffer to the frozen mixture for its dissolution, obtaining a liquid composition; and d) possible removal of the radical and/or its reaction products from the liquid composition. The invention also relates to use of such a composition and to a radical of formula (I).

EFFECT: obtaining a composition for use as MP of a visualising agent.

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The invention relates to a method of obtaining a composition containing hyperpolarizability13C-pyruvate, for this composition and to its use as an imaging agent for Mr imaging.

Magnetic resonance (Mr) imaging (MRI) is an imaging technique that has become particularly attractive to physicians as it allows to obtain images of the patient's body or its parts is a non-invasive way, without exposing the patient and the medical staff exposure to potentially hazardous radiation such as x-rays. Due to high quality images, MRI is the preferred method of imaging soft tissues and organs, which allows to distinguish between normal tissue and diseased tissue, such as tumors and pathological changes.

Mr visualization of a tumor can be performed with or without the use of Mr contrast agents. In a Mr image obtained without the use of contrast agent, quite clearly will be visible tumor size from about 1-2 centimeters and more. However, MRI with contrast enhancement provides detection of much smaller changes in the tissue, i.e. much smaller tumors, which makes the Mr imaging with contrast enhancement is a powerful tool for the detection of tumors at an early stage and about what Eugenia metastases.

In Mr imaging of tumors using multiple types of contrast agents. Water-soluble chelates of paramagnetic metals, such as gadolinium chelates, such as Omniscan™ (Amersham Health), are widely used as MRI contrast agents. When introduced into the vascular network due to its low molecular weight, they are rapidly distributed in the extracellular space (i.e. in the blood and the interstitium). They are also relatively rapidly excreted from the body. It was found that gadolinium chelates are particularly useful for increasing the percentage of detection of metastases and small tumors and to improve classification of tumors, the latter is provided by the differentiation of vital tumor tissue (high perfusion and/or breach the blood-brain barrier) from the Central necrosis and surrounding edema or macroscopically intact tissue (see, for example, .Claussen et al., Neuroradiology 1985; 27: 164-171).

On the other hand, Mr contrast agents for blood pool, for example particles of superparamagnetic particles of iron oxide, remain in the vascular network for a long time. It turned out that they are extremely useful to enhance the contrast in the liver, as well as for anomaly detection in capillary permeability, such as "with flow" of the walls of the capillaries in tumors, for example as a result of angiogenesis.

N is looking at unquestionably the excellent properties of these contrast agents, their use is not without risk. Although chelate complexes of paramagnetic metals usually have high stability constants, it is possible that ions of toxic metals are released in the body after injection. In addition, the contrast agents of this type show poor specificity.

In WO-A-99/35508 disclosed a method of Mr investigation of a patient using hyperpolarizing solution agent with high T1as Mr imaging agent. The term "hyperpolarization" means the enhancement of the nuclear polarization NMR active nuclei present in the agent with high T1i.e. nuclei with nonzero nuclear spin, preferably nuclei13With or15N. In strengthening nuclear polarization NMR active nuclei difference between the populations of the excited and the main nuclear spin States of these nuclei is greatly increased, and therefore the intensity of the MRI signal is amplified a hundred times and more. When using hyperpolarizing13C - and/or15N-enriched agent with high T1interference from background signals are practically absent, because the prevalence of13With and/or15N in nature is negligible, and therefore the image contrast is predominantly high. Disclosed are a number of possible agents with high T1suitable for hyperpolarizes and subsequent use as Mr imaging agents including, but not limited to them, endogene and endogenous compounds such as acetate, pyruvate, oxalate, or gluconate, sugars such as glucose or fructose, urea, amides, amino acids, such as glutamate, glycine, cysteine or aspartate, nucleotides, vitamins such as ascorbic acid, derivatives of penicillin and sulfonamides. It was also established that intermediate compounds in normal metabolic cycles such as the citric acid cycle, such as fumaric acid and pyruvic acid are preferred imaging agents for imaging of metabolic activity.

It must be emphasized that the signal from hyperpolarizing visualizing agent is weakened due to relaxation and after introduction into the patient due to dilution. Therefore, the value of T1imaging agents in biological fluids (e.g. blood) should be high enough to ensure the distribution agent at the site of a target in a patient's body in highly hyperpolarization condition. In addition to a contrast agent having a high value of T1extremely useful to achieve a high level of polarization.

Several methods of hyperpolarization disclosed in WO-A-99/35508, and one of them is a method of dynamic polarization of nuclei (DPJ), which polarizes the th sample exercise paramagnetic compound, the so-called paramagnetic agent, or the DPJ agent. During the implementation process DPJ bring energy, usually in the form of microwave radiation, which initially stimulates the paramagnetic agent. When fading to the initial state is the polarization transfer from the unpaired electron paramagnetic agent to the NMR active nuclei of the sample. Usually during the DPJ use moderate or strong magnetic field and very low temperature, for example, carry out the process of the DPJ in liquid helium in a magnetic field of about 1 Tesla or higher. Alternatively, you can use a moderate magnetic field and any temperature at which achieved a sufficient strengthening of the polarization. Methodology the DPJ is described, for example, in international publications WO-A-98/58272 and in WO-A-01/96895, which are both included in this description by reference.

Paramagnetic agent plays a crucial role in the process of the DPJ, and his choice has a great impact on the achievable level of polarization. There are a number of paramagnetic agents in WO-A-99/35508 designated as "OMRI contrast agents, for example organic free radicals on the basis of oxygen, sulphur based or carbon-based or magnetic particles mentioned in WO-A-99/35508, WO-A-88/10419, WO-A-90/00904, WO-A-91/12024, WO-A-93/02711 or WO-A-96/39367.

Now the authors have unexpectedly found an improved method of obtaining what idcol composition, containing hyperpolarizability13C-pyruvate, which gives the opportunity to get hyperpolarizability13C-pyruvate with an extremely high level of polarization. It was also found that such a composition is particularly suitable for Mr imaging of tumors in vivo.

Thus, in one aspect of the present invention, a method for producing a liquid composition containing hyperpolarizability13C-pyruvate, including

a) formation of liquid mixtures containing radical of the formula (I)

where

M represents hydrogen or one equivalent of a cation; and

R1, which are identical or different, each represents gidrauxilirovaniu and/or alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain,

13With-pyruvic acid and/or13C-pyruvate, and freezing the mixture;

b) strengthening polarized13With cores of pyruvic acid and/or pyruvate in the mixture by the DPJ;

C) adding a buffer and substrate to the frozen mixture to dissolve and for the conversion of the13With pyruvic acid in the13With pyruvate to form a liquid composition or, when on the stage (a) use only13C-pyruvate, adding a buffer to the frozen mixture to dissolve with the receiving MS is coy composition; and

g) you can delete radical and/or its reaction products from the liquid composition.

The terms "hyperpolarizing" and "polarized"used here interchangeably and mean polarization above detected at room temperature and 1 Tesla.

In the method according to the invention using a radical of the formula (I)

where

M represents hydrogen or one equivalent of a cation; and

R1, which are identical or different, each represents gidrauxilirovaniu and/or alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain,

Here below, the term "moiety" refers to a radical of the formula (I).

In the preferred embodiment M represents hydrogen or one equivalent of a physiologically portable cation. The term "physiologically tolerable cation" means a cation, which bring a living human or animal, not a person. Preferably, M represents hydrogen or the cation of an alkali metal, ammonium ion or an ion of an organic amine, such as meglumine. Most preferably, M represents hydrogen or sodium.

In another preferred embodiment R1 is the same or different and each represents a hydroxymethyl or hydroxyethyl. In other the MD preferred embodiment R1 is the same or different and each represents alkoxycarbonyl 1-C4is a hydrocarbon group with a straight or branched chain, preferably-CH2-O-(C1-C3-alkyl), -(CH2)2-O-CH3or -(C1-C3-alkyl)-O-CH3. In another preferred embodiment R1 is the same or different and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain, bearing a hydroxyl end group, preferably-CH2-O-C2H4OH or-C2H4-O-CH2OH. In a more preferred embodiment R1 is the same and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight chain, preferably methoxy, -CH2-Och3, -CH2-OC2H5or-CH2-CH2-Och3most preferably-CH2-CH2-Och3.

