Generation of artificial contrast-enhanced radiological images

Abstract

The invention relates to the technical field of generating artificial contrast-enhanced radiological images.

Description

[0001] Generation of artificial contrast-enhanced radiological images

[0002] The present disclosure relates to the technical field of generating artificial contrast-enhanced radiological images.

[0003] WO2019 / 074938A1 discloses a method for reducing the amount of contrast agent when generating radiological images using an artificial neural network.

[0004] In the disclosed method, a training dataset is generated in a first step. The training dataset comprises, for a plurality of individuals, i) a native radiological image (zero-contrast image), ii) a radiological image after the application of a small amount of contrast agent (low-contrast image), and iii) a radiological image after the application of a standard amount of contrast agent (full-contrast image).

[0005] In a second step, an artificial neural network is trained to predict an artificial radiological image for each person in the training dataset based on the native image and the image after application of a small amount of contrast agent. This image shows an acquisition area after application of the standard amount of contrast agent. The measured radiological image after application of a standard amount of contrast agent serves as the reference (ground truth) during training.

[0006] In a third step, the trained artificial neural network can be used to predict an artificial radiological image for a new person based on a native image and a radiological image after the application of a small amount of contrast agent, which shows the imaged area as it would look if a standard amount of contrast agent had been applied.

[0007] The method disclosed in WO2019 / 074938A1 has disadvantages.

[0008] Training data is required to train the artificial neural network. A large number of radiological examinations must be performed on a large number of individuals, and the training data must be generated to train the network.

[0009] The artificial neural network disclosed in WO2019 / 074938A1 is trained to predict a radiological image after the application of a standard amount of contrast agent. The artificial neural network is not configured or trained to predict a radiological image after the application of a smaller or larger amount of contrast agent than the standard amount. The method described in WO2019 / 074938A1 can, in principle, be trained to predict a radiological image after the application of a different amount of contrast agent than the standard amount. However, this requires additional training data and further training.

[0010] It would be desirable to be able to generate radiological images with variable contrast enhancement without having to generate training data and train an artificial neural network for each individual contrast enhancement. It would also be desirable to be able to generate radiological images with variable contrast enhancement using a comprehensible, deterministic process to generate the variable contrast enhancement. This would facilitate the approval and application of such a procedure in the medical field, where false negative and false positive findings must be minimized. Machine learning methods use statistical models whose generalizability is limited because they are typically based on a limited set of training data.It would also be desirable to be able to generate radiological images with variable contrast enhancement using a wide variety of contrast agents. It would also be desirable to be able to apply the method for generating radiological images with variable contrast enhancement using a wide variety of different contrast agents, regardless of their physical, chemical, physiological, or other properties. It would also be desirable to be able to use the method for generating radiological images with variable contrast enhancement with at least two different contrast agents—preferably an extracellular and an intracellular contrast agent—with different properties, in order to fully exploit the imaging potential of the different contrast agents.When using different contrast agents in the process of generating radiological images with variable contrast enhancement, it would be particularly desirable if these different contrast agents were contained in a single composition and could thus be administered at once.

[0011] These and other objects are achieved by the subject matter of the independent claims. Preferred embodiments of the present disclosure can be found in the dependent claims, in the present description, and in the drawings.

[0012] A first subject of the present disclosure is thus a computer-implemented method for generating a contrast-enhanced radiological image, comprising the steps:

[0013] Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0014] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0015] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0016] Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation a times, where a is a positive or negative real number,

[0017] Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

[0018] Another subject of the present disclosure is a computer system comprising: a processor; and a memory storing an application program configured to, when executed by the processor, perform an operation, the operation comprising:

[0019] Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0020] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0021] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number,

[0022] Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

[0023] Another subject of the present disclosure is a computer program that can be loaded into a working memory of a computer system and causes the computer system to perform the following steps:

[0024] Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0025] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0026] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0027] Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number,

[0028] Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

[0029] A further subject of the present disclosure is a use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent in a radiological examination, the use comprising:

[0030] Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of the composition,

[0031] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0032] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0033] Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a 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.

[0034] A further subject of the present disclosure is a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent for use in a radiological examination method, the use comprising:

[0035] Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of the composition,

[0036] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0037] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0038] Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number,

[0039] Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

[0040] A further subject matter of the present disclosure is a kit comprising 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 a working memory of a computer system and causes the computer system to carry out the following steps:

[0041] Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of the composition,

[0042] Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount,

[0043] Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0044] Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number,

[0045] Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system. The subject matter of the present disclosure is explained in more detail below, without distinguishing between the subject matter (method, computer system, computer program (product), use, composition for use, kit). Rather, the following explanations are intended to apply analogously to all subject matter, regardless of the context (method, computer system, computer program (product), use, composition for use, kit) in which they occur.

