Generating artificial contrast enhanced radiographic image

Abstract

The present invention relates to the technical field of generating an artificial contrast enhanced radiographic image.

Description

[0001] The present invention relates to the technical field of generating artificially contrast-enhanced radiological images.

[0002] WO2019 / 074938A1 discloses a method for reducing the amount of contrast agent in generating radiological images by means of an artificial neural network.

[0003] In the disclosed method, in the first step, a training data set is generated. For multiple individuals, the training data set includes, for each individual, i) the original radiological image (zero-contrast image), ii) the radiological image after administration of a low amount of contrast agent (low-contrast image), and iii) the radiological image after administration of a standard amount of contrast agent (full-contrast image).

[0004] In the second step, the artificial neural network is trained based on the original image and the image after administration of a low amount of contrast agent, so as to predict, for each individual in the training data set, an artificial radiological image that shows the acquisition area after administration of the standard amount of contrast agent. In each case, the radiological image measured after administration of the standard amount of contrast agent is used as a reference (ground truth) in the training.

[0005] In the third step, the trained artificial neural network can be used to predict, for a new individual, an artificial radiological image based on the original image and the radiological image after administration of a low amount of contrast agent, the artificial radiological image showing the acquisition area as if after administration of the standard amount of contrast agent.

[0006] The method disclosed in WO2019 / 074938A1 has multiple drawbacks.

[0007] For example, training an artificial neural network requires training data. A large number of radiological examinations need to be performed on a large number of people, and training data needs to be generated in order to be able to train the network.

[0008] The artificial neural network disclosed in WO2019 / 074938A1 is trained to predict the radiological image after administration of the standard amount of contrast agent. The artificial neural network is not configured and not trained to predict the radiological image after administration of a contrast agent below or above the standard amount. In principle, the method described in WO2019 / 074938A1 can be trained to predict the radiological image after administration of a contrast agent different from the standard amount. However, this requires further training data and further training.

[0009] It is desirable to be able to generate radiographic images with variable contrast enhancement without having to generate training data for each individual contrast enhancement and without having to train an artificial neural network. Furthermore, it is desirable to be able to generate variable contrast enhancement using a reproducible deterministic method, thereby generating radiographic images with variable contrast enhancement. This facilitates the approval and use of the corresponding medical procedures while minimizing false negative and false positive results. Machine learning methods employ statistical models with limited generality as they are typically based on a selection of limited training data. Furthermore, it is desirable to be able to generate radiographic images with variable contrast enhancement using multiple contrast agents. Additionally, it is desirable to be able to generate radiographic images with variable contrast enhancement using multiple different contrast agents (regardless of their physical, chemical, physiological or other properties) using the method. Additionally, it is desirable to be able to use such a method for generating radiographic images with variable contrast enhancement that uses at least two different contrast agents with different properties (preferably using extracellular and intracellular contrast agents) in order to be able to fully exploit the imaging potential of the different contrast agents. When different contrast agents are used in a method for generating radiographic images with variable contrast enhancement, it would be particularly desirable if the different contrast agents were included in a single composition and thus could be administered in one go.

[0010] These and other objects are achieved by the subject matter of the independent claims. Preferred embodiments of the invention can be found in the dependent claims, the description and the drawings.

[0011] Accordingly, in a first aspect, the present invention provides a computer-implemented method for generating contrast-enhanced radiographic images, comprising the steps of:

[0012] - receiving or generating a first representation that represents an examination region of an object that has not been administered a contrast agent or has been examined after administration of a first amount of a composition that comprises (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0013] - receiving or generating a second representation that represents the examination region of the object after administration of a second amount of the composition, the second amount being greater than the first amount,

[0014] - generating a third representation based on the first representation and the second representation, the generating of the third representation comprising subtracting the first representation from the second representation,

[0015] - generating a fourth representation, the generating of the fourth representation comprising adding α times the third representation to the first representation, where α is a positive or negative real number,

[0016] - outputting and / or storing the fourth representation of the examination region and / or transmitting the fourth representation of the examination region to a separate computer system.

[0017] The present invention also provides a computer system, comprising:

[0018] a processor; and

[0019] a memory storing an application program, the application program being configured to perform operations when executed by the processor, the operations including:

[0020] - receiving or generating a first representation, the first representation representing an examination region of an object without using a contrast agent or after administering a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0021] - receiving or generating a second representation, the second representation representing an examination region of an object after administering a second amount of the composition, the second amount being greater than the first amount,

[0022] - generating a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation,

[0023] - generating a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number,

[0024] - outputting and / or storing the fourth representation of the examination region and / or transmitting the fourth representation of the examination region to a separate computer system.

[0025] The present invention also provides a computer program, which can be loaded into the working memory of a computer system, wherein the computer program causes the computer system to perform the following steps:

[0026] - receiving or generating a first representation, the first representation representing an examination region of an object without administering a contrast agent or after administering a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0027] - receiving or generating a second representation, the second representation representing an examination region of an object after administering a second amount of the composition, the second amount being greater than the first amount,

[0028] - generating a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation,

[0029] - generating a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number,

[0030] - Output and / or store a fourth representation of the examination region and / or transmit the fourth representation of the examination region to a separate computer system.

[0031] The present invention also provides the use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent in a radiological examination, said use comprising:

[0032] - Receiving or generating a first representation that represents the examination region of an examination subject without administration of a contrast agent or after administration of a first amount of the composition,

[0033] - Receiving or generating a second representation that represents the examination region of an examination subject after administration of a second amount of the composition, the second amount being greater than the first amount,

[0034] - Generating a third representation based on the first representation and the second representation, said generating the third representation comprising subtracting the first representation from the second representation,

[0035] - Generating a fourth representation, said generating the fourth representation comprising adding α times the third representation to the first representation, where α is a positive or negative real number,

[0036] - Output and / or store a fourth representation of the examination region and / or transmit the fourth representation of the examination region to a separate computer system.

[0037] The present invention also provides a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent for use in a radiological examination method, said use comprising:

[0038] - Receiving or generating a first representation that represents the examination region of an examination subject without use of a contrast agent or after administration of a first amount of the composition,

[0039] - Receiving or generating a second representation that represents the examination region of an examination subject after administration of a second amount of the composition, the second amount being greater than the first amount,

[0040] - Generating a third representation based on the first representation and the second representation, said generating the third representation comprising subtracting the first representation from the second representation,

[0041] - Generating a fourth representation, said generating the fourth representation comprising adding α times the third representation to the first representation, where α is a positive or negative real number,

[0042] - Output and / or store a fourth representation of the examination region and / or transmit the fourth representation of the examination region to a separate computer system.

[0043] The present invention also provides a kit, which comprises a computer program product and a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, wherein the computer program product comprises a computer program that can be loaded into the working memory of a computer system, and wherein the computer program causes the computer system to perform the following steps:

[0044] - receiving or generating a first representation that represents an examination region of an object that has not been examined using a contrast agent or after administration of a first amount of the composition,

[0045] - receiving or generating a second representation that represents an examination region of an object after administration of a second amount of the composition, the second amount being greater than the first amount,

[0046] - generating a third representation based on the first representation and the second representation, the generating of the third representation comprising subtracting the first representation from the second representation,

[0047] - generating a fourth representation, the generating of the fourth representation comprising adding α times the third representation to the first representation, where α is a positive or negative real number,

[0048] - outputting and / or storing the fourth representation of the examination region and / or transmitting the fourth representation of the examination region to a separate computer system.

[0049] The present invention will be explained in more detail below without distinguishing between the subject matter of the invention (method, computer system, computer program (product), use, composition used, kit). On the contrary, the following explanations are intended to apply analogously to all subject matter (method, computer system, computer program (product), use, composition used, kit), regardless of the context in which they occur.

[0050] If steps are stated in a particular order in this specification or in the claims, this does not necessarily mean that the invention is limited to the stated order. On the contrary, it is contemplated that the steps may also be performed in a different order or in parallel with each other, unless one step is based on another step and thus the step based on the previous step must be performed subsequently (however, this will be clear in individual cases). Thus, the order constitutes a preferred embodiment.

[0051] The present invention describes a method for generating one or more artificial radiological images based on at least two representations representing an examination region of an object to be examined, after addition / administration / use of different amounts of a contrast agent, wherein the contrast between regions with a contrast agent and regions without a contrast agent can be varied.

[0052] The "object to be examined" is generally a living being, preferably a mammal, most preferably a human.

[0053] The "examination area" is a part of the object to be examined, such as an organ, a part of an organ or multiple organs, or another part of the object to be examined.

[0054] For example, the examination area may be the liver, kidney, heart, lung, brain, stomach, bladder, prostate, intestine or a part thereof, or another part of the body of a mammal (such as a human).

[0055] In one embodiment, the examination area includes the liver or a part of the liver, or the examination area is the liver or a part of the liver of a mammal (preferably a human).

[0056] In a further embodiment, the examination area includes the brain or a part of the brain, or the examination area is the brain or a part of the brain of a mammal (preferably a human).

[0057] In a further embodiment, the examination area includes the heart or a part of the heart, or the examination area is the heart or a part of the heart of a mammal (preferably a human).

[0058] In a further embodiment, the examination area includes the chest cavity or a part of the chest cavity, or the examination area is the chest cavity or a part of the chest cavity of a mammal (preferably a human).

[0059] In a further embodiment, the examination area includes the stomach or a part of the stomach, or the examination area is the stomach or a part of the stomach of a mammal (preferably a human).

[0060] In a further embodiment, the examination area includes the pancreas or a part of the pancreas, or the examination area is the pancreas or a part of the pancreas of a mammal (preferably a human).