In the preferred embodiment M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3.

Methods of synthesis of these radicals known in this field and are disclosed in WO-A-91/12024, WO-A-96/39367, WO 97/09633 and WO-A-98/39277. Briefly, these radicals can be synthesized by the interaction of three molar equivalents metallizovannogo Monomeric aryl compounds with one molar equivalent of the appropriate Conn is spent carboxylic acid derivative with the formation of the trimeric intermediate compounds. This intermediate connection metallinou and then subjected to the interaction, for example, with carbon dioxide with the formation of tricarboxymethyl that the next phase is treated with a strong acid with the formation of triarylmethyl cation. This cation then restore to the formation of stable trailing radical.

The isotopic enrichment of13With-pyruvic acid and/or13With pyruvate used in the method according to the invention, is preferably at least 75%, more preferably at least 80% and especially preferably at least 90%, and the isotopic enrichment of over 90% is most preferred. Ideally, the enrichment is 100%.13With-pyruvic acid and/or13C-pyruvate can be enriched isotope in position C1 (below labeled13With1-pyruvic acid and13With1-pyruvate), at the position C2 (below labeled13With2-pyruvic acid and13C2-pyruvate), at position C3 (below labeled13With3-pyruvic acid and13With3-pyruvate), at positions C1 and C2 (which are outlined below as13With1,2-pyruvic acid and13With3-pyruvate), at positions C1 and C3 (below labeled13With1,3-proving Adna acid and 13With1,3-pyruvate), at positions C2 and C3 (which is below labeled13With2,3-pyruvic acid and13C2,3-pyruvate) or in positions C1, C2 and C3 (which is below labeled13With1,2,3-pyruvic acid and13With1,2,3-pyruvate), at the position C1 is preferred.

In this area there are several known methods of synthesis13C1-pyruvic acid. Briefly, in Seebach et al., Journal of Organic Chemistry 40(2), 1975, 231-237, described the path of synthesis, based on the protection and activation of carbonyl-containing source materials in the form of S,S-acetal, for example 1,3-dithiane or 2-methyl-1,3-dithiane. Dition metallinou and subjected to interaction with methylcobalamin connection and/or13CO2. Using the corresponding enriched isotope13With component, as described in this reference can be obtained13With1-pyruvate,13With2-pyruvate or13With1,2-pyruvate. Carbonyl functional group then release the conventional methods described in the literature. Other ways of synthesis begins with acetic acid, which was at the first turn in acetylmuramic, and then subjected to interaction with Cu13CN. The resulting nitrile converted into pyruvic acid via amide (see, for example, S.H.Anker et al., J. Biol. Chem. 176 (1948), 1333 or J.E.Thirkettle, Chem Commun. (1997) 1025). 13With-pyruvic acid can also be obtained by protonation of the commercially available13With pyruvate sodium, for example by the method described in U.S. patent 6232497.

Depending mostly on the radical in the method according to the invention using13With-pyruvic acid and/or13C-pyruvate. If the radical is soluble in13With-pyruvic acid, preferably using13With pyruvic acid to form a liquid mixture, preferably a liquid solution, radical and13With pyruvic acid. If the radical is not soluble in13With-pyruvic acid, then use13C-pyruvate and/or13With-pyruvic acid and at least one co-solvent for the formation of a liquid mixture, preferably a liquid solution. It was found that the successful implementation of the DPJ and, consequently, the level of polarization depends on finding the polarizable compounds and radical agent in close contact with each other. Therefore, the co-solvent is preferably the co-solvent or mixture of co-solvents, which(th) dissolves as radical, and13With-pyruvic acid and/or13C-pyruvate. For13With pyruvate as a co-solvent preferably use water.

It was also found that the higher ovni polarization at the stage (b) is achieved, when the mixture upon cooling/freezing forms a glass, and not crystallized sample. Again, the formation of glass provides closer contact radical and subjected to polarization of the connection.13With-pyruvic acid is a good stekloobrazuyuschego substance, and so preferably it is used in the method according to the invention, when the radical is soluble in13With pyruvic acid.13C-pyruvate is a salt, and freezing a liquid mixture of an aqueous solution13With pyruvate and radical will be formed crystallized sample. To prevent this, it is preferable to add the co-solvents that are good stekloobrazuyuschego substances, such as glycerin, propandiol or glycol.

Thus, in one embodiment of the13C-pyruvate dissolved in water to obtain an aqueous solution and add radical, glycerin and possibly also the co-solvent to form a liquid mixture according to stage (a) of the method according to the invention. In the preferred embodiment of the13With-pyruvic acid radical and unite co-solvent to form a liquid mixture according to stage (a) of the method according to the present invention. In the most preferred embodiment of the13With-pyruvic acid and radicals combine to form a liquid mixture which according to stage (a) of the method according to the present invention. Mixing compounds to a homogeneous state can be achieved in several ways known in this field, such as mixing, vortexian or sonication.

A liquid mixture of stage (a) according to the method according to the invention preferably contains from 5 to 100 mm radical, more preferably from 10 to 20 mm radical, particularly preferably from 12 to 18 mm radical and most preferably from 13 to 17 mm radical. It was found that the rise time for the polarization stage (b) of the method according to the invention is shorter when using more radical, however, achieved a lower level of polarization. Therefore, these two effects must be balanced to one another.

The liquid mixture in stage (a) of the method according to the invention, a freeze, followed by polarization. Cooling/freezing liquid mixture can be achieved by methods known in this field, for example by freezing the liquid mixture in liquid nitrogen, or simply place it on the polarizer, where the sample will be frozen with liquid helium.

At the stage (b) of the method according to the invention the polarized13S-nuclei13With-pyruvic acid and/or13With pyruvate increase by the DPJ. As described above, the dynamic polarization of nuclei (DPJ) is a method of polarizer and, namely, that the polarization of the connection, which polarize, carry out the DPJ agent, i.e. paramagnetic compound. As for the method according to the invention, the polarization exercise used by radical. During the DPJ bring energy, preferably in the form of microwave radiation, which initially stimulates radical. When fading to the initial state is the polarization transfer from the unpaired electron of the radical to13With core13With-pyruvic acid and/or13With pyruvate.

Methodology the DPJ is described, for example, in international publications WO-A-98/58272 and in WO-A-01/96895, which are both included in this description by reference to them. Usually during the DPJ use moderate or strong magnetic field and very low temperature, for example, carry out the process of the DPJ in liquid helium and in a magnetic field of about 1 Tesla or higher. Alternatively, you can use a moderate magnetic field and any temperature at which achieved a sufficient strengthening of the polarization. In the preferred embodiment of the method according to the invention the process of the DPJ is carried out in liquid helium and in a magnetic field of about 1 Tesla or higher. Suitable devices for carrying out stage (b) of the method according to the invention are described, for example, in WO-A-02/37132. In the preferred embodiment of the installation for polarization contains the cryostat and polars the user device, for example, the microwave chamber is connected by a waveguide with a source of microwave radiation, in the Central channel surrounded generate a magnetic field device, such as a superconducting magnet. The channel extends vertically down to at least level the field of R near the superconducting magnet where the magnetic field strength is sufficiently high, for example from 1 to 25 T, for the implementation of the polarized13C-cores. Channel for sample preferably is configured to sealing, and can be evacuated to low pressures, for example pressures of the order of 1 mbar (100 PA) or less. Inside this channel may be placed in the device for input of the sample (for example, a frozen mixture of stage (a) of the method according to the invention), for example recoverable transporting the sample tube, and this tube can be inserted into the channel from the top down to the position inside the microwave chamber in the region R. the Region R is cooled with liquid helium to a temperature low enough so that the polarization, preferably to a temperature of the order of 0.1 To 100, more preferably 0.5 to 10, most preferably 1-5 K. the Device to enter the sample preferably is configured to seal at its upper end in any suitable way to save a partial vacuum in the channel. In the lower end of the device to enter education the CA can be installed with the possibility of extracting holding the sample container, for example holding the sample Cup. Holding the sample container is preferably made of light weight material with low specific heat capacity and good cryogenic properties, such as, for example, KeIF (polychlorotrifluoroethylene) or PEEK (polyetheretherketone). The container for the sample can contain one or more than one of the polarizable model.