[0046] If steps are mentioned in a particular order in this description or in the claims, this does not necessarily mean that this disclosure is limited to the specified order. Rather, it is conceivable that the steps may be performed in a different order or even in parallel; unless a step builds on another step, which absolutely requires that the subsequent step be performed (which will become clear in individual cases). The specified sequences therefore represent preferred embodiments.

[0047] The present disclosure describes means by which one or more artificial radiological images are generated on the basis of at least two representations which represent an examination region of an examination object after the addition / application / use of different amounts of contrast agent, in which the contrast between regions with contrast agent and regions without contrast agent can be varied.

[0048] The “object under investigation” is usually a living being, preferably a mammal, most preferably a human.

[0049] The “area of ​​investigation” is a part of the object of investigation, for example an organ or a part of an organ or several organs or another part of the object of investigation.

[0050] The area of ​​investigation may, for example, be a liver, a kidney, a heart, a lung, a brain, a stomach, a bladder, a prostate gland, an intestine or a part thereof or another part of the body of a mammal (e.g. a human).

[0051] In one embodiment, the examination region comprises a liver or a part of a liver or the examination region is a liver or a part of a liver of a mammal, preferably a human.

[0052] In a further embodiment, the examination area comprises a brain or a part of a brain or the examination area is a brain or a part of a brain of a mammal, preferably a human.

[0053] In a further embodiment, the examination region comprises a heart or a part of a heart or the examination region is a heart or a part of a heart of a mammal, preferably a human.

[0054] In a further embodiment, the examination region comprises a thorax or a part of a thorax or the examination region is a thorax or a part of a thorax of a mammal, preferably a human.

[0055] In a further embodiment, the examination area comprises a stomach or a part of a stomach or the examination area is a stomach or a part of a stomach of a mammal, preferably a human.

[0056] In a further embodiment, the examination region comprises a pancreas or a part of a pancreas, or the examination region is a pancreas or a part of a pancreas of a mammal, preferably a human. In a further embodiment, the examination region comprises a kidney or a part of a kidney, or the examination region is a kidney or a part of a kidney of a mammal, preferably a human.

[0057] In a further embodiment, the examination area comprises one or both wings or part of a wings of a mammal, preferably a human.

[0058] In a further embodiment, the examination area comprises a breast or part of a breast or the examination area is a breast or part of a breast of a female mammal, preferably a female human.

[0059] In a further embodiment, the examination region comprises a prostate or a part of a prostate or the examination region is a prostate or a part of a prostate of a male mammal, preferably a male human.

[0060] The examination area, also called the field of view (FOV), represents a volume depicted in radiological images. The examination area is typically defined by a radiologist, for example, on a localizer image. Alternatively or additionally, the examination area can also be defined automatically, for example, based on a selected protocol.

[0061] The examination area is subjected to a radiological examination.

[0062] "Radiology" is the branch of medicine that deals with the application of electromagnetic radiation and (including ultrasound diagnostics, for example) mechanical waves for diagnostic, therapeutic, and / or scientific purposes. In addition to X-rays, other ionizing radiation such as gamma radiation or electrons is also used. Since a key application is imaging, other imaging techniques such as sonography and magnetic resonance imaging (MRI) are also considered radiology, even though these techniques do not involve the use of ionizing radiation. The term "radiology" within the meaning of this disclosure thus encompasses, in particular, the following examination methods: computed tomography, magnetic resonance imaging, and sonography.

[0063] In one embodiment of the present disclosure, the radiological examination is a magnetic resonance imaging examination.

[0064] In another embodiment, the radiological examination is a computed tomography examination

[0065] In one embodiment, the radiological examination is an ultrasound examination.

[0066] In radiological examinations, contrast agents are often used to enhance contrast.

[0067] “Contrast agents” are substances or mixtures of substances that enhance the visualization of structures and functions of the body during radiological examinations.