[0061] In a further embodiment, the examination area includes the kidney or a part of the kidney, or the examination area is the kidney or a part of the kidney of a mammal (preferably a human).

[0062] In a further embodiment, the examination area includes one or both lungs or a part of the lungs of a mammal (preferably a human).

[0063] In a further embodiment, the examination area includes the breast or a part of the breast, or the examination area is the breast or a part of the breast of a female mammal (preferably a human female).

[0064] In a further embodiment, the examination area includes the prostate or a part of the prostate, or the examination area is the prostate or a part of the prostate of a male mammal (preferably a human male).

[0065] The examination area (English: field of view, FOV) is in particular the volume imaged in the radiological image. The examination area is usually defined by a radiologist, for example on a localizer image. Of course, the examination area can alternatively or additionally be defined in an automated manner, for example based on a selected protocol.

[0066] A radiological examination is performed on the examination area.

[0067] "Radiology" is a branch of medicine that involves the use of electromagnetic rays and mechanical waves (including, for example, ultrasound diagnostics) for diagnostic, therapeutic, and / or scientific purposes. In addition to X-rays, other ionizing radiations are also used, such as gamma radiation or electrons. Imaging is the main application, and other imaging methods (such as ultrasound examination and magnetic resonance imaging (nuclear magnetic resonance imaging)) are also considered radiology, even if ionizing radiation is not used in these methods. Thus, the term "radiology" in the context of the present invention particularly encompasses the following examination methods: computed tomography, magnetic resonance imaging, ultrasound examination.

[0068] In one embodiment of the present invention, the radiological examination is a magnetic resonance imaging examination.

[0069] In a further embodiment, the radiological examination is a computed tomography examination.

[0070] In one embodiment, the radiological examination is an ultrasound examination.

[0071] In a radiological examination, a contrast agent is usually used for contrast enhancement.

[0072] A "contrast agent" is a substance or mixture of substances that improves the description of the human body's structures and functions in a radiological examination.

[0073] In computed tomography, an iodine-containing solution is typically used as a contrast agent. In magnetic resonance imaging (MRT), superparamagnetic substances (e.g., iron oxide nanoparticles, superparamagnetic iron-platinum particles (SIPPs)) or paramagnetic substances (e.g., gadolinium chelates, manganese chelates) are typically used as contrast agents. In contrast-enhanced ultrasound, a liquid containing gas-filled microbubbles is typically administered intravenously. Examples of contrast agents can be found in the literature (see, for example, A.S.L. Jascinth et al.: Contrast Agents in computed tomography: A Review, Journal of Applied Dental and Medical Sciences, 2016, Vol. 2, No. 2, 143-149; H. Lusic et al.: X-ray-Computed Tomography Contrast Agents, Chem. Rev, 2013, 113, 3, 1641-166; https: / / www.radiology.wisc.edu / wp-content / uploads / 2017 / 10 / contrast-agents-tutorial.pdf, M.R. Nough et al.: Radiographic and magnetic resonances contrast agents: Essentials and tips for safe practices, World J Radiol, September 28, 2017, 9(9): 339-349; L.C. Abonyi et al.: Intravascular Contrast Media in Radiography: Historical Development & Review of Risk Factors for Adverse Reactions, South American Journal of Clinical Research, 2016, Vol. 3, No. 1, 1-10; ACR Manual on Contrast Media, 2020, ISBN: 978-1-55903-012-0; A. Ignee et al.: Ultrasound contrast agents, Endosc Ultrasound, November-December 2016, 5(6), 355-362).

[0074] MRT contrast agents act by changing the relaxation time of the structures that take up the contrast agent. A distinction can be made between two groups of substances: paramagnetic substances and superparamagnetic substances. Both groups of substances have unpaired electrons, which induce a magnetic field around the individual atoms or molecules. Superparamagnetic contrast agents mainly cause shortening of T2, while paramagnetic contrast agents mainly cause shortening of T1. The action of the contrast agent is indirect, since the contrast agent itself does not emit a signal, but instead only affects the signal intensity in its vicinity. An example of a superparamagnetic contrast agent is iron oxide nanoparticles (SPIO, English: superparamagnetic iron oxide). Examples of paramagnetic contrast agents are gadolinium chelates, such as gadopentetic acid (trade name: etc.), gadoteric acid gadodiamide gadoteridol gadobutrol and gadoxetic acid

[0075] The present invention includes the use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent. Contrast agents are classified as "extracellular" or "intracellular" according to their distribution pattern in tissues.

[0076] After intravenous administration, the high hydrophilicity and low molecular weight of the extracellular contrast agent result in rapid diffusion into the interstitial space. After circulating in the blood for a relatively short period of time, the contrast agent is excreted via the kidneys.

[0077] Extracellular MRT contrast agents include, for example, the gadolinium chelate gadobutrol gadoteridol gadoteric acid gadopentetic acid and gadodiamide Other extracellular gadolinium-containing contrast agents are described in WO2016 / 193190 (gadoquatrane).

[0078] Intracellular contrast agents are taken up to a certain extent by tissue cells and then excreted. For example, hepatobiliary contrast agents have the following characteristic manifestations: specific uptake by liver cells (hepatocytes), accumulation in functional tissue (parenchyma), and enhancement of the contrast of healthy liver tissue. An example of a hepatobiliary contrast agent is gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid disodium salt (Gd-EOB-DTPA disodium), which is described in US Patent No. 6039931A and is commercially available under the trade names and Commercially available. In addition, other hepatobiliary contrast agents are described in WO2022 / 194777.

[0079] The generation of artificial radiographic images with variable contrast enhancement is based on at least two characterizations of the examination region: a first characterization and a second characterization.

[0080] The first characterization represents the examination region without the administration of a contrast agent or after the administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0081] The second characterization represents the examination region after the administration of a second amount of the composition. The second amount is greater than the first amount (as noted, the first amount can also be zero). The expression "after the second amount of the composition" should not be understood to mean that the first and second amounts of the composition are added in the examination region (unless the first amount is zero). Thus, the expression "the characterization represents the examination region after the administration of (the first or second) amount" should be understood to mean: "the characterization represents the examination region having (the first or second) amount" or "the characterization represents the examination region containing (the first or second) amount".

[0082] If the first amount is not equal to zero, the first and second characterizations preferably (but not necessarily) represent the examination region at the same time interval starting from the administration of the contrast agent. If the first amount is equal to zero, the time interval of the second characterization starting from the administration of the contrast agent can be selected as desired.

[0083] Preferably, both the first and second amounts of the composition are less than the standard amount. Preferably, the amounts of the respective components of the composition (i.e., the extracellular contrast agent and the intracellular contrast agent) in the first and second amounts of the composition are less than the standard amount.

[0084] Preferably, the molar ratios of the respective components in the first and second amounts of the composition are equal.

[0085] The standard amount is generally the amount recommended by the manufacturer and / or distributor of the composition and / or its components and / or the amount authorized by the regulatory agency and / or the amount stated in the package insert of the composition and / or its components.

[0086] For example, thus the standard amount of is 0.025 mmol of gadolinium-EOB-DTPA disodium / kg body weight.

[0087] In one embodiment of the present invention, the composition is a composition comprising (i) an extracellular contrast agent and (ii) a hepatobiliary contrast agent.

[0088] In one embodiment of the present invention, the composition is a composition comprising (i) an extracellular contrast agent and (ii) a hepatobiliary contrast agent (comprising a paramagnetic metal center and a macrocyclic chelator).

[0089] In one embodiment of the present invention, the composition is a composition comprising (i) an extracellular contrast agent (comprising a paramagnetic metal center and a macrocyclic chelator) and (ii) a hepatobiliary contrast agent (comprising a paramagnetic metal center and a macrocyclic chelator).

[0090] In one embodiment, the paramagnetic metal center in the extracellular contrast agent and / or hepatobiliary contrast agent is a lanthanide. Preferably, the paramagnetic metal center in the extracellular contrast agent and / or hepatobiliary contrast agent is Gd, particularly preferably Gd 3+ .

[0091] In one embodiment, the extracellular contrast agent is a compound of formula (I), a compound of formula (II) or a compound of formula (III), wherein the compound of formula (I) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof,

[0092]

[0093] in:

[0094] for Group,

[0095] * is the same as R 1 The connection key,

[0096] R 1 For R 3 Group,

[0097] n=4,

[0098] R 2 is a hydrogen atom,

[0099] R 3 is a group selected from the following:

[0100]

[0101] * is the bond to the rest of the molecule,

[0102] R 4 is a hydrogen atom or a methyl group;

[0103] The compound of formula (II) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof,

[0104]

[0105] in

[0106] R 5 is a hydrogen atom,

[0107] R 6 is a group selected from the following:

[0108] C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl), and phenyl, wherein the C1-C4 alkyl group is optionally and identically or differently substituted by phenyl, and the phenyl is optionally mono-substituted, di-substituted, or tri-substituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy,

[0109] and

[0110] the phenyl is optionally mono-substituted, di-substituted, or tri-substituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy;

[0111] The compound of formula (III) has the following formula

[0112]

[0113] In one embodiment, the hepatobiliary contrast agent is a compound of formula (IV) or a compound of formula (V), the compound of formula (IV) has the following formula, or its stereoisomer, tautomer, hydrate, solvate, or salt, or a mixture thereof,

[0114]

[0115] wherein

[0116] Ar is a group selected from the following:

[0117]

[0118] # is a bonding site to X,

[0119] X is a group selected from CH2 and (CH2)3,

[0120] R 7 and R 9 are each independently a hydrogen atom or a -CH2OH group,

[0121] R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3,

[0122] R 10 is a group selected from the following:

[0123] C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-, and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the C1-C3 alkoxy and C2-C5 alkoxy groups are optionally mono-substituted, di-substituted, tri-substituted, or tetra-substituted by fluorine atoms;

[0124] The compound of formula (V) has the following formula, or its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof,

[0125]

[0126] wherein

[0127] Ar is a group selected from the following:

[0128]

[0129] # is the bond connecting to X,

[0130] X is a group selected from CH2 and (CH2)2,

[0131] R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3,

[0132] R 12 is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O-, and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

[0133] In one embodiment of the present invention, the composition is a composition comprising (i) an extracellular contrast agent of formula (I), formula (II), or formula (III) and (ii) a hepatobiliary contrast agent of formula (IV) or formula (V),

[0134] The compound of formula (I) has the following formula, or its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof,

[0135]

[0136] wherein:

[0137] is group,

[0138] * is the bond connecting to R 1The linking bond,

[0139] R 1 is R 3 group,

[0140] n = 4,

[0141] R 2 is a hydrogen atom,

[0142] R 3 is selected from

[0143] group,

[0144] * is the linking bond with the rest of the molecule,

[0145] R 4 is a hydrogen atom or a methyl group;

[0146] The compound of formula (II) has the following formula, or its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof,

[0147]

[0148] wherein

[0149] R 5 is a hydrogen atom,

[0150] R 6 is selected from the following groups:

[0151] C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl) and phenyl, the C1-C4 alkyl group is optionally substituted by phenyl identically or differently, and the phenyl is optionally mono-substituted, di-substituted or tri-substituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy,

[0152] and

[0153] the phenyl is optionally mono-substituted, di-substituted or tri-substituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy;

[0154] The compound of formula (III) has the following formula

[0155]

[0156] The compound of formula (IV) has the following formula, or its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof,

[0157]

[0158] wherein

[0159] Ar is a group selected from

[0160] the group,

[0161] # is a bonding key to X,

[0162] X is a group selected from CH2 and (CH2)3,

[0163] R 7 and R 9 are each independently a hydrogen atom or a -CH2OH group,

[0164] R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3,

[0165] R 10 is a group selected from the following:

[0166] C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, the C1-C3 alkoxy and C2-C5 alkoxy groups are optionally mono-substituted, di-substituted, tri-substituted or tetra-substituted by fluorine atoms;

[0167] The compound of formula (V) has the following formula, or its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof,

[0168]

[0169] wherein

[0170] Ar is a group selected from

[0171] the group,

[0172] # is a bonding key to X,

[0173] X is a group selected from CH2 and (CH2)2,

[0174] R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3,

[0175] R 12is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

[0176] In a preferred embodiment of the present invention, the composition is a composition comprising (i) an extracellular contrast agent of formula (I), or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, and (ii) a hepatobiliary contrast agent of formula (IV), or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof

[0177]

[0178]

[0179] wherein:

[0180] is a group,

[0181] * is a bonding site to R 1 a bonding site,

[0182] R 1 is an R 3 group,

[0183] n = 4,

[0184] R 2 is a hydrogen atom,

[0185] R 3 is selected from

[0186] groups,

[0187] * is a bonding site to the rest of the molecule,

[0188] R 4 is a hydrogen atom or a methyl group;

[0189]

[0190] wherein

[0191] Ar is selected from

[0192] groups,

[0193] # is a bonding site to X,

[0194] X is a group selected from CH2 and (CH2)3,

[0195] R 7 and R 9 are each independently a hydrogen atom or a -CH2OH group,

[0196] R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3,

[0197] R 10 is a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

[0198] The term "C1-C2 alkyl" means a straight-chain saturated monovalent hydrocarbon group having 1 or 2 carbon atoms, such as methyl, ethyl.

[0199] The term "C1-C3 alkyl" means a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl.

[0200] The term "C1-C4 alkyl" means a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

[0201] The term "C2-C4 alkyl" means a straight-chain or branched-chain saturated monovalent hydrocarbon group having 2, 3, or 4 carbon atoms.

[0202] The term "C1-C2 alkoxy" means a straight-chain saturated monovalent group of the formula (C1-C2 alkyl)-O-, where the term "C1-C2 alkyl" is as defined above.

[0203] The term "C1-C3 alkoxy" means a straight-chain or branched-chain saturated monovalent group of the formula (C1-C3 alkyl)-O-, where the term "C1-C3 alkyl" is as defined above.

[0204] The term "C2-C4 alkoxy" means a straight-chain or branched-chain saturated monovalent group of the formula (C2-C4 alkyl)-O-, where the term "C2-C4 alkyl" is as defined above, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0205] The term "C2-C5 alkoxy" means a straight-chain or branched-chain saturated monovalent group of the formula (C2-C5 alkyl)-O-, where the term "C2-C5 alkyl" is as defined above.

[0206] The term "C3-C5 cycloalkyl" represents a saturated monovalent monocyclic or bicyclic hydrocarbon radical ring containing 3, 4 or 5 carbon atoms. The "C3-C5 cycloalkyl" is, for example, a monocyclic hydrocarbon radical ring such as cyclopropyl, cyclobutyl or cyclopentyl.

[0207] The term "C1-C3 haloalkyl" represents a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C1-C3 alkyl" is as defined above, and wherein one or more hydrogen atoms are identically or differently substituted by halogen atoms. Preferably, the halogen atom is a fluorine atom. The "C1-C3 haloalkyl" group is, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl group.

[0208] In a preferred embodiment of the present invention, the composition is an extracellular contrast agent comprising (i) the following formula, or its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof

[0209]

[0210] and (ii) a composition of the following formula, or its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof,

[0211]

[0212] In one embodiment, the molar amounts of the extracellular contrast agent and the hepatobiliary contrast agent in the composition are the same or there is an excess of the hepatobiliary contrast agent. Thus, in a preferred embodiment, the molar ratio of the extracellular contrast agent to the hepatobiliary contrast agent is from 1:1 to 1:10, preferably from 1:1 to 1:5, and more preferably from 1:1 to 1:3.

[0213] In another embodiment, the molar amounts of the extracellular contrast agent and the hepatobiliary contrast agent are the same or an excess of the extracellular contrast agent is used. Thus, in a preferred embodiment, the molar ratio of the extracellular contrast agent to the hepatobiliary contrast agent ranges from 1:1 to 10:1, preferably from 1:1 to 5:1, and more preferably from 1:1 to 3:1.

[0214] Preferably, the extracellular contrast agent has a relaxation rate greater than 3 L·mmol -1 ·s -1 measured in plasma or water at 37 °C at 1.5 T. Preferably, the hepatobiliary contrast agent has a relaxation rate greater than 4 L·mmol -1 ·s -1 .

[0215] In a preferred embodiment of the present invention, the composition comprises (i) an extracellular contrast agent having a relaxivity of at least 3 L·mmol -1 ·s -1 (measured at 1.5 T, in plasma or water at 37 °C) and (ii) a hepatobiliary contrast agent having a relaxivity of at least 4 L·mmol -1 ·s -1 (measured at 1.5 T, in plasma or water at 37 °C).

[0216] In a first step, a first representation and a second representation are received or generated.

[0217] The term "receive" encompasses both retrieving a representation and accepting a representation transmitted to, for example, a computer system of the present invention. These representations can be received from a computed tomography system, a magnetic resonance imaging system, or an ultrasound scanner. These representations can be read from one or more data memories and / or transmitted from a separate computer system.

[0218] These representations can also be generated as described below.

[0219] Radiological images produced by radiological examinations (especially in the case of computed tomography and ultrasound examinations) are typically obtained in the form of representations in real space (also referred to as the image space).

[0220] "Real space" is the ordinary three-dimensional Euclidean space, which corresponds to the space in which we humans experience with our senses and move. Thus, a representation in real space is a more familiar representation.

[0221] In an embodiment of the present invention, the first representation and the second representation received or generated in the first step are representations in real space.

[0222] In a representation in real space (also referred to in this specification as a real space image or real space representation), the examination region is typically represented by a large number of image elements (pixels or voxels), which can, for example, be arranged in a raster pattern, in which case each image element represents a part of the examination region and each image element can be assigned a color value or a gray level value. The DICOM format is widely used in radiology for storing and processing representations in real space. DICOM (Digital Imaging and Communications in Medicine) is an open standard for storing and exchanging information in medical image data management. Other formats for storing, processing, and / or displaying representations in real space are also feasible.

[0223] Before processing a representation in real space as described in this specification, the representation in real space can be co-registered. "Co-registration" (also known as "image registration" in the prior art) is used to achieve an optimal alignment of two or more real space images of the same examination region with each other. One of the real space images is defined as a reference image and the other is called a target image. To best match the target image with the reference image, a compensatory transformation operation is calculated.

[0224] In one embodiment of the present invention, a third representation in real space is generated based on a first representation and a second representation in real space. This third representation also represents at least a part of the examination region in real space.

[0225] However, the first representation and the second representation received or generated in the first step may also be representations in the frequency space. In other words, in one embodiment, the first representation and the second representation represent the examination region in the frequency space.

[0226] "Frequency space" is a domain where a signal is regarded as the sum of its individual frequency components.

[0227] In a representation in the frequency space (also referred to as a frequency space image or a frequency space representation in this specification), the examination region is represented by the superposition of fundamental frequencies. For example, the examination region can be represented by the sum of sine and / or cosine functions with different amplitudes, frequencies, and phases. These amplitudes and phases can be plotted as a function of frequency, for example, in a two-dimensional or three-dimensional representation. Usually, the lowest frequency (the origin) is located at the center. The farther away from this center, the higher the frequency. An amplitude (representing the frequency in the frequency space image) and a phase (representing the degree of offset of the corresponding wave relative to a sine or cosine wave) can be assigned to each frequency.