The sample is inserted in a holding sample container, immersed in liquid helium and subjected to microwave irradiation, preferably at a frequency of about 94 GHz at 200 mW. Monitoring the level of polarization can be performed by obtaining13C-NMR signals from the sample in the solid state during microwave irradiation, therefore, at the stage (b) is preferably used setup for polarization containing device to obtain13C-NMR spectra in the solid state. Usually get the saturation curve on the graph based13C-NMR signal from time to time. Consequently, it is possible to determine when the optimum level of polarization.

At the stage (C) of the method according to the invention of the frozen polarized mixture is dissolved in a buffer, preferably a physiologically tolerable buffer, to form a liquid composition. The term "buffer" in the context of this application means one or more than one buffer, then there is also a mixture of Botero is.

The preferred buffers are physiologically tolerated buffers, more preferably buffers, which provide a pH in the range from about 7 to 8, such as, for example, phosphate buffer (KH2PO4/Na2HPO4), ACES, PIPES, imidazole/HCl, BES, MOPS, HEPES, TES, TRIS, HEPPS or TRICIN. The preferred buffers are phosphate buffer and TRIS, the most preferred is TRIS. In another embodiment use more than one of the above preferred buffers, that is, a mixture of buffers.

When the connection is subject polarization, use13With-pyruvic acid, stage (C) also includes the transformation of13With pyruvic acid in the13C-pyruvate. To achieve this,13With-pyruvic acid is subjected to interaction with the bottom. In one embodiment of the13With-pyruvic acid is subjected to interaction with the bottom to turn it into a13C-pyruvate, and then add the buffer. In another preferred embodiment the buffer and the base together in one solution, and this solution is added to the13With-pyruvic acid, it dissolves and turns into13With pyruvate at the same time. In the preferred embodiment the base is an aqueous solution of NaOH, Na2CO3or NaHCO3and the most preferred bases which is of NaOH. In a particularly preferred embodiment for dissolution13With-pyruvic acid and its conversion into the sodium salt13With pyruvate use a solution of TRIS buffer containing NaOH.

In another preferred embodiment the buffer or, where applicable, the combined solution buffer/base further comprises one or more compounds which are capable of binding free paramagnetic ions or to form complexes with them, for example, chelating agents such as DTPA (diethylenetriaminepentaacetic acid) or EDTA (ethylenediaminetetraacetic acid). It was found that free paramagnetic ions can cause a decrease in T1hyperpolarizing connection, and this is preferably avoided.

The dissolution can be carried out preferably using the methods and/or devices disclosed in WO-A-02/37132. Briefly, use the installation for dissolution, which is either physically separated from the polarizer, or is part of the device that contains the polarizer and installation for dissolution. In the preferred embodiment of stage (C) is carried out at high magnetic field to improve relaxation and save the maximum hyperpolarization. Nodes magnetic fields should be avoided, and, despite the above measures, the weak field can lead to increased relaxation.

Since the radical of the formula (I) has a characteristic absorption spectrum in the UV/visible region, you can use the measurement of the absorption in the UV/visible region as a method of verification of its presence in the Jew is the second song after its removal. To obtain quantitative results, i.e. the concentration of radicals present in the liquid composition, optical spectrometer can be calibrated so that the absorption at a specific wavelength for sample gives the corresponding concentration of the radical in the sample. The removal of the radical and/or its reaction products is particularly preferred if the liquid composition is used as a visualizing agent for Mr imaging of in vivo human or animal, not a person.

In another aspect of the present invention proposed a composition comprising hyperpolarizability13C-pyruvate, preferably hyperpolarizability13With a sodium pyruvate, and a buffer selected from the group consisting of phosphate buffer and TRIS.

In the preferred embodiment hyperpolarizability13C-pyruvate is the level of polarization of at least 10%, more preferably at least 15%, particularly preferably at least 20% and most preferably more than 20%.

It was found that such compositions are excellent imaging agents for Mr imaging in vivo, especially for Mr studies of metabolic processes in vivo and for Mr imaging of tumors in vivo, the composition comprising hyperpolarizability13C-pyruvate and a buffer, you the early group, consisting of phosphate buffer and TRIS, for use as Mr imaging agent forms another aspect of the invention.

The composition according to the invention is preferably produced by the method claimed in claim 1 of the formula of the invention, preferably using13With pyruvate at the stage (a) of the method according to claim 1 and a radical of the formula (I), where M represents hydrogen or a physiologically tolerable cation, and R1 are the same and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain, preferably methoxy, -CH2-Och3, -CH2-OS2H5or-CH2-CH2-Och3stage (d) is required. In a particularly preferred embodiment the composition according to the invention obtained by the method claimed in claim 1 claims, where at stage (a) use13C-pyruvate and a radical of the formula (I), where M represents hydrogen, and R1 are the same and each represents-CH2CH2-Och3stage (d) is required.

Another aspect of the invention is the use of a composition containing hyperpolarizability13C-pyruvate, preferably hyperpolarizability13With a sodium pyruvate, and a buffer selected from the group consisting of phosphate buffer and TRIS for the manufacture of Mr visualize the ith agent for the study of metabolic processes in vivo in a human or animal, not a person.

Another aspect of the invention is the use of a composition containing hyperpolarizability13C-pyruvate, preferably hyperpolarizability13With a sodium pyruvate, and a buffer selected from the group consisting of phosphate buffer and TRIS for the manufacture of an Mr imaging agent for imaging tumors in vivo in a human or animal, non-human, preferably for the diagnosis of a tumor, and/or staging of the tumor, and/or monitoring treatment of a tumor in vivo, more preferably, to diagnose tumors of the prostate, and/or staging prostate tumors, and/or for monitoring treatment of prostate tumors in vivo.

The composition according to the invention can be used as a "normal" MRI imaging agent, i.e. providing increased contrast, for anatomical visualization. An additional advantage of the composition according to the invention is that pyruvate is an endogenous compound that the human body carries very well even in high concentrations. As a predecessor in the citric acid cycle pyruvate plays an important metabolic role in the body. Pyruvate is converted into different compounds: as a result of its transamination alanine is formed in the oxidative Dec is roxellana pyruvate is converted into acetyl-COA and bicarbonate, in the recovery of pyruvate lactate is formed, and as a result of its carboxylation is formed oxaloacetate.

Now discovered that the transformation hyperpolarizing13With pyruvate in hyperpolarizability13S-lactate, hyperpolarizability13C-bicarbonate (only in case of13With1pyruvate,13With1,2pyruvate or13With1,2,3pyruvate) and hyperpolarizability13With-alanine can be used for MRI for staging of metabolic processes in the human body in vivo. This is unexpected since it is known that T1hyperpolarized compounds decreases due to relaxation and dilution. In whole human blood at 37°C13C-pyruvate is a relaxation of T1approximately 42 seconds, however, it was found that the transformation hyperpolarizing13With pyruvate in hyperpolarizability13S-lactate, hyperpolarizability13C-bicarbonate and hyperpolarizability13With-alanine is fast enough to be able to detect the signal from13With-pyruvate parent compound and its metabolites. The number of alanine, bicarbonate and lactate depends on the metabolic status of the tissue studied. The intensity of the Mr signal hyperpolarizing13S-lactate, hyperpolarizing13C-bicarbonate and hyperpolarization is th 13With-alanine is associated with a number of these compounds and the degree of polarization, the remaining by the time of detection. Therefore, monitoring the transformation hyperpolarizing13With pyruvate in hyperpolarizability13S-lactate, hyperpolarizability13C-bicarbonate and hyperpolarizability13With-alanine gives you the opportunity to explore the metabolic processes in vivo in a human or animal, not a person, using non-invasive Mr imaging.