[0068] In computed tomography, iodine-containing solutions are typically used as contrast agents. In magnetic resonance imaging (MRI), superparamagnetic substances (e.g., iron oxide nanoparticles, superparamagnetic iron-platinum particles (SIPPs)) or paramagnetic substances (e.g., gadolinium chelates, manganese chelates) are commonly used as contrast agents. In sonography, fluids containing gas-filled microbubbles are typically administered intravenously. Examples of contrast agents can be found in the literature (see e.g. ASL Jascinth et al.: Contrast Agents in computed tomography: A Review, Journal of Applied Dental and Medical Sciences, 2016, Vol. 2, Issue 2, 143 - 149; H. Lusic et al.: X-ray-Computed Tomography Contrast Agents, Chem. Rev. 2013, 113, 3, 1641-1666; https: / / www.radiology.wisc.edu / wp- content / uploads / 2017 / 10 / contrast-agents-tutorial.pdf, MR Nough et al.: Radiographic and magnetic resonances contrast agents: Essentials and tips for safe practices, World J Radiol. 2017 Sep 28; 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, Issue 1, 1-10; ACR Manual on Contrast Media, 2020, ISBN: 978-1-55903-012-0; A. Ignee et al.: Ultrasound contrast agents , Endosc Ultrasound. 2016 Nov-Dec; 5(6): 355-362).

[0069] MR contrast agents exert their effect by altering the relaxation times of the structures that absorb the contrast agent. Two groups of substances can be distinguished: paramagnetic and superparamagnetic substances. Both groups of substances have unpaired electrons that induce a magnetic field around the individual atoms or molecules. Superparamagnetic contrast agents lead to a predominant T2 shortening, whereas paramagnetic contrast agents essentially lead to a Tl shortening. The effect of these contrast agents is indirect, as the contrast agent itself does not emit a signal but only influences the signal intensity in its surroundings. An example of a superparamagnetic contrast agent is iron oxide nanoparticles (SPIO). Examples of paramagnetic contrast agents are gadolinium chelates such as gadopentetate dimeglumine (trade name: Magnevist®, etc.).), gadoteric acid (Dotarem®, Dotagita®, Cyclolux®), gadodiamide (Omniscan®), gadoteridol (ProHance®), gadobutrol (Gadovist®) and gadoxetic acid (Primovist® / Eovist®) .

[0070] The present disclosure encompasses the use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent. The classification of "extracellular" / "intracellular" contrast agent is based on its distribution pattern in the tissue.

[0071] The highly hydrophilic properties of extracellular contrast agents and their low molecular weight lead to rapid diffusion into the interstitial space after intravenous administration. They are excreted via the kidneys after a certain, comparatively short period of circulation in the bloodstream.

[0072] Examples of extracellular MR contrast agents include the gadolinium chelates gadobutrol (Gadovist®), gadoteridol (Prohance®), gadoteric acid (Dotarem®), gadopentetic acid (Magnevist®), and gadodiamide (Omnican®). Other extracellular gadolinium-containing contrast agents are described in W02016 / 193190 (Gadoquatrane).

[0073] Intracellular contrast agents are absorbed to a certain extent into tissue cells and then excreted again. Hepatobiliary contrast agents, for example, are characterized by their specific absorption by liver cells, the hepatocytes, their accumulation in functional tissue (parenchyma), and their contrast enhancement in healthy liver tissue. An example of a hepatobiliary contrast agent is the disodium salt of gadoxetic acid (Gd-EOB-DTPA disodium), which is described in US Patent No. 6,039,931 A and is commercially available under the brand names Primovist® and Eovist®. Other hepatobiliary contrast agents are described, among others, in WO2022 / 194777.

[0074] The generation of an artificial radiological image with variable contrast enhancement is based on at least two representations of the examination area, a first representation and a second representation. The first representation represents the examination area without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0075] The second representation represents the area of ​​investigation after the application of a second set of the composition. The second set is larger than the first set (where, as described, the first set can also be zero). The expression "after the second set of the composition" should not be understood to mean that the first set and the second set of the composition add up in the area of ​​investigation (unless the first set is zero). The expression "the representation represents the area of ​​investigation after the application of a (first or second) set" should therefore rather mean: "the representation represents the area of ​​investigation with a (first or second) set" or "the representation represents the area of ​​investigation comprising a (first or second) set".

[0076] If the first set is non-zero, then the first representation and the second representation preferably (but not necessarily) represent the examination area at the same time interval from the application of the contrast agent. If the first set is zero, the time interval from the time of contrast agent application can be chosen arbitrarily for the second representation.

[0077] Preferably, both the first and second amounts of the composition are smaller than the standard amount. Preferably, the amount of the individual components of the composition, i.e., the extracellular and intracellular contrast agents, in both the first and second amounts of the composition is smaller than the standard amount.