[0228] The raw data (so-called k-space data) obtained in a magnetic resonance imaging examination is an example of a representation in the frequency space. Such raw data (k-space data) from a magnetic resonance imaging examination can be directly used as the first and / or second representation in the frequency space in the context of the present disclosure.

[0229] The radiographic images generated by a radiological examination (especially in the case of computed tomography and ultrasound examinations) are usually obtained in the form of a representation in the real space (also known as the image space).

[0230] The representation in the real space can be transformed (converted) into a representation in the frequency space, for example, by Fourier transform. Conversely, the representation in the frequency space can be transformed (converted) into a representation in the real space, for example, by inverse Fourier transform. Therefore, the term "generating a representation" preferably refers to generating an image of the inspection area in the frequency space from the real space image of the inspection area by a transform operation, or generating an image of the inspection area in the real space from the frequency space image of the inspection area by a transform operation.

[0231] Details regarding real space images and frequency space images and their respective mutual conversions are described in many publications. See, for example, https: / / see.stanford.edu / materials / lsoftaee261 / book-fall-07.pdf.

[0232] Therefore, if the first representation and / or the second representation represent the inspection area in the real space, the corresponding real space representation can first be transformed (changed, converted) into a representation in the frequency space by a transform operation (such as Fourier transform). In other words, the representation in the frequency space can be generated from the representation in the real space by a transform operation (such as Fourier transform).

[0233] Co-registration can also be performed on the representation in the frequency space; it should be noted here that translation in the real space constitutes an additive linear phase ramp in the frequency space. On the other hand, scaling and rotation are preserved in Fourier transform and inverse Fourier transform - scaling and rotation in the frequency space are also scaling and rotation in the real space (for example, see S. Skare: Rigid Body Image Realignment in Image Space vs. k-Space, ISMRM SCIENTIFIC WORKSHOP on Motion Correction, 2014, https: / / cds.ismrm.org / protected / Motion_14 / Program / Syllabus / Skare.pdf).

[0234] It should be noted that co-registration in the frequency space does not have to be very precise because the high frequencies that map image details and thus map the errors in registration are attenuated by the frequency filter. This is an advantage of the method described in the present disclosure over the method of performing operations in the real space.

[0235] In a preferred embodiment of the present invention, the first representation and the second representation received or generated in the first step are representations in the frequency space.

[0236] In one embodiment of the present invention, a third representation in the frequency space is generated based on a first representation in the frequency space and a second representation in the frequency space. This third representation also represents at least a portion of the examination region in the frequency space.

[0237] Regardless of whether the third representation represents at least a portion of the examination region in real space or in frequency space, the third representation represents the signal enhancement caused by a second amount of contrast agent in the examination region. In other words, the third representation includes the difference between the second representation caused by the second amount of contrast agent and the first representation. In the third representation in the frequency space, each frequency is represented by an amplitude value, where the stronger the influence of the second amount of contrast agent on the frequency, the higher the value. If the third representation is generated in the frequency space (rather than in real space), the low frequencies can be weighted, so that the contrast in the fourth representation in real space can be enhanced.

[0238] In a preferred embodiment, generating the third representation includes subtracting the first representation from the second representation. In other words, in a preferred embodiment, the third representation is the difference between the first representation and the second representation.

[0239] If the third representation is a representation of the examination region in the frequency space, a weighted third representation can be generated in a further step based on the third representation. Due to the weighting of the third representation, frequencies that contribute more to the contrast are given higher weights than frequencies that contribute less to the contrast. The term "contrast" refers to the real space image corresponding to the frequency space image. The contrast information is represented by low frequencies in the frequency space image, while higher frequencies represent information about fine structures. Image noise is usually evenly distributed in the frequency image. Therefore, a weighted third representation can be generated by applying a frequency-dependent weight function to the third representation, where the low frequencies are given higher weights relative to the higher frequencies. The frequency-dependent weight function has the effect of a filter. The filter increases the signal-to-noise ratio by reducing the spectral noise density of the high frequencies.

[0240] Therefore, weighting the third frequency space representation has several advantages: First, it focuses on the contrast information, that is, the features emphasized in the resulting fourth frequency space representation are the features generated by the contrast enhancement caused by the second amount of contrast agent; Second, the weighted third frequency space representation can be added to the third frequency space representation multiple times to achieve further contrast enhancement without enhancing the interference and / or noise to the same extent as the contrast.

[0241] Figure 1 An embodiment of a frequency-dependent weight function that can be used to weight the third representation is shown. For simplicity, the weight function is represented as a two-dimensional graph, where the weight factor wf (ordinate) is plotted as a function of the frequency f (abscissa).

[0242] Figure 1 (a) shows a weight function in which the weight factor decreases exponentially from the center as the frequency increases.

[0243] Figure 1 (b) shows a weight function in which the weight factor decreases linearly from the center as the frequency increases.

[0244] Figure 1 (c) shows a weight function in which the weight factor decreases from the center in the form of an inverse parabola as the frequency increases.

[0245] Figure 1 (d) shows a weight function in which the weight factor remains constant within a defined range around the center and then decreases exponentially from the threshold frequency.

[0246] Figure 1 (e) shows a weight function in which the weight factor has a cosine function shape around the center.

[0247] Figure 1 (f) shows a weight function in which the weight factor has a step function shape around the center.

[0248] Figure 1 (g) shows a weight function in which the weight factor has a Gaussian normal distribution function shape around the center.

[0249] Figure 1 (h) shows a weight function in which the weight factor has a Hann function shape around the center.

[0250] Combinations of the shown weighting function with further / other weighting functions are possible. Examples of other weighting functions can be found, for example, at https: / / de.wikipedia.org / wiki / Fensterfunktion#Beispiele_von_Fensterfunktionen; F.J. Harris et al.: On the Use of Windows for Harmonic Analysis with the Discrete Fourier Transform, Proceedings of the IEEE, Vol. 66, No. 1, 1978; https: / / docs.scipy.org / doc / scipy / reference / signal.windows.html; K.M.M. Prabhu: Window Functions and Their Applications in Signal Processing, CRC Press, 2014, 978-1-4665-1583-3.

[0251] The weighting functions that can be used are also referred to as window functions in the literature.

[0252] In magnetic resonance imaging and spectroscopy, weighting functions that have proven their utility are preferably used to weight k-space data, such as the Gaussian function or the Hann function (also known as the Hann window or Hanning window, see, for example: R. Pohmann et al.: Accurate phosphorus metabolite images of the human heart by 3D acquisition-weighted CSI, Magnetic Resonance in Medicine: An Official Journal of the International Society for Magnetic Resonance in Medicine 45.5 (2001): 817-826). Another preferred weighting function is the Poisson function (Poisson window).

[0253] In a further step, a fourth representation is generated by combining the first representation with the third representation. The third representation can be a third representation in real space, a third representation in frequency space, or a weighted third representation in frequency space. This combination transfers information about the contrast enhancement brought about by the second amount of contrast agent in the examination region to the first representation.

[0254] The combination for generating the fourth representation can be or include, for example, the addition of the first representation and the third representation (or the weighted third representation). However, multiplicative combination or non-linear combination is also feasible. In a preferred embodiment of the present invention, generating the fourth representation by combining the first representation with the (weighted) third representation is or includes adding α times the (weighted) third representation to the first representation, where α (the gain factor) is a positive real number or a negative real number, and the third representation can be the third representation in the real space, the third representation in the frequency space, or the weighted third representation in the frequency space. In other words, the (weighted) third representation is multiplied by the gain factor α, and the result of the multiplication operation is added to the first representation.

[0255] In a preferred embodiment of the present invention, the fourth representation is generated or produced as follows: (i) adding the third representation multiplied by the gain factor α in the real space to the first representation in the real space; (ii) adding the third representation multiplied by the gain factor α in the frequency space to the first representation in the frequency space; or (iii) adding the weighted third representation multiplied by the gain factor α in the frequency space to the first representation in the frequency space. Mathematical operations (subtraction, addition, multiplication) generally involve the hue values of individual image elements (pixels, voxels) or the amplitude values of individual frequencies (in the case of a frequency space image).

[0256] The gain factor is a positive real number or a negative real number.

[0257] The gain factor represents the degree of contrast enhancement or attenuation in the fourth representation.

[0258] This means that the third (weighted) representation can also be added to the first representation multiple times to produce a higher contrast than that shown by the second representation in the real space.

[0259] By selecting the gain factor α, it is also possible to achieve a greater enhancement effect than the contrast enhancement brought about by the standard amount of contrast agent. The method described in WO2019 / 074938A1 cannot achieve such contrast enhancement unless training data is generated by administering to the human body an amount of contrast agent that is higher than the standard amount and thus outside the scope approved by the regulatory authorities.

[0260] It is also possible to select a gain factor α less than 1, that is, the contrast between the region with contrast agent and the region without contrast agent in the fourth representation is lower than the contrast in the second representation.

[0261] The contrast can be further reduced by a negative value of the gain factor α. For example, this can be used to generate a representation of the examination region without the use of a contrast agent based on a first representation of an examination region representing a composition having a first amount and a second representation of an examination region representing a composition having a second amount. For example, if the second amount is twice the first amount, a gain factor α = -1 will produce a fourth representation that looks like no contrast agent has been administered, provided that the signal enhancement brought about by the contrast agent increases linearly with the amount of the contrast agent, and the first and second representations represent the examination region within the same time interval starting from the administration of the first / second amount.