It was found that the amplitude of the Mr signals from different metabolites pyruvate vary depending on tissue type. Unique painting metabolic peaks formed by alanine, lactate, bicarbonate and pyruvate can be used as a typical characteristic for the metabolic state of the tissue studied and, therefore, provides the distinction between healthy tissue and tumor tissue. This makes the composition according to the invention an excellent agent for Mr imaging of tumors in vivo.

Usually for the conduct of Mr imaging with use of the composition according to the invention of the subject, which subject to study, for example the patient or animal, is placed in the Mr magnet. Specially designed13With-Mr RF coils are located so that they cover the area of interest.

The composition from which bretania, i.e. composition comprising hyperpolarizability13C-pyruvate and a buffer selected from the group consisting of phosphate buffer and TRIS, administered parenterally, preferably intravenously, intraarterially or directly in the area of interest or authority. Dosage and concentration of the composition according to the invention depend on several factors such as toxicity, the ability to directionally delivered to the authority and administration. Typically, the composition is administered in concentrations up to 1 mmol of pyruvate per kg of body weight, preferably from 0.01 to 0.5 mmol/kg, more preferably from 0.1 to 0.3 mmol/kg, the Rate of administration is preferably less than 10 ml/sec, more preferably less than 6 ml/sec, and most preferably from 5 ml/sec to 0.1 ml/sec. Through less than 400 seconds after administration, preferably less than 120 seconds, more preferably less than 60 seconds after injection, particularly preferably every 20-50 seconds after administration, and most preferably 30-40 sec after the introduction of the applied sequence Mr imaging, which encodes the amount of aggregate interest polling frequency and spatial characteristics of the way. This results in metabolic images13S-lactate,13With-alanine and13With pyruvate and, more preferably, metabolic images 13S-lactate,13With-alanine,13C-bicarbonate and13With pyruvate. In the same period of time can be obtained proton image with proton MRI contrast agent, or without obtaining anatomical and/or perfusion information.

The encoding of the volume of interest can be achieved using the so-called sequence spectroscopic imaging, as described, for example, in T.R.Brown et al., Proc. Natl. Acad. Sci. USA 79, 3523-3526 (1982); A.A.Maudsley, et al., J. Magn. Res 51, 147-152 (1983). Spectroscopic data of the images contain a lot of volume elements, where each element contains the full13With-Mr spectrum.13C-pyruvate and its13S-metabolites all have their unique position in the13With-Mr spectrum, and their resonant frequency can be used to identify them. The integral of the peak at its resonance frequency is directly linked to the number of13With pyruvate and its13With-metabolites, respectively. When the number of13With pyruvate and each13C-metabolite appreciate using, for example, routine methods of alignment in the time domain, as described, for example, in L.Vanhamme et al., J. Magn. Reson. 129, 35-43 (1997), it is possible to generate images for the13With pyruvate and each13C-metabolite, in which the color coding or luminance encoding is the character of Arnim for the measured quantity 13With pyruvate and each13With-metabolite.

Although the methods spectroscopic imaging has proven its worth in creating metabolic images using all kinds Mr nuclei, such as1H,31P,23Na, the number of iterations required to fully encode the spectroscopic image, makes this approach less suitable for hyperpolarizing13C. it is Necessary to ensure the presence of a signal from hyperpolarizing13With during the entire period for which Mr data. This can be achieved by reducing the signal/noise ratio by decreasing the angle RF pulse that is applied in each phase of the coding. The higher the size of the matrix, the more phases stages of coding and longer periods of time scanning is required.

Visualization techniques based on the pioneering work ..Lauterbur (Nature, 242, 190-191 (1973) and P.Mansfield (J.Phys. C.6 L422-L426 (1973)), involving the use of gradient reads in the data collection process, should provide images with higher signal-to-noise ratio or, equivalently, images with higher spatial resolution. However, these visualization techniques in their basic form can not produce separate images for the13With pyruvate and its13With-metabolites, and the image is containing a series of signals from the 13With pyruvate and all its13With-metabolites, i.e. the identification of specific metabolites impossible.

In the preferred embodiment used sequence visualization using multiple echo to encode in relation to frequency information. Sequence, which can produce a1H-images of water and fat, is described, for example, in G.Glover, J.Magn. Reson. Visualization 1991: 1: 521-530 and S..Reederet al., MRM 51 35-45 (2004). Because to be detected metabolites and essentially their Mr frequency is known, the approach discussed in the above references can be used to receive live images13With pyruvate,13With-alanine and13With-lactate and, preferably,13With pyruvate,13With-alanine,13With-lactate and13C-bicarbonate. This method makes more efficient use of hyperpolarizing13With-Mr signal, providing in comparison with the classical spectroscopic methods of rendering the best signal quality, higher spatial resolution and shorter detection time.

Tumor tissue is often characterized by increased perfusion and higher metabolic activity. The process of increasing the vasculature, angiogenesis, induced cells, which because of their higher metabolic needs and/or b is lesego distance from the capillary can not get enough of substances, which can give the energy needed to maintain energy homeostasis. It is in this area where cells have problems with producing enough energy, it is expected significant change in the metabolic pattern. Fabric with problems related to the maintenance of energy homeostasis changes its energy metabolism, which leads, in particular, to increased production of lactate. Suddenly it was possible to make this change metabolism visible using hyperpolarizing13With pyruvate within the shortest available time window of Mr imaging, that is, through the use of a high signal from the13With-lactate in the tumor area to distinguish tumor from healthy tissue. Because perfusion in the tumor tissue is heterogeneous, it is preferable to adjust13With-lactate signal in relation to the amount of pyruvate (13With-piruvate signal), available in the same area. As a result of this adjustment receive weighted lactate relatively pyruvate image. This provides the selection of regions of tissue with relatively high lactate signal for pyruvate signal and, thus, the best distinction between tumor tissue and healthy tissue.

For adjustment in respect of pyruvate signal as lactate and pyruvate of the images normalize with respect to the maximum value for each individual image. Secondly, the normalized lactate image is multiplied by the inverted pyruvate image, such as the maximum piruvate signal in the image minus piruvate level for each pixel. And at the last stage of the intermediate result obtained in the above operation, multiplied by the initial lactate image.

To highlight regions with altered metabolism high13With-lactate signal due to low13With-alanine signal can be used in an operation similar to that described in the above paragraph, whereby receive weighted lactate relatively pyruvate image. Unexpectedly, the identification of the tumour region, i.e. the distinction between tumor tissue and healthy tissue is also improved due to this adjustment. For adjustment in respect of the alanine signal as lactate and alanine image normalize with respect to the maximum value for each individual image. Secondly, the normalized lactate image is multiplied by the inverted alanine image, such as the maximum alanine signal in the image minus alanine level for each pixel. And at the last stage of the intermediate result obtained in the above operation, multiplied by the original lacquer is atoe image. In this way the analysis can also be included13C-bicarbonate signal. In addition, the proton image obtained with or without proton MRI contrast agent may be included in the analysis to obtain anatomical and/or perfusion information.

In another preferred embodiment the composition according to the invention is administered repeatedly, thus providing the opportunity for dynamic studies. It is a further advantage of the method according to the invention in comparison with other methods Mr imaging of tumor using other Mr imaging agents due to their relatively long circulation in the body of the patient does not enable such dynamic studies.

The composition according to the invention is also useful as an imaging agent for MRI for staging of the tumor in vivo. The same metabolic images and/or metabolic weighted images, which are described in the previous paragraphs can be used for this purpose with the relevant categories cutoff defined depending on the size and metabolic activity of the tumor.