[0078] Preferably, the ratio of the molar amounts of the individual components of the composition in the first amount and the second amount is the same.

[0079] The standard amount is usually the amount recommended by the manufacturer and / or distributor of the composition and / or the components of the composition and / or the amount approved by a regulatory authority and / or the amount listed in a package leaflet accompanying the composition and / or the components of the composition.

[0080] For example, the standard amount of Primovist® is 0.025 mmol Gd-EOB-DTPA disodium / kg body weight.

[0081] In one embodiment of the present disclosure, the composition is a composition comprising (i) an extracellular contrast agent and (ii) a hepatobiliary contrast agent.

[0082] In one embodiment of the present disclosure, 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.

[0083] In one embodiment of the present disclosure, 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.

[0084] In one embodiment, the paramagnetic metal center in the extracellular and / or hepatobiliary contrast agent is a guanthanide. Preferably, the paramagnetic metal center in the extracellular and / or hepatobiliary contrast agent is Gd, particularly preferably Gd 3+. 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 formula where * is the connection to R 1 represents,

[0085] R 1 a group R 3 represents, n = 4,

[0086] R 2 represents a hydrogen atom,

[0087] R 3 represents a group consisting of where * represents the link to the rest of the molecule,

[0088] R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula

[0089] (II), where

[0090] R 5 represents a hydrogen atom, R 6 a group selected from

[0091] C1-C4-alkyl, C5-C8-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, wherein the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C3-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula,

[0092] In one embodiment, the hepatobiliary contrast agent is a compound of formula (IV) or a compound of formula (V) wherein the compound of formula (IV) has the formula

[0093] (IV), where

[0094] Are a group selected from where # represents the linkage to X, X represents a group selected from CH2 and (CH2)s,

[0095] R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group,

[0096] R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3,

[0097] R 10 represents a group consisting of

[0098] C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times with a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula

[0099] Are a group selected from and represents, where # represents the connection to X,

[0100] X represents a group selected from CH2 and (CH2)2,

[0101] R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12 a group selected

[0102] C2-C5-alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and

[0103] (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0104] In one embodiment of the present disclosure, the composition is a composition comprising (i) an extracellular contrast agent of formula (I), formula (II) or formula (III), wherein the compound of formula (I) has the formula sented, where * is the connection to R 1 represents,

[0105] R 1 a group R 3 represents, n = 4,

[0106] R 2 represents a hydrogen atom,

[0107] R 3 represents a group consisting of where * represents the link to the rest of the molecule,

[0108] R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula

[0109] (II), where

[0110] R 5 represents a hydrogen atom, R 6 a group selected from

[0111] C1-C4-alkyl, C5-C8-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, wherein the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula, and (ii) a hepatobiliary contrast agent of formula (IV) or formula (V) wherein the compound of formula (IV) has the formula

[0112] (IV), where

[0113] Are a group selected from where # represents the linkage to X, X represents a group selected from CH2 and (CH2)s,

[0114] R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group,

[0115] R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3,

[0116] R 10 represents a group consisting of

[0117] C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times by a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula

[0118] Are a group selected from and represents, where # represents the connection to X,

[0119] X represents a group selected from CH2 and (CH2)2,

[0120] R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12 a group selected from

[0121] C2-C5-alkoxy, (H3C-CH2O)-(CH2)2-O-, (H3C-CH2O)-(CH2)2-O-(CH2)2-O- and

[0122] (H3C-CH2O)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0123] In a preferred embodiment of the present disclosure, the composition is a composition comprising (i) an extracellular contrast agent of formula (I) e ne ruppe arstellt, where * is the connection to R 1 represents;

[0124] R 1 a group R 3 represents; n = 4,

[0125] R 2 represents a hydrogen atom,

[0126] R 3 represents a group consisting of where * represents the link to the rest of the molecule,

[0127] R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and (ii) a hepatobiliary contrast agent of formula (IV)

[0128] ( IV > , where

[0129] Are a group selected from where # represents the connection to X,

[0130] X represents a group selected from CH2 and (CH2)s,

[0131] R 7 and R 9 independently represent a hydrogen atom or a -CH2OH group,

[0132] R 8 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3,

[0133] R 10 a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-

[0134] O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0135] The term "Ci-C2-alkyl" means a linear saturated, monovalent hydrocarbon group having 1 or 2 carbon atoms, e.g. methyl, ethyl.