[0262] A negative α value can also be selected such that the regions of the examination region that experience contrast-agent-induced signal enhancement in the representation generated by the measurement are completely dark (black) in the artificially generated representation.

[0263] The gain factor α can be selected by the user, i.e., it can be variable, or it can be predefined, i.e., it can be predetermined.

[0264] The gain factor can also be determined in an automated manner. For example, at least one region in the real-space image of the first and / or second representation and / or the region can be selected by the user, and the gain factor is set such that the gray values in the real-space image (or, in the case of an image other than a gray-value image, different hue values) take a defined value and / or are above or below a threshold, and / or such that the two gray values in two different selected or defined regions have a defined spacing from each other and / or the spacing between them is above or below a threshold. Other criteria can also be employed in the automatic determination of the gain factor. The criteria for the automatic determination of the gain factor can be based, for example, on the histogram of the first, second, third, weighted third, and / or fourth representation transformed into the real-space image. Such a histogram can show the number of image elements having a defined hue value or gray value.

[0265] If the fourth representation is a representation of the examination region in real space, it can be output, i.e., displayed on a screen, printed using a printer, and / or stored in a data memory. It can also be transmitted to another computer system (e.g., via a network).

[0266] If the fourth representation is a representation of the examination region in the frequency space, the frequency-space representation can be transformed into a real-space representation (e.g., by an inverse Fourier transform). Then the real-space representation can be output, i.e., displayed on a screen, printed using a printer, and / or stored in a data memory. It can also be transmitted to another computer system (e.g., via a network).

[0267] Figure 2Schematically shown by way of example is the generation of a third representation in the real space and a fourth representation in the real space based on a first representation in the real space and a second representation in the real space.

[0268] Figure 2 The inspection area of the inspection object is shown in the form of different representations. Figure 2 The shown inspection area includes the liver of a pig.

[0269] The first representation R1 represents the inspection area in the real space without a contrast agent. The first representation R1 is a magnetic resonance image.

[0270] The second representation R2 represents the same inspection area of the same inspection object in the real space as the first representation R1. The second representation R2 is also a magnetic resonance image.

[0271] The second representation R2 represents the inspection area after administration of a certain amount of a composition containing an extracellular contrast agent and an intracellular contrast agent. The intracellular contrast agent is a hepatobiliary contrast agent. The composition contains 10 μmol / kg body weight of the extracellular contrast agent and 10 μmol / kg body weight of the intracellular contrast agent. The composition is administered intravenously to the inspection object. The second representation R2 represents the inspection area in the so-called portal venous phase after administration of the contrast agent.

[0272] Based on the first representation R1 and the second representation R2, a third representation R3 is generated. In Figure 2 the shown example, the third representation R3 is the difference between the second representation R2 and the first representation R1.

[0273] In the third representation R3, negative tone values that would occur when subtracting the first representation from the second representation can be set to zero (or another value) to avoid negative values.

[0274] The third representation R3 represents the contrast enhancement caused by the second amount of the contrast agent in the inspection area.

[0275] The third representation R3 is multiplied by a gain factor α, and the result of the multiplication operation is added to the first representation R1. This generates the fourth representation R4. In Figure 2 the shown example, the gain factor α = 3, that is, 3 times the third representation R3 is added to the first representation R1.

[0276] The fourth representation R4 can be normalized, that is to say, the tone values can be multiplied by a factor such that the tone value with the highest value is represented by a tone such as "white", and the tone value with the lowest value is represented by a tone such as "black".

[0277] Figure 3Schematically shown by way of example is the generation of a third representation in the frequency space and a fourth representation in the frequency space based on a first representation in the frequency space and a second representation in the frequency space.

[0278] Figure 3 The inspection area of the inspection object is shown in different representation forms. Figure 3 The shown inspection area includes the liver of a pig.

[0279] First representation R1 I Represents the inspection area without contrast agent in the real space. First representation R1 I Is a magnetic resonance image.

[0280] Through a transformation operation T (such as Fourier transform), the first real space representation R1 I Can be converted into a first representation R1 of the inspection area in the frequency space F . First frequency space representation R1 F Represents the same inspection area of the same inspection object without contrast agent as the first real space representation R1 I .

[0281] First frequency space representation R1 F Can be converted into the first real space representation R1 through an inverse transformation operation T -1 . Inverse transformation operation T I Is the inverse transformation of the transformation operation T. -1

[0282] Second representation R2 I Represents the same inspection area of the same inspection object as the first representation R1 in the real space. Second representation R2 I . Second representation R2 I Is also a magnetic resonance image. Second real space representation R2 I Represents the inspection area after administration of a certain amount of a composition containing an extracellular contrast agent and an intracellular contrast agent. The intracellular contrast agent is a hepatobiliary contrast agent. The inspection object is administered the composition intravenously. The composition contains 10 μmol / kg body weight of the extracellular contrast agent and 10 μmol / kg body weight of the hepatobiliary contrast agent. Second representation R2 I Represents the inspection area at the so-called hepatobiliary phase 15 minutes after injection of the composition. In the second real space representation R2 I , due to the action of the administered amount of the composition, the contrast between the liver tissue and the surrounding tissue is enhanced.

[0283] Second real space representation R2 I Can be converted into a second representation R2 of the inspection area in the frequency space through the transformation operation T F . Second frequency space representation R2 Fis the same as the second real space representation R2 I and both represent the same examination area of the same examination object after the composition is applied.

[0284] The second frequency space representation R2 F can be converted into the second real space representation R2 -1 through the inverse transformation operation T I .

[0285] Based on the first frequency space representation R1 F and the second frequency space representation R2 F , a third frequency space representation R3 F is generated. In the example shown in Figure 3 , the third frequency space representation R3 F is the difference between the second frequency space representation R2 F and the first frequency space representation R1 F (R3 F = R2 F - R1 F ).

[0286] The third frequency space representation R3 F can be normalized, that is, the amplitude values can be multiplied by a factor such that the amplitude with the highest value is represented by a hue such as "white", and the amplitude with the lowest value is represented by a hue such as "black".

[0287] In this normalization process, the negative values that may occur when subtracting the first representation from the second representation can also be set to zero (or another value) to avoid the appearance of negative values. In Figure 3 , all frequency space representations are shown in the same logarithmic gray scale.

[0288] The third frequency space representation R3 F represents the contrast enhancement in the examination area caused by the applied amount of the composition.

[0289] In Figure 3 , it is further shown that the weight function WF is applied to the third frequency space representation R3 F to generate the weighted third representation R3 F，w . In this case, the weight function is a Gaussian weight function.

[0290] Since for the third representation R3 FWeighting is performed, giving higher weights to frequencies that contribute more to the contrast than to frequencies that contribute less. The term "contrast" refers to the real-space image corresponding to the frequency-space image. Contrast information is represented by low frequencies in the frequency-space image, while higher frequencies represent information about fine structures. Image noise is typically evenly distributed in the frequency representation. Therefore, a weighted third representation in the frequency space can be generated by applying a frequency-dependent weight function to the third representation in the frequency space, where lower frequencies are given higher weights than higher frequencies. The frequency-dependent weight function has the effect of a filter. The filter improves the signal-to-noise ratio by reducing the spectral noise density of high frequencies.

[0291] To generate the weighted third representation R3 F,w , the amplitude values of the third frequency-space representation R3 F are multiplied by the weight factors of the weight function. The weight factors are frequency-dependent, i.e., the weight factors are functions of frequency. For the sake of illustration, the weight function WF is shown in Figure 1 in two-dimensional form. The weight function WF shows the weight factor wf as a function of frequency f along one dimension.

[0292] Compared to higher-frequency amplitudes (which are further away from the center of the representation R3 F ), the WF weight function multiplies lower-frequency amplitudes (in the illustrated embodiment, the frequencies increase outward from the center of the representation R3 F ) by a higher weight factor; that is, lower frequencies are given higher weights compared to higher frequencies. This can be recognized in the weighted representation R3 F,w , where the gray values towards the edges of the representation are darker than in the case of the representation R3 F , and the overall brightness decreases faster from the center outward than in the case of the representation R3 F .

[0293] In Figure 3 , it is further shown that by combining the first frequency-space representation R1 F with the weighted third frequency-space representation R3 F,w , a fourth representation R4 F of the examination area of the object to be examined in the frequency space is generated. In this example, the combination is achieved by multiplying the weighted third frequency-space representation R3 F,w by a gain factor α and adding the result to the first frequency-space representation R1 F . In the example shown in Figure 3 , the gain factor α = 3, i.e., three times the weighted third frequency-space representation R3 F,w is added to the first frequency-space representation R1 F .

[0294] The fourth representation R4F Perform normalization processing.

[0295] In Figure 3 it is further shown that the fourth representation R4 of the inspection area of the object to be inspected in the frequency space is F converted into the representation R4 of the inspection area of the object to be inspected in the real space I .

[0296] Figure 4 Exemplarily and schematically shown are various representations of the inspection area of the object to be inspected in the real space. The difference between these representations lies in the gain factor α. In this example, it is assumed that the gain factor α value can be 0, 1, 2, 3, and 4. These representations are generated by Figure 3 the method described above. This means that subtraction and addition operations are performed in the frequency space and weighting is carried out.

[0297] The gain factor α = 0 means that no contrast enhancement is performed in the first representation. Therefore, this representation shows the original first representation in the real space.

[0298] The gain factor α = 1 means that the weighted third frequency space representation is added to the first representation in the frequency space once. The contrast enhancement is similar to the contrast enhancement in the corresponding second real space representation, but has less noise / interference because lower frequencies are given higher weights.

[0299] The gain factor α = 2, 3, or 4 means that twice, three times, or four times the weighted third frequency space representation is added to the first representation in the frequency space. The contrast enhancement increases as the gain factor increases.