The composition according to the invention is also useful as an imaging agent for Mr monitoring of treatment of a tumor in vivo, for example by direct monitoring of changes in the pattern of the IU is abolism tumors in the treatment of therapeutic anticancer agents and/or irradiation treatment or in connection with any type of intervention with ablation of any kind or without it, chemical ablation in combination with radio frequencies, microwaves or ultrasound.

Mr visualization of a tumor can be influenced and you can improve by training the patient or animal in a way that usually affects protein metabolism, lipid metabolism, or energy metabolism. Ways of achieving this are known in this field, such as starvation (e.g. during the night), infusion of glucose, and the like.

In the preferred embodiment of the composition according to the invention are useful as imaging agent for Mr imaging of tumors in vivo monitoring of treatment of tumors and tumor staging for tumors of the brain, breast tumors, tumors of the colon, rectum, lung tumors, kidney tumors, tumors in the head and neck, muscle tumors, stomach tumors, tumors of the esophagus, ovary cancer, pancreatic tumors and prostate tumors. It was also found that the composition according to the invention is particularly useful as an imaging agent for Mr imaging of prostate tumor in vivo, i.e. for the diagnosis of prostate tumors, and/or staging prostate tumors, and/or monitoring treatment of prostate tumors.

When a man turns to the doctor with symptoms of pain or discomfort when urinating, suggest prostate cancer. If a man bol is above 50 years, do a test for prostate specific antigen (PSA). Prostate cancer suggest on the basis of elevated PSA and/or abnormal digital rectal examination (ORE). If the PSA test is positive, the patient referred to a specialist (urologist) for diagnosis using the induced ultrasound biopsy. When two million procedures biopsy in the year, conducted in the United States and Europe, 5 from 6 and 2 3, respectively, are negative. When detected at an early stage five-year survival for these patients is equal to 100%. Because prostate cancer is the most common cancer and the second leading cause of cancer death in men, there is a high medical need in the way of diagnostics of prostate tumors, which are able to detect prostate tumors at an early stage and which can reduce the number of biopsy procedures.

For13With visualization of the prostate requires transceiver volume13With-RF-coil. Preferably, use transmitting bulk13With RF coil in combination only with Mr foster endorectal RF coil, and more preferably used transceiver volume13With-RF-coil with a phased antenna array in combination only with Mr foster endorectal13With the RF coil. Especially preferred and are coils, which provide1H-image of the prostate after13With visualization.

Another aspect of the invention is a composition containing13With-pyruvic acid and/or13C-pyruvate and a radical of the formula (I).

In the preferred embodiment of this composition comprises a radical of the formula (I), where M represents hydrogen or one equivalent of a physiologically portable cation. Preferably, M represents hydrogen or an alkaline cation, ammonium ion or an ion of an organic amine, such as meglumine. Most preferably, M represents hydrogen or sodium.

In an additional preferred embodiment of this composition comprises a radical of the formula (I), where R1 are identical or different and each represents a hydroxymethyl or hydroxyethyl. In another preferred embodiment R1 is the same or different and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain, preferably-CH2-O-(C1-C3-alkyl), -(CH2)2-O-CH3or -(C1-C3-alkyl)-O-CH3. In another preferred embodiment, R1 is the same or different and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain, bearing con is ewww hydroxyl group, preferably-CH2-O-C2H4OH or-C3H4-O-CH2OH. In a more preferred embodiment R1 is the same and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight chain, preferably methoxy, -CH2-Och3, -CH2-OC2H5or-CH2-CH2-Och3most preferably-CH2-CH2-Och3.

In a particularly preferred embodiment of this composition comprises a radical of the formula (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3.

In yet another preferred embodiment of the specified composition contains13With-pyruvic acid and/or13C-pyruvate with isotopic enrichment of at least 75%, more preferably at least 80% and especially preferably at least 90%, and the isotopic enrichment of over 90% is most preferred. Ideally, the enrichment is 100%.13With-pyruvic acid and/or13C-pyruvate can be enriched isotope position C1 to position C2, the position C3, the positions C1 and C2 in terms of C1 and C3, on the provisions of the C2 and C3 or positions C1, C2 and C3, and the position C1 is preferred.

In a particularly preferred embodiment is shown composition contains 13With-pyruvic acid and a radical of the formula (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3most preferably, this composition contains13With-pyruvic acid and a radical of the formula (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH3-CH2-Och3.

The composition of the invention containing13With-pyruvic acid and/or13C-pyruvate and a radical of the formula (I)are particularly useful for obtaining hyperpolarizing13With pyruvate, for example, to retrieve hyperpolarizing13With pyruvate method according to the invention. Therefore, another aspect of the invention is the use of a composition containing13With-pyruvic acid and/or13C-pyruvate and a radical of the formula (I), to obtain hyperpolarizing13With pyruvate.

It is established that the radicals of the formula (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3especially useful for use in the method according to the invention due to the following properties: they are soluble in13With-pyruvic acid and stable when dissolved in it. Moreover, they show high efficiency polarization n the stage (b) of the method according to the invention and stable in the process of dissolution at the stage (C), even when at this stage use basis. They can easily be removed at stage (d) of the method according to the invention, for example by filtration using a hydrophobic filter material.

These new radicals, therefore, another aspect of the invention are radicals of the formula (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3.

Radicals according to the invention can be synthesized as described in Example 1. Briefly, the radicals can be synthesized by the interaction of three molar equivalents metallizovannogo Monomeric aryl compounds with one molar equivalent of a suitably protected carboxylic acid derivative with the formation of the trimeric intermediate compounds. This intermediate connection metallinou and then throw the interaction, for example, with carbon dioxide, which leads to the formation of tricarboxymethyl that the next phase is treated with a strong acid with the formation of triarylmethyl cation. This cation then restore to the formation of stable trailing radical.

Another aspect of the invention is the use of radicals according to the invention as a paramagnetic agent for the hyperpolarization of connection during the DPJ.

The use of the s

Example 1: Synthesis of sodium salt of Tris(8-carboxy-2,2,6,6-(Tetra(methoxyethyl)benzo-[1,2-4,5']bis(1,3)dithiol-4-yl)-methyl

In 280 ml of dimethylacetamide in an argon atmosphere suspended 10 g (70 mmol) of sodium salt of Tris(8-carboxy-2,2,6,6-(Tetra(hydroxyethyl)benzo-[1,2-4,5']-bis(1,3)dithiol-4-yl)-methyl, which was synthesized in accordance with Example 7 of WO-A-1-98/39277. Was added sodium hydride (2,75 g), and then methyliodide (5,2 ml), and reaction, which is slightly exothermic, was allowed to proceed for 1 hour in a water bath at 34°C for 60 minutes Adding sodium hydride and methyliodide was repeated twice with the same quantities of each connection, and after the last addition the mixture was stirred at room temperature for 68 hours and then was poured into 500 ml of water. Then the pH was brought to pH>13 using 40 ml of 1M NaOH (aq.), and the mixture was stirred at ambient temperature for 15 hours for hydrolysis of the resulting methyl esters. The mixture is then acidified with 50 ml of 2M HCl (aq.) to a pH of about 2 and was extracted 3 times with ethyl acetate (500 ml and 2×200 ml). The combined organic phase was dried over Na2SO4and then was evaporated to dryness. The crude product (24 g) was purified preparative HPLC using acetonitrile/water as eluents. The collected fraction was evaporated to remove acetonitrile. The remaining aqueous phase is extra is Aravali with ethyl acetate and the organic phase was dried over Na 2SO4and then was evaporated to dryness. To the residue was added water (200 ml)and the pH carefully brought to pH 7 using 0.1 m NaOH (aq.), during this process, the residue was slowly dissolved. After neutralization of the aqueous solution was subjected to freeze-drying.

Example 2: Getting hyperpolarizing13With pyruvate using13With-pyruvic acid and radical Example 1

By dissolving 5.0 mg radical Example 113With1-pyruvic acid (164 μl) received 20 mm solution. The sample was mixed to a homogeneous state and an aliquot of the solution (41 mg) were placed in cuvettes for sample and inserted into the DPJ-polarizer.

The sample is polarized in terms of the DPJ at 1.2 K in a magnetic field at 3.35 T under the influence of microwave radiation (93,950 GHz). After 2 hours, the polarization was stopped and the sample was dissolved using the installation for dissolution in accordance with WO-A-02/37132, in an aqueous solution of sodium hydroxide and Tris(hydroxymethyl)aminomethane (TRIS) to obtain a neutral solution hyperpolarizing13With1pyruvate sodium. The dissolved sample is quickly analyzed by the method of13C-NMR to evaluate the polarization and received13With polarization 19,0%.

Example 3: Getting hyperpolarizing13With pyruvate using13With-pyruvic acid and radical Example 1

The dissolution of the radical of Example 1 (209,1 mg) in a mixture of13With1-pyruvic acid (553 mg) and unlabeled pyruvic acid (10,505 g) received a 15 mm solution. The sample was mixed to a homogeneous state and an aliquot of the solution (2,015 g) were placed in cuvettes for sample and inserted into the DPJ-polarizer.

The sample is polarized in terms of the DPJ at 1.2 K in a magnetic field at 3.35 T under the influence of microwave radiation (93,950 GHz). After 4 hours, the polarization was stopped and the sample was dissolved using the installation for dissolution in accordance with WO-A-02/37132, in an aqueous solution of sodium hydroxide and Tris(hydroxymethyl)aminomethane (TRIS) to obtain a neutral solution hyperpolarizing13With1pyruvate sodium with a total concentration of pyruvate 0.5 M in 100 mm TRIS-buffer. The chromatographic column was sequentially coupled with installation for dissolution. The column consists of a cartridge (diameter =38 mm; height =10 mm)containing a hydrophobic filler (Bondesil-C18, 40UM Part #: 12213012)supplied by the company Varian. The dissolved sample was pumped through the column, which was selectively adsorbing radical. The filtered solution is quickly analyzed by the method of13C-NMR to evaluate the polarization and received13With the polarization of 16.5%. Then the residual concentration of the radical were analyzed on a UV spectrophotometer at 469 nm and determined, is it below the detection limit (0.1 ám.

Example 4: Obtaining hyperpolarizing13With pyruvate using13With-pyruvic acid and sodium salt of Tris(8-carboxy-2,2,6,6-Tetra(hydroxyethoxy)methyl-benzo[1,2-d:4,5-a']bis(1,3)dithiol-4-yl)-methyl

Sodium salt of Tris(8-carboxy-2,2,6,6-Tetra(hydroxyethoxy)methyl-benzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)-methyl synthesized as described in Example 29 in WO-A-97/09633.

By dissolving the sodium salt of Tris(8-carboxy-2,2,6,6-Tetra(hydroxyethoxy)methyl-benzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)-methyl13With1-pyruvic acid (83,1 mg) received 20 mm solution. The sample was mixed to a homogeneous state, were placed in cuvettes for sample and inserted into the DPJ-polarizer. The sample is polarized in terms of the DPJ at 1.2 K in a magnetic field at 3.35 T under the influence of microwave radiation (93,950 GHz).13C-NMR signal from the sample is then obtained using the NMR spectrometer Varian lnova-200. Strengthening the DPJ was calculated based on measurement results13C-NMR signal at thermal equilibrium and enhanced NMR signal. Received13With the polarization of 16%.

Example 5: a Visualization of the tumor using hyperpolarizing13With pyruvate as visualizing agent

5.1 Animal model tumors and tumor

R3230AC is a mammary adenocarcinoma in rats, which can poddergivaiu female rats Fischer 344. To create animal models of tumor frozen tube of cells R32030 containing RPMI 1640, 10% FBS (fetal bovine serum) and 10% DMSO (dimethyl sulfoxide)was rapidly thawed at 37°C. After this, the solution with the cells was transferred into FBS and added increasing amounts of RPMI 1640. At the end of the cell suspension was transferred into a culture flask 25 cm2and put in the incubator at 37°C, 5% CO2. Growth medium was changed every other day. On the day of infection in rats, the cells were removed either mechanically or by using trypsin. Cells were washed in phosphate buffer without calcium and magnesium. Trypsin (0.05% trypsin in 0.02% EDTA) was added in about 2-5 minutes Then added 5 ml of FBS and the cells transferred in chemical beaker containing RPMI 1640 with FCS (fetal calf serum) and antibiotics (100 M.E. Ter-Minassian/ml penicillin, 100 M.E. Ter-Minassian/ml streptomycin, 2.5 µg/ml amphotericin b). The solution containing the cells was centrifuged and the cell sediment resuspendable in 20 ml of RPMI with FBS and antibiotics, centrifugation and re-suspension repeated. Then, taking aliquots of the cells in tubes containing 4×106cells/ml of RPMI 1640. To obtain donor tumors in female rats, Fischer 344 (Charles River, 180-200 g) were anestesiology and made them a subcutaneous injection of 0.3 ml of cell suspension in the femoral region on both sides. After 15 days and 22 days received pieces of the tumor, as described in F.A.Burgener et al., Invest Radiol 22/6 (1987), 72-478; S.Saini et al., J. Magn. Reson. 129/1 (1997), 35-43). The ventral abdomen of recipient-female Fischer rats did two sections. A piece of tumor was inserted into each pocket and the incision was sutured. Rats were transported to the visualization in the 12-14 days after implantation of the tumor.

5.2 Preparation of rats and proton Mr imaging

Suspended rats did anesthesia with isoflurane (2-3%) and left them on the heating table to maintain body temperature of about 37°C. In the tail vein and the left common carotid artery was introduced catheter. Rats were transported in the MRI apparatus and placed on a special litter, which was heated to approximately 37°C by circulating Fluorinert FC-104. This fluid should not create a background signals when1H and13With Mr imaging. Anesthesia was maintained with 1-2%isoflurane delivered through a long tube into the open respiratory system with a speed of 0.4 l/min Arterial catheter was connected via a T-shaped tube with a recording pressure gauge and a pump that delivers saline (rate of 0.15 l/min), in order to prevent clogging of the catheter. Rats were placed in the MRI coil for rat (Rapid Biomedicals, Germany) and were rendering using a standard sequence of proton Mr imaging to obtain anatomical information and to determine the location of the tumor.

5.313 With-MRI visualization

Based on the proton frequency, found Mr system, to calculate the Mr frequency for13With1-alanine according to the following equation:

Frequency13With1-alanine = 0,25144 × [(system proton frequency × 1,00021)-0,000397708].

Calculated frequency positioned Mr signal from13With1-alanine on resonance with13With1-lactate on the left and13With1-pyruvate, resonating to the right of13With1-alanine. Performed a sequence of non-localized Mr spectroscopy, to make sure that the13With-Mr coil system and the Mr frequency is set correctly. Localization13With images positioned so as to cover the tumor (slice thickness 10 mm, the pixel size in the same plane 5×5 mm2). In the reconstruction phase of video data filled with zeros, in order to have a resolution of 2.5×2.5 to×10 mm3.13With1-pyruvate in TRIS-buffer (90 mm) were injected with the dose of 10 ml/kg over a period of time of 12 seconds with a minimum volume of 2 ml into the tail vein and 30 seconds after start of injection (i.e. after 18 seconds after injection) started13With-Mr series of chemical changes.

5.4 data Analysis Mr imaging

Mr imaging has given matrix containing 16×6 elements, where each element, or voxel/pixel contains13With-Mr SPECT is. In the reconstruction phase of the matrix is filled with zeros up to 32×32, which is a mathematical operation, which helps to improve the spatial resolution. The dataset to be analyzed contained 1024 range when exporting to Dicom® (DICOM is a registered trademark of the National Electrical Manufactures Association for its standards publications relating to the transmission of digital medical information for further analysis. About half of these spectra does not contain Mr signals, since the position of these voxels was out of the animal. Localization within the animal revealed voxels with high pyruvate signals and negligible lactate and alanine signal (blood pool), while other voxels showed pyrolatry, alanine and lactate with approximately equal intensity.