[0300] In Figure 4 the example shown, in all cases, an integer multiple of the weighted third frequency space representation is added to the first representation. As described, a non-integer ratio of the weighted third frequency space representation can also be added to the first representation (e.g., α = 1.5, α = 3.7, or α = 4.159). This means that the enhancement can be increased in a continuous manner.

[0301] Figure 5 Shown is a preferred embodiment of outputting an artificially contrast-enhanced radiographic image of the inspection area by a computer system / computer program. This output is provided to the user of the computer system and / or computer program of the present invention.

[0302] The first spatial representation R1 of the inspection area of the object to be inspected I the second spatial representation R2 of the inspection area of the object to be inspected I and the predicted fourth spatial representation R4 of the inspection area of the object to be inspected I are displayed to the user (e.g., on a monitor).

[0303] First representation R1 I Represents the examination area without administration of a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0304] Second representation R2 I Represents the examination area after administration of a second amount of the composition. The second amount is greater than the first amount.

[0305] Fourth representation R4 I Represents the examination area with enhanced contrast. The contrast between the area without the contrast agent and the area with the contrast agent is greater in the case of the fourth representation R4 I than in the case of the second representation R2 I and is greater.

[0306] Such as Figure 3 The generation of the fourth representation R4 I .

[0307] All the displayed representations are representations of the examination area in real space. In Figure 5 the illustrated embodiment, no frequency space representation is shown to the user. This is generally not envisioned either, as many users are not familiar with frequency space representations.

[0308] Below the displayed representations R1 I , R2 I and R4 I , the histogram of the representation is shown to the user in the form of an overlay histogram.

[0309] Above the displayed representations R1 I , R2 I and R4 I , three virtual sliders are provided for the user, and the user can use the sliders for adjustment. The first slider α allows the user to freely select a gain factor in the range from 1 to 10. The slider indicates that the gain factor can be increased continuously from 1 to 10.

[0310] The second slider β and the third slider γ allow the user to change the parameters of the weighting function. For example, these parameters can determine how much the weighting factor decreases with increasing frequency.

[0311] Figure 5 The output shown is preferably configured such that when the user makes a change via one of the sliders, the display of the fourth representation R4 I is updated immediately. Then, the user can, for example, change the gain factor α and immediately see how the change in the gain factor affects the representation R4 IThis allows the user to identify the fourth representation R4 that is optimal for the user with respect to the inspection area. I settings.

[0312] Any change in one of the parameters α, β, and / or γ causes the computer system to perform only background calculations with the changed parameter and display the fourth representation R4 I This also applies to the fourth representation R4 I histogram.

[0313] So far, the contrast enhancement in the frequency space according to the present invention may result in an undesired contrast enhancement for the user. This will be explained using an example. The example is schematically shown in Figure 6 FIG.

[0314] Figure 6 shows a first representation R1 of an inspection area of an inspection object I and a second representation R2 I . The inspection area includes the liver L and the gallbladder B of a pig. The first representation R1 I represents the inspection area without the administration of a contrast agent in the real space. The second representation R2 I represents the inspection area in the real space after the administration of a composition containing an extracellular contrast agent and an intracellular contrast agent. In the second representation R2 I , it can be seen that the gallbladder has been partially filled, for example, using a liquid containing one contrast agent or two contrast agents or another liquid, resulting in a high contrast between the partially filled gallbladder and the surrounding area.

[0315] So far, the contrast enhancement described in the present invention results in a further enhancement of the contrast between the partially filled gallbladder and other areas in the artificial contrast-enhanced radiographic image R4 of the inspection area I . However, it is conceivable that the user may alternatively be interested in the contrast enhancement of the liver.

[0316] In a preferred embodiment, the computer system and computer program of the present invention are configured to receive an input from the user. In the input, the user can specify one or more areas where they do not want contrast enhancement. The user can draw such areas in the first, second, and / or fourth representations in the real space using, for example, a mouse or other input means. For example, in Figure 6 the embodiment shown, the user can select and / or highlight the gallbladder in the first representation R1 I , the second representation R2 I and / or the fourth representation R4 I . The computer system and computer program can be configured to set the hue values or gray values of all image elements (pixels, voxels) representing (highlighted) the gallbladder to zero. As a result, the representation R2I* in which the gallbladder is represented by black image elements. If contrast enhancement is performed based on the characterizations R1 I and R2 I* (or based on their corresponding frequency space characterizations), an artificially contrast-enhanced radiographic image R4 is produced I* in which there is currently enhanced contrast especially between the liver L and other regions, but the partially filled gallbladder is no longer displayed with enhanced contrast.

[0317] In a preferred embodiment, the regions for which (to which) contrast enhancement is not to be performed are determined automatically. Preferably, the quotient of the hue values of all corresponding image element pairs (i.e., having the same coordinates) of the first real space characterization R1 I and the second real space characterization R2 I is determined:

[0318] Q = g2(x,y,z) / g1(x,y,z)

[0319] where Q is the quotient of the hue values, g2(x,y,z) is the hue value of the image element having coordinates x, y, z in the second characterization R2 I and g1(x,y,z) is the hue value of the image element having the same coordinates x, y, z in the first characterization R1 I . The quotient of the hue values Q is a measure of the brightness of the image element having coordinates x, y, z depicted in the second characterization compared to the corresponding image element in the first characterization. It specifies the contrast enhancement brought about by the second quantity of the composition in the examination region represented by the image element having coordinates x, y, z.

[0320] The computer system and the computer program can be configured to compare the quotient of the hue values of all image elements with a predetermined threshold. The predetermined threshold specifies the maximum contrast enhancement expected due to the contrast agent present in the composition.

[0321] If the quotient of the hue values of the corresponding image elements is greater than the predetermined threshold, the hue value of the corresponding image element can be set to zero.

[0322] Figure 7 Exemplarily and schematically, a computer system according to the invention is shown.

[0323] A "computer system" is an electronic data processing system that processes data according to programmable computing rules. Such a system typically includes a "computer" and peripheral devices, where the "computer" is a unit including a processor for performing logical operations.

[0324] In computer technology, a "peripheral device" refers to all devices that are connected to a computer and are used to control the computer and / or serve as input and output devices. Examples of peripheral devices are monitors (screens), printers, scanners, mice, keyboards, drives, cameras, microphones, speakers, etc. Internal ports and expansion cards are also considered peripheral devices in computer technology.

[0325] Figure 7 The computer system (1) shown in includes an input unit (10), a control and computing unit (20), and an output unit (30).

[0326] The control and computing unit (20) is used to control the computer system (1), coordinate the data flow between the units of the computer system (1), and perform calculations.

[0327] The control and computing unit (20) is configured to:

[0328] - Cause the receiving unit (10) to receive a first representation that represents an examination region of an examination subject without administering a contrast agent, or an examination region of the examination subject after administering a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0329] - Cause the receiving unit (10) to receive a second representation that represents an examination region of the examination subject after administering a second amount of the composition, the second amount being greater than the first amount,

[0330] - Generate a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation,

[0331] - Generate a fourth representation based on the first representation and the third representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number,

[0332] - Cause the output unit (30) to output a representation of the examination region and / or store it and / or transmit it to a separate computer system.

[0333] Figure 8 Another embodiment of the computer system of the present invention is shown exemplarily and schematically.

[0334] The computer system (1) includes a processing unit (21) connected to a memory (22). The processing unit (21) and the memory (22) form a control and computing unit, as Figure 7 shown in.

[0335] The processing unit (21) may include one or more processors, either alone or in combination with one or more memories. The processing unit (21) may be standard computer hardware capable of processing information such as digital images, computer programs, and / or other digital information. The processing unit (21) typically consists of an arrangement of electronic circuits, some of which may be designed as integrated circuits or a plurality of interconnected integrated circuits (integrated circuits are sometimes also referred to as "chips"). The processing unit (21) may be configured to execute a computer program, which may be stored in the working memory of the processing unit (21) or in the memory (22) of the same or a different computer system.

[0336] The memory (22) may be conventional computer hardware capable of temporarily and / or permanently storing information such as digital images (e.g., representations of the examination area), data, computer programs, and / or other digital information. The memory (22) may include volatile and / or non-volatile memory and may be non-removable or removable. Examples of suitable memories are RAM (random access memory), ROM (read-only memory), hard drives, flash memory, exchangeable computer floppy disks, optical disks, magnetic tapes, or combinations thereof. Optical disks may include compact discs with read-only memory (CD-ROM), compact discs with read / write capabilities (CD-R / W), DVDs, Blu-ray discs, etc.

[0337] The processing unit (21) may be connected not only to the memory (22) but also to one or more interfaces (11, 12, 31, 32, 33) for displaying, transmitting, and / or receiving information. The interfaces may include one or more communication interfaces (32, 33) and / or one or more user interfaces (11, 12, 31). One or more communication interfaces may be configured to send and / or receive information, such as sending and / or receiving information to / from an MRT scanner, a CT scanner, an ultrasound camera, other computer systems, a network, a data memory, etc. One or more communication interfaces may be configured to transmit and / or receive information via physical (wired) and / or wireless communication connections. One or more communication interfaces may include one or more interfaces for connecting to a network, for example using technologies such as cellular phones, Wi-Fi, satellite, cable, DSL, fiber optics, etc. In some embodiments, one or more communication interfaces may include one or more near-field communication interfaces configured to connect devices with short-range communication technologies such as NFC, RFID, Bluetooth, Bluetooth LE, ZigBee, infrared (e.g., IrDA), etc.