The amplitude of pyruvate, alanine and lactate were estimated using the methods of the alignment of the data in the time domain, which included the following: phase zero order is constant over the data set, the phase of the first order is 1.4 MS, Pets variation of the line width or decay in the time domain from 0.5 to 3 times the average line width of the entire data set for each metabolite independently and Pets variation of frequency from 20 Hz in both directions relative to the average frequency found is on the entire dataset for the highest peak, must be identified by the user.

The amplitude of lactate, alanine and pyruvate in the matrix was perioperatively in the matrix and did a re-sampling for the selection of resolution proton anatomical Mr image.13With-Mr images were projected on the anatomical images using automated methods of obtaining control of the operator result. These results showed many images containing anatomical proton image of a rat tumor, metabolic13With image for pyruvate, lactate and alanine, projected onto the anatomical image, and images are shown for each pixel

a) ([lactate]standards×([pyruvate]max-[pyruvate])standards)×[lactate] and

b) ([lactate]standards×([alanine]max-[alanine])standards)×[lactate]

where the term "[...]standards" mean normalized amplitude, that is scaled relative to the highest value in metabolic image, and[lactate]" means the calculated amplitude.

A successful outcome distinguish between tumor tissue and healthy tissue metabolism13With-Mr image was defined as the highest lactate signal in the tumor area or high weighted ratio of lactate relatively pyruvate in the field is the tumor and high weighted ratio of lactate relative to alanine in the same pixel location.

5.5 Biological analysis

The localization of tumors were examined visually for signs of bleeding. Tumors were removed from the bodies of rats, weighed and cut in half. The inner part of the tumor examined visually assessing uniformity, necrosis and bleeding. Tumor tissue was preserved in 4% formalin.

A rat with a tumor was considered appropriate to assess if there was compliance with the following criteria: tumor weight >100 mg, no visible necrosis or cysts in the inner part of the tumor, while Mr studies of body temperature above 35°C and mean arterial blood pressure above 60 mm Hg

5.6 Results

In total 30 different tumors were visualized in 18 rats. Biological criteria described in the previous section 5.5, did not meet 1 rat and 3 tumors. The remaining 26 tumors in 17 rats were homogeneous and had not massive necrotic inner part. The average polarization13With1pyruvate at the time of injection amounted to 21.2±2,9% (average ± standard deviation), and the pH value was 8,08±0,14 (mean ± standard deviation).

Figure 1 presents a typical set of images one visualized rats with (1) proton image comparison, where the arrows indicate the location of the tumor, (2)13With-pyruvate image, (3)13S-lacto who tym image, (4)13With-alanine image, (5)13With-lactate image adjusted in relation to13With-pyruvate and (6)13With-lactate image adjusted in relation to13With-alanine. Image (2)to(6) combined with proton image comparison.

Figure 2 presents the same set of images, but images (2)-(6), which are not combined with anatomical proton image.

As a result, the location of the tumor indicates high piruvate signal (2) due to the high metabolic activity. However, the lactate signal (3) ultimately identifies the exact location of the tumor. Alanine is seen in skeletal muscle and not in the tumor tissue (4). Adjusted in relation to pyruvate and alanine lactate image (5) and (6) also provide excellent contrast for tumor.

Thus, it is demonstrated that the location of the tumor on the metabolic images indicates high lactate signal, high lactate signal, adjusted in respect of pyruvate, and high lactate signal, adjusted in relation to alanine.

Analysis of metabolic13With-Mr images revealed metabolic contrast in the tumor area in

- 24 of 26 tumors for lactate signal,

- 26 of 26 tumors to lactate with the persecuted, adjusted in relation to pyruvate (5.5)),

- 26 of 26 tumors for lactate signal, adjusted in respect of alanine 5.5, b)).

The overall degree of success for this study was 26 out of 26 or 100%.

This study demonstrated that tumors can be identified using hyperpolarizing13With1pyruvate, which reaches the region of interest (tumor) for a period of time, which gives the possibility to visualize the compound and its metabolites.

1. The method of producing a liquid composition containing hyperpolarizability13C-pyruvate, including:
a) formation of liquid mixtures containing radical of the formula (I)

where M represents hydrogen or one equivalent of a cation; and
R1, which are identical or different, each represents gidrauxilirovaniu and/or alkoxycarbonyl1-C4-carbohydrate group with a straight or branched chain,
13With-pyruvic acid and/or13C-pyruvate, and freezing the mixture;
b) strengthening polarized13With cores of pyruvic acid and/or pyruvate in the mixture by the DPJ (dynamic polarization of nuclei);
C) adding a physiologically portable buffer which provides a pH in the range from 7 to 8, and frozen grounds to the mixture to dissolve and for the conversion of the 13With pyruvic acid in the13With pyruvate to form a liquid composition or, when on the stage (a) use only13C-pyruvate, adding a buffer to the frozen mixture to dissolve to form a liquid composition; and
g) you can delete radical and/or its reaction products from the liquid composition.

2. The method according to claim 1, where the radical is a radical of the formula (I), where M represents hydrogen or one equivalent of a physiologically portable cation, and R1 are the same or different and each represents alkoxycarbonyl1-C4-otivational group with a straight or branched chain bearing a terminal hydroxyl group, or R1 are the same or different and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain.

3. The method according to claim 2, where R1 is the same and each represents alkoxycarbonyl1-C4is a hydrocarbon group with a straight or branched chain, preferably-CH2-CH2-Och3.

4. The method according to claim 1, where13With-pyruvic acid and/or13C-pyruvate-enriched isotope in position C1, C2, C3, C1 and C2, C1 and C3, C2 and C3, or in the position of C1, C2 and C3, preferably in position C1.

5. The method according to claim 1, where Stepnoe enrichment 13With-pyruvic acid and/or13Since pyruvate is at least 75%, preferably at least 90%.

6. The method according to claim 1, where the buffer is a buffer selected from the group consisting of phosphate buffer, ACES (N-2-acetamido-2-aminoetansulfonovaya acid), PIPES (piperazine-1,4-bis-2-econsultancy acid), imidazole/HCl, BES (N,N-bis(2-hydroxyethyl)-2-aminoetansulfonovaya acid), MOPS (3-morpholine-propanesulfonic acid), HEPES (2-[4-(2-hydroxyethylpiperazine-1-yl]-econsultancy acid), TES (N-Tris(hydroxymethyl)methyl-2-aminoetansulfonovaya acid), TRIS (Tris(hydroxymethyl)aminomethan), HEPPS (4-(2-hydroxyethyl)-1-piperazine-propanesulfonic acid) and TRICIN (N-[Tris(hydroxymethyl)methyl] glycine), preferably selected from the group consisting of phosphate buffer and TRIS.

7. The method according to claim 1, where at stage (a) use13With-pyruvic acid, and where at the stage (in) buffer and Foundation combined in one solution.

8. The method according to claim 1, where at stage (a) use13With-pyruvic acid, and the base is NaOH.

9. The method according to claim 1, where stage (g) is required.

10. The method according to claim 9 to obtain a composition for use as an imaging agent for Mr imaging of in vivo human or animal, not a person.

11. The composition containing hyperpolarization is th 13C-pyruvate and a buffer selected from the group consisting of phosphate buffer and TRIS, for use as Mr imaging agent.

12. The composition according to claim 11, where hyperpolarizability13C-pyruvate has a polarization of at least 10%, preferably at least 15% and more preferably at least 20%.

13. The composition according to claim 11, where hyperpolarizability13C-pyruvate is hyperpolarizability13With a sodium pyruvate.

14. The composition according to claim 11, obtained by the method according to claims 1 to 10.

15. The use of a composition according to § § 11 to 14 for the manufacture of an Mr imaging agent for in vivo studies of metabolic processes in the human body or an animal, not a person.

16. The use of a composition according to § § 11 to 14 for the manufacture of an Mr imaging agent for imaging tumors in vivo in a human or animal, non-human, preferably for diagnosing and/or staging, and/or monitoring treatment of a tumor in vivo.