[0338] The user interface may include a display (31). The display (31) may be configured to display information to the user. Suitable examples thereof are a liquid crystal display (LCD), a light emitting diode display (LED), a plasma display panel (PDP), etc. The user input interfaces (11, 12) may be wired or wireless and may be configured to receive information from a user in the computer system (1) for processing, storage, and / or display, for example. Suitable examples of user input interfaces are a microphone, an image or video recording device (such as a camera), a keyboard or keypad, a joystick, a touch sensing interface (separate from or integrated in a touch screen), etc. In some embodiments, the user interface may incorporate automatic identification and data capture technology (AIDC) for machine-readable information. This may include barcodes, radio frequency identification (RFID), magnetic stripes, optical character recognition (OCR), integrated circuit cards (ICC), etc. The user interface may also include one or more interfaces for communicating with peripheral devices such as printers.

[0339] One or more computer programs (40) may be stored in the memory (22) and executed by the processing unit (21) to program the processing unit (21) to implement the functions described in this specification. The retrieval, loading, and execution of the instructions in the computer program (40) may be performed sequentially to retrieve, load, and execute the instructions respectively. However, the retrieval, loading, and / or execution may also be performed in parallel.

[0340] The computer system of the present invention may be designed as a laptop, notebook, netbook, and / or tablet PC; it may also be a component of an MRT scanner, a CT scanner, or an ultrasonic diagnostic device.

[0341] Figure 9 An embodiment of the computer-implemented method of the present invention is exemplarily and schematically shown in the form of a flowchart.

[0342] The method (100) includes the following steps:

[0343] (110) Receive or generate a first representation that represents an examination region of an examination object without administering a contrast agent or after administering a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0344] (120) Receive or generate a second representation that represents an examination region of an examination object after administering a second amount of the composition, the second amount being greater than the first amount,

[0345] (130) Generate a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation,

[0346] (150)Generate a fourth representation, where generating the fourth representation includes adding α times the third representation to the first representation, and α is a positive or negative real number.

[0347] (170)Output and / or store the representation of the inspection area and / or transmit the representation of the inspection area to a separate computer system.

[0348] The present invention can be used for various purposes. Some examples of uses are described below, but the present invention is not intended to be limited to these examples of uses.

[0349] The first example of use relates to magnetic resonance imaging (MRI) examinations for differentiating intra-axial tumors, such as brain metastases and malignant gliomas. The infiltrative growth of these tumors makes it difficult to accurately distinguish the tumor from healthy tissue. However, determining the extent of the tumor is crucial for surgical resection. Differentiating the tumor from healthy tissue is made easier by administering an extracellular MRT contrast agent; after intravenous administration of a standard dose of 0.1 mmol / kg body weight of the extracellular MRT contrast agent gadobutrol, intra-axial tumors can be more easily distinguished. At higher doses, the contrast between the lesion and healthy brain tissue is further increased; the detection rate of brain metastases increases linearly with the contrast agent dose (see, for example, M. Hartmann et al.: Does the administration of a high dose of a paramagnetic contrast medium (Gadovist) improve the diagnostic value of magnetic resonance tomography in glioblastomas? doi: 10.1055 / s - 2007 - 1015623).

[0350] Here, a single triple dose or a second subsequent dose can be administered, up to a total dose of 0.3 mmol / kg body weight. This exposes the patient and the environment to additional gadolinium and incurs additional costs during the second scan.

[0351] The present invention can be used to avoid exceeding the standard amount of the contrast agent. A first MRT image can be generated without administering the contrast agent or with an amount less than the standard amount, and a second MRT image can be generated with the standard amount. Based on these generated MRT images, a synthetic MRT image can be generated as described in the present invention, where the contrast between the lesion and healthy tissue can be changed within a wide range by changing the gain factor α. This enables achieving a contrast that can only be achieved in other methods by administering a contrast agent in an amount greater than the standard amount.

[0352] Another embodiment of the use relates to reducing the amount of MRT contrast agent during magnetic resonance imaging examinations. Gadolinium-containing contrast agents (such as gadobutrol) are used in a variety of examinations. They are used for contrast enhancement in cranial examinations, spinal examinations, breast examinations, or other examinations. In the central nervous system, gadobutrol emphasizes areas with impaired blood-brain barrier and / or vascular abnormalities. In breast tissue, gadobutrol can visualize the presence and extent of malignant breast diseases. Gadobutrol is also used in contrast-enhanced magnetic resonance angiography for diagnosing strokes, detecting tumor blood perfusion, and detecting focal cerebral ischemia.

[0353] Due to the increasing impact on the environment, the cost burden on the healthcare system, and concerns about acute side effects and possible long-term health risks, especially in the case of repeated and long-term exposure, there is a desire to reduce the dose of gadolinium-containing contrast agents. This can be achieved by the present invention.

[0354] A first MRT image without the administration of a contrast agent and a second MRT image after administering less than the standard amount of the contrast agent can be generated. Based on these generated MRT images, a synthetic MRT image can be generated as described in the present invention, where the contrast can be varied within a wide range by changing the gain factor α. This enables obtaining the same contrast as that obtained after administering the standard amount while using less than the standard amount of the contrast agent.

[0355] Another embodiment of the use is to detect, identify, and / or characterize lesions in the liver with the aid of hepatobiliary contrast agents (such as ).

[0356] It is administered intravenously (i.v.) at a standard dose of 0.025 mmol / kg body weight. This standard dose is lower than the standard dose of 0.1 mmol / kg body weight in the case of extracellular MRT contrast agents. Different from contrast-enhanced MRT using extracellular gadolinium-containing contrast agents, dynamic multi-phase T1w imaging is allowed. However, the lower dose of and the observed transient motion artifacts that may occur shortly after intravenous administration mean that radiologists will perceive that the contrast enhancement effect of using

[0357] in the arterial phase is worse than that of using extracellular MRT contrast agents. However, evaluating the contrast enhancement effect in the arterial phase and the vascular distribution of focal liver lesions is crucial for accurately characterizing the lesions.

[0358] A first MRT image without administration of a contrast agent and a second MRT image in the arterial phase after administration of a contrast agent corresponding to a standard amount can be generated. Based on these generated MRT images, a synthetic MRT image can be generated as described in the present invention, wherein the contrast in the arterial phase can be varied within wide limits by varying the gain factor α. This enables a contrast to be achieved that can only be achieved in other methods by administering a contrast agent in an amount greater than the standard amount.

[0359] Another embodiment of the use relates to the use of an MRT contrast agent in a computed tomography examination.

[0360] In a CT examination, an MRT contrast agent generally has a lower contrast enhancement effect than a CT contrast agent. However, it would be advantageous to apply an MRT contrast agent in a CT examination. One embodiment is a minimally invasive intervention on a patient's liver, in which the surgeon monitors the procedure using a CT scanner. Compared to magnetic resonance imaging, the advantage of computed tomography (CT) is that more major surgical interventions can be performed in the examination area of the examination object while generating CT images of the examination area. In contrast, only a few surgical instruments and surgical devices are compatible with MRT. In addition, the magnets used in MRT limit access to the patient. Therefore, when performing a surgery in the examination area, the surgeon will be able to visualize the examination area using CT and be able to follow the surgery on a monitor.

[0361] For example, if a surgeon wishes to perform a surgery on a patient's liver, such as to perform a biopsy on a liver lesion or remove a tumor, the contrast between the liver lesion or tumor and healthy liver tissue will not be as obvious in the CT image of the liver as it is in the MRT image after administration of a hepatobiliary contrast agent. Currently, there is no known and / or approved CT-specific hepatobiliary contrast agent in CT. Therefore, the use of an MRT contrast agent (more particularly a hepatobiliary MRT contrast agent) in computed tomography combines the possibility of differentiating between healthy and diseased liver tissue and the possibility of visualizing the liver during the surgery.

[0362] By means of the present invention, the relatively low contrast enhancement achieved by an MRT contrast agent can be increased without administering a dose higher than the standard dose.

[0363] A first CT image without administration of an MRT contrast agent and a second CT image after administration of an MRT contrast agent corresponding to a standard amount can be generated. Based on these generated CT images, a synthetic CT image can be generated as described in the present disclosure, wherein the contrast produced by the MRT contrast agent can be varied within wide limits by varying the gain factor α. This enables a contrast to be achieved that can only be achieved in other methods by administering an MRT contrast agent in an amount greater than the standard amount.

Claims

1. A computer-implemented method, comprising: - Receive or generate a first representation that represents an examination region of an object examined without administration of a contrast agent or after administration of a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent. - Receive or generate a second representation that represents an examination region of an object examined after administration of a second amount of the composition, the second amount being greater than the first amount. - Generate a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation. - Generate a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number. - Output and / or store the fourth representation of the examination region and / or transmit the fourth representation of the examination region to a separate computer system.

2. The method according to claim 1, wherein the first representation and the second representation represent an inspection area in real space.

3. The method according to claim 1, wherein the first representation and the second representation represent an inspection area in frequency space.

4. The method according to claim 3, wherein generating the fourth representation comprises: - Transform the result of adding α times the third representation to the first representation into real space.

5. The method according to claim 3 or 4, wherein generating the third representation comprises: - Apply a frequency-dependent weighting function to the result of subtracting the first representation from the second representation.

6. The method according to claim 3 or 4, wherein generating the third representation comprises: - Generate a weighted third representation by applying a frequency-dependent weighting function to the result of subtracting the first representation from the second representation.

7. The method according to any one of claims 1 to 6, further comprising: - Receive a first real-space representation that represents an examination region of an object examined without administration of a contrast agent or after administration of a first amount of the composition in real space. - Transform the first real-space representation into a first representation of the examination region of the object in frequency space. - Receive a second real-space representation that represents an examination region of an object examined after administration of a second amount of the composition in real space. - Transform the second real-space representation into a second representation of the examination region of the object in frequency space.