17. The application of article 16, where the specified tumor is a tumor of the prostate.

18. Composition containing13With-pyruvic acid and/or13C-pyruvate and a radical of the formula (I), for use as Mr imaging agent.

19. The composition according to p containing13With-pyruvic acid and the radical forms of the crystals (I), where M represents hydrogen or sodium and R1 are the same and each represents-CH2-CH2-Och3.

20. The use of a composition according PP and 19 for receiving hyperpolarizing13With pyruvate.

21. The radical of the formula (I)

where M represents hydrogen or sodium; and
R1 represents-CH2-CH2-Och3.

22. The use of radicals according to item 21 as a paramagnetic agent for the hyperpolarization13With pervinova acid and/or13With pyruvate in the process of the DPJ.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: chemistry.

SUBSTANCE: ergot alkaloid is extracted from ergot with high yield and purity level using method including extraction of Claviceps purpurea, i.e. ergot, mix of solvents toluene/ethanol that leads to production of primary extract. The primary extract can be additionally treated within two stages of liquid-liquid extraction to provide alkaloid purification that gives purified toluene extract. Toluene extract can be additionally partially softened by stream, and crystalline product is produced by toluene crystallisation or mixture of toluene and aliphatic hydrocarbon.

EFFECT: development of method of ergot extraction with high yield and purity level.

23 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds of formula I which can be used in photopolymer composition hardening with catalyst, possible during rays, and as photoinitiators for coating preparation. In formulas (I) and (II) $ , in which R1 denotes phenyl, naphthyl, phenanthryl, anthryl, pyrenil 5,6,7,8-tetrahydro-2-naphthyl,5,6,7,8-tetrahydro-1-naphthyl, thienyl, tiantrenyl, anthraquinonyl, xantenyl, thioxantyl, phenoxantyinyl, carbazol, phenantridinyl, akridinyl, fluorenyl or phenoxazinyl, besides radicals is unsubstituted or once or several times substituted by C1-C18alkyl, C2-C18alkenyl, C1-C18haloalkyl, NO2, NR10R11, CN, OR12, SR12, halogen atom or radical of formula II or radical R1 denotes radical of formula III . R2 and R3 independently denote a hydrogen atom; R10, R11 R12 independently denote a hydrogen atom or C1-C18alkyl; R4 and R6 form C2-C12alkylen bridge, which is not substituted or substituted by or several C1-C4alkyl radicals; R15 denotes H or radical of formula II.

EFFECT: production of the nitrogen bases that can be used as a photopolymer composition, hardening with catalyst, and as photoinitiator for coating.

11 cl, 4 tbl, 21 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: medicine.

SUBSTANCE: invention relates to using a gadolinium complex of [1-(4-perfluorooctylsulfonyl)piperazine]amide of 6-N-[1,4,7-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-α-D-carbonylmethylmannopyranose]-L-lysine as a contrasting substance used in method of the magnetic-resonance tomography in visualization of patches.

EFFECT: enhanced precision of diagnosis.

3 tbl, 136 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with polar residues of the general formula (I):

wherein R means a polar residue; G means a trifunctional residue, a perfluorinated carbon chain; K means a metal complex; Z means a linker group. Proposed complexes can be used for intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis. Also, invention describes a method for synthesis of these complexes.

EFFECT: valuable medicinal properties of complexes.

16 cl, 1 tbl, 26 ex

The invention relates to the objects of the invention characterized in the claims, i.e

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image
The invention relates to histochemistry

FIELD: medicine.

SUBSTANCE: invention can be used for tumor visualisation using hyperpolarisable 13C-pyruvate as magnetic resonance imaging agent, which can distinguish healthy tissue from tumor tissue. The following shall be performed: a) acquisition of direct 13C-MP images of 13C-pyruvate and its 13C-containing metabolites of alanine and lactate in the patient previously injected with composition containing hyperpolarisable 13C-pyruvate, b) correcting lactate signal with respect to quantity of pyruvate and/or alanine with acquisition of lactate relative to pyruvate and/or lactate relative to alanine image whereby tumor tissue is indicated by the highest signal and/or high weighted lactate signal relative to pyruvate signal and/or lactate signal relative to alanine signal in specified13C-images.

EFFECT: improved imaging accuracy when distinguishing healthy tissue from tumor tissue.

8 cl, 2 dwg, 5 ex

FIELD: medical equipment.

SUBSTANCE: therapy system includes central control device; acoustic energy applicator; mechanical device driving and localising the acoustic energy applicator; real-time B-type ultrasound image generator. Additionally the therapy system includes: patient position immobiliser, diagnostic image generator, register of B-type ultrasound image with diagnostic images allowing ultrasound image alignment with diagnostic images in real-time mode, and device B-type ultrasound image superimposition with diagnostic images on the basis of registration for performance of therapy.

EFFECT: enhanced efficiency of system.

5 dwg

FIELD: medicine.

SUBSTANCE: decrease or increase of rate of diffusion of water protons in brain matter is determined from measured diffusion coefficient (MDC) for a patient with acute cerebrovascular event using timed diffusion-weighted magnetic resonance imaging (DW MRI). Through timed magnetic resonance imaging of perfusion, cerebral blood flow is determined from average time of flow of contrast medium (rMTT) and from the average time before achieving maximum concentration of contrast medium (rTTP). The given indicators are also determined in corresponding brain regions of the "undamaged" hemisphere. During small supratentorial intracerebral bleeding in the perifocal region, absence of ischemic damage to brain matter is diagnosed if the ratio of the measured diffusion coefficient in the "damaged" and "undamaged" hemispheres is greater than 1.5 and decreases towards the end of the subacute period, and rMTT and rTTP in the "damaged" and "undamaged" hemispheres during the acute and subacute periods are identical.

EFFECT: diagnosis method allows for evaluating functional state of zones, surrounding hematoma, detecting presence or absence of ischemic factor in the region of perifocal changes during small supratentorial intracerebral bleeding.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine and is intended for lifetime diagnostics of intrasellar hypertension on low-field magnetic resonance tomograph. T1 - protocol with parametres for hypophysis: TR (time repetition) is equal 340; TE (Time echo) is equal 26; quantity of slices (No slices) is equal 7, thickness of slices (slices thickness) is equal 3 mm; field of view (Field of view) is equal 230; matrix is equal 192×256; number of data collection (No Acquisition) is equal 6, is used. On obtained images by means of adjustment of brightness and contrast scale hypophysis diaphragm is additionally highlighted. If dome-like risen diaphragm is present, distance from chiasma to diaphragm is measured. If the distance is less than 2 mm, as well as concave upper hypophysis boundary, intrasellar hypertension is diagnosed.

EFFECT: ensuring possibility to perform diagnostics of intrasellar hypertension on low-field magnetic resonance tomograph.

1 tbl, 4 ex, 7 dwg

FIELD: medical equipment.

SUBSTANCE: ultrasonic therapeutic device comprises a magnet to generate the static magnetic field in a certain space and at least one ultrasonic applicator supplied with a mechanical positioner bringing ultrasound into a certain space within specified region of the patient's body. The magnet for static magnetic field generation is open from both ends and aside with an upper or lower clearance, while the mechanical positioner is being in immediate proximity, however outside of the open clearance.

EFFECT: solving of interference elimination from the magnetic field generated by electric operating current in power leads of the converter within MR-scanning system.

7 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention pertains to physiology, engineering psychology and particularly to such a physiological characteristic of the person as vision acuity. Vision acuity is measured with the help of functional magnetic- resonance tomography when showing test-images with adjusted parametres at a certain distance. Activation of the brain areas caused by the differences between the shown images is registered. Threshold angular parametres of the distinguished test-images are detected and measured; they are correlated with gradation of vision acuity by division of threshold angular parametres by coefficient of the ratio equal to 60.

EFFECT: present method is an objective control method of detection of vision acuity.

1 ex, 1 dwg

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