8. The method according to any one of claims 1 to 7, wherein α is greater than 1.

9. The method according to any one of claims 5 to 8, wherein By applying a frequency-dependent weighting function to the third representation, the amplitude values with low frequencies are multiplied by a weight factor that is larger than the amplitude values with high frequencies.

10. The method according to any one of claims 5 to 8, wherein applying a frequency-dependent weight function to the third representation comprises multiplying the amplitude value by a window function, and the window function is a Gaussian distribution function or a Hann function or a Poisson function.

11. The method according to any one of claims 1 to 10, further comprising: - Receive one or more α values from a user.

12. The method according to any one of claims 1 to 10, further comprising: - Receive a first hue value of a first image element of a real-space image of the first representation or the second representation. - Receive a second hue value of a second image element of a real-space image of the first representation or the second representation. - Determine a value of α such that the difference between the first hue value and the second hue value takes a predetermined value or is above or below a predetermined threshold.

13. The method according to any one of claims 3 to 10 further comprises: - Receive a highlighted region in the real-space image of the second representation. - Set the hue value of the region in the real-space image of the second representation to zero, thereby generating a modified second real-space image. - Generate a second representation in frequency space from the modified second real-space image.

14. The method according to any one of claims 3 to 10 further comprises: - For all image elements of the first real-space image of the first representation: Determine the first hue value. - For all image elements of the second real-space image of the second representation: Determine the second hue value. - For all corresponding image elements of the first and second real-space images: Determine the quotient of the second hue value and the first hue value. - Set the hue values of the second real-space image whose quotient is greater than a predetermined threshold to zero, thereby generating a modified second real-space image. - Generate a second representation in frequency space from the modified second real-space image.

15. The method according to any one of claims 1 to 14, wherein the first characterization and the second characterization are the results of magnetic resonance imaging examinations and / or are generated from magnetic resonance images.

16. The method according to any one of claims 1 to 15, wherein the object to be examined is a living being, preferably a mammal, and most preferably a human.

17. The method according to any one of claims 1 to 15, wherein the examination region comprises the liver, kidneys, heart, lungs, brain, stomach, bladder, prostate, intestine, and / or a part of them and / or another / other part of the human body.

18. The method according to any one of claims 1 to 17, wherein (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), The compound of formula (I) has the following formula, or its stereoisomer, tautomer, hydrate, solvate, or salt, or a mixture thereof, wherein: is group *As the connection key to R 1 ​ R 1 is R 3 group n＝4， R 2 is a hydrogen atom, R 3 selected from group * is a linking bond to the rest of the molecule. R 4 is a hydrogen atom or a methyl group; The compound of formula (II) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein R 5 is a hydrogen atom, R 6 is a group selected from the following: C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl) and phenyl, the C1-C4 alkyl groups are optionally the same or different and substituted by phenyl, and the phenyl is optionally mono-substituted, di-substituted or tri-substituted by the same or different halogen atoms or groups selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy, and the phenyl is optionally mono-substituted, di-substituted or tri-substituted by the same or different halogen atoms or groups selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The compound of formula (III) has the following formula and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), the compound of formula (IV) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is the bond connecting to X, X is a group selected from CH2 and (CH2)3, R 7 and R 9 each independently represents a hydrogen atom or a -CH2OH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3, R 10 is a group selected from the following: C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, the C1-C3 alkoxy and C2-C5 alkoxy groups are optionally mono-substituted, di-substituted, tri-substituted or tetra-substituted by fluorine atoms; and the compound of formula (V) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is the bond connecting to X, X is a group selected from CH2 and (CH2)2, R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3, R 12 is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

19. A computer system, comprising: a processor; and a memory storing an application program, the application program being configured to perform operations when executed by the processor, the operations including: - receiving or generating a first representation that represents an examination region of an object without administering a contrast agent or after administering a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, - receiving or generating a second representation that represents the examination region of the object after administering a second amount of the composition, the second amount being greater than the first amount, - generating a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation, - generating a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, α being a positive or negative real number, - outputting and / or storing the fourth representation of the examination region and / or transmitting the fourth representation of the examination region to a separate computer system.

20. A computer program product comprising a data carrier on which a computer program is stored, the computer program being loadable into the working memory of a computer system, wherein the computer program causes the computer system to perform the following steps: - receiving or generating a first representation that represents an examination region of an examination object without administration of a contrast agent or after administration of a first amount of a composition, the composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, - receiving or generating a second representation that represents an examination region of an examination object after administration of a second amount of the composition, the second amount being greater than the first amount, - generating a third representation based on the first representation and the second representation, the generating of the third representation comprising subtracting the first representation from the second representation, - generating a fourth representation, the generating of the fourth representation comprising adding α times the third representation to the first representation, where α is a positive or negative real number, - outputting and / or storing the fourth representation of the examination region and / or transmitting the fourth representation of the examination region to a separate computer system.

21. Use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent in a radiological examination method, the method comprising: - receiving or generating a first representation that represents an examination region of an object without administering a contrast agent or after administering a first amount of a composition, - Receive or generate a second representation that represents an examination region of an object examined after administering a second amount of the composition, the second amount being greater than the first amount, - Generate a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation, - Generate a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number, - Output and / or store the fourth representation of the examination region and / or transmit the fourth representation of the examination region to a separate computer system.

22. Use according to claim 21, wherein the radiological examination method is a magnetic resonance imaging examination, and wherein (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II) or a compound of formula (III), The compound of formula (I) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein: For group *For connection with R 1 as the connection key R 1 is R 3 group n＝4， R 2 is a hydrogen atom, R 3 selected from group * is a linking bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group; The compound of formula (II) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein R 5 is a hydrogen atom, R 6 is a group selected from the following: C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl) and phenyl, the C1-C4 alkyl groups being optionally and identically or differently substituted by phenyl, the phenyl being optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy, and the phenyl being optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The compound of formula (III) has the following formula and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), the compound of formula (IV) having the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a linking bond to X, X is a group selected from CH2 and (CH2)3, R 7 and R 9 each independently represents a hydrogen atom or a -CH2OH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3 R 10 is a group selected from the following: C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, the C1-C3 alkoxy and C2-C5 alkoxy groups being optionally mono-, di-, tri- or tetra-substituted by a fluorine atom; and the compound of formula (V) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a linking bond to X, X is a group selected from CH2 and (CH2)2, R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3, R 12 is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

23. A composition for a radiological examination method, comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, the method comprising: - Receive or generate a first representation that represents an examination region of an object examined without administering a contrast agent or after administering a first amount of the composition, - Receive or generate a second representation that represents an examination region of an object examined after administering a second amount of the composition, the second amount being greater than the first amount, - Generate a third representation based on the first representation and the second representation, the generating of the third representation including subtracting the first representation from the second representation, - Generate a fourth representation, the generating of the fourth representation including adding α times the third representation to the first representation, where α is a positive or negative real number, -Output and / or store a fourth representation of the inspection area and / or transmit the fourth representation of the inspection area to a separate computer system.

24. The composition used as described in claim 23, wherein the radiological examination method is magnetic resonance imaging examination, and wherein (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), The compound of formula (I) has the following formula, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, Wherein: For group *For the connection key with R 1 and R 1 is R 3 group n＝4， R 2 is a hydrogen atom, R 3 selected from group * is a linking bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group; The compound of formula (II) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein R 5 is a hydrogen atom, R 6 is a group selected from the following: C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl) and phenyl, the C1-C4 alkyl groups are optionally the same or different and substituted by phenyl, and the phenyl is optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy, and The phenyl is optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The compound of formula (III) has the following formula and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), the compound of formula (IV) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a linking bond to X, X is a group selected from CH2 and (CH2)3, R 7 and R 9 each independently represents a hydrogen atom or a —CH2OH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3 R 10 is a group selected from the following: C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, the C1-C3 alkoxy and C2-C5 alkoxy groups are optionally monosubstituted, disubstituted, trisubstituted or tetrasubstituted by a fluorine atom; and the compound of formula (V) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a linking bond to X, X is a group selected from CH2 and (CH2)2, R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3, R 12 is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

25. A kit, which comprises the computer program product and the composition as described in claim 20, and the composition comprises an extracellular contrast agent and an intracellular contrast agent.

26. The kit as described in claim 25, wherein (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II) or a compound of formula (III), The compound of formula (I) has the following formula, or its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof, Wherein: For group *For the connection key with R 1 and R 1 is R 3 group n＝4， R 2 is a hydrogen atom, R 3 selected from group * is a linking bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group; The compound of formula (II) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein R 5 is a hydrogen atom, R 6 is a group selected from the following: C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl) and phenyl, the C1-C4 alkyl groups are optionally the same or different and substituted by phenyl, and the phenyl is optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy, and The phenyl is optionally monosubstituted, disubstituted or trisubstituted identically or differently by a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The compound of formula (III) has the following formula and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), the compound of formula (IV) having the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a bond connecting to X, X is a group selected from CH2 and (CH2)3, R 7 and R 9 each independently represents a hydrogen atom or a -CH2OH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3 R 10 is a group selected from the following: C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, the C1-C3 alkoxy and C2-C5 alkoxy groups being optionally mono-substituted, di-substituted, tri-substituted or tetra-substituted by fluorine atoms; and the compound of formula (V) has the following formula, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, wherein Ar is selected from group # is a bond connecting to X, X is a group selected from CH2 and (CH2)2, R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3, R 12 is a group selected from C2-C5 alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-.

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