[0136] The term "Ci-CAalkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2 or 3 carbon atoms, e.g. methyl, ethyl, n-propyl and isopropyl.

[0137] The term "Ci-C4 alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.

[0138] The term "C2-C4 alkyl" means a linear or branched, saturated, monovalent hydrocarbon group containing 2, 3 or 4 carbon atoms.

[0139] The term "Ci-C2-alkoxy" means a linear saturated, monovalent group of the formula (C1-C2-alkyl)-O-, in which the term "Ci-C2-alkyl" is as defined above. The term "Ci-Cs-alkoxy" means a linear or branched, saturated, monovalent group of the formula (Ci-C3-alkyl)-O-, in which the term "Ci-Cs-alkyl" is as defined above.

[0140] The term "C2-C4alkoxy" means a linear or branched, saturated, monovalent group of the formula (C2-C4alkyl)-O-, in which the term "C2-C4alkyl" is as defined above, e.g. a methoxy, ethoxy, n-propoxy or isopropoxy group.

[0141] The term "C2-C5 alkoxy" means a linear or branched, saturated, monovalent group of the formula (C2-C5 alkyl)-O-, in which the term "C2-C5 alkyl" is as defined above.

[0142] The term "C3-C8-cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring containing 3, 4, or 5 carbon atoms. The "C3-C8-cycloalkyl" group in question is, for example, a monocyclic hydrocarbon ring, e.g., a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0143] The term "Ci-Cs-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-Cs-alkyl" is as defined above, and in which one or more of the hydrogen atoms are replaced, identically or differently, by a halogen atom. Preferably, the halogen atom is a fluorine atom. The said "Ci-Cs-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-2yl group.

[0144] In a preferred embodiment of the present disclosure, the composition is a composition comprising (i) an extracellular contrast agent of the formula or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof and (ii) a hepatobiliary contrast agent of the formula or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0145] In one embodiment, the molar amounts of extracellular contrast agent and hepatobiliary contrast agent in the composition are equal, or there is an excess of hepatobiliary contrast agent. Thus, in a preferred embodiment, the molar ratio of extracellular contrast agent to hepatobiliary contrast agent is in the range of 1:1 to 1:10, preferably in the range of 1:1 to 1:5, more preferably in the range of 1:1 to 1:3.

[0146] In a further embodiment, the molar amounts of extracellular contrast agent and hepatobiliary contrast agent are equal, or an excess of extracellular contrast agent is used. Thus, in a preferred embodiment, the molar ratio of extracellular contrast agent to hepatobiliary contrast agent is in the range of 1:1 to 10:1, preferably in the range of 1:1 to 5:1, more preferably in the range of 1:1 to 3:1.

[0147] Preferably, the extracellular contrast agent has a relaxivity of more than 3 L-mmol 1 - s 1 , measured at 1.5 T in plasma or water at 37 °C. Preferably, the hepatobiliary contrast agent has a relaxivity of more than 4 L'mmol 1 's 1 measured at 1.5 T in plasma or water at 37 °C.

[0148] In a preferred embodiment of the present disclosure, the composition is a composition comprising (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 with a relaxivity of at least 4 L-mmol 1 's 1 measured at 1.5 T in plasma or water at 37 °C.

[0149] In a first step, the first representation and the second representation are received or generated.

[0150] The term "receiving" encompasses both retrieving representations and receiving representations that are transmitted, for example, to the computer system of the present disclosure. The representations can be received from a computer tomography scanner, a magnetic resonance imaging scanner, or an ultrasound scanner. The representations can be read from one or more data storage devices and / or transmitted from a separate computer system.

[0151] The representations can also be created as described below.

[0152] Radiological images are usually obtained as a result of radiological examinations (particularly in the case of computed tomography and sonography) as representations in spatial space (also called image space).

[0153] The "local space" is ordinary three-dimensional Euclidean space, which corresponds to the space we humans experience with our senses and in which we move. A representation in local space is therefore the more familiar representation for humans. In one embodiment of the present disclosure, the first representation and the second representation received or generated in a first step are representations in local space.

[0154] In a spatial representation, also referred to in this description as a spatial representation or spatial representation, the examination area is usually represented by a large number of image elements (pixels or voxels), which can be arranged in a grid, for example, with each image element representing a part of the examination area, whereby each image element can be assigned a color value or gray value. A widely used format in radiology for storing and processing spatial representations is the DICOM format. 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 spatial representations are also possible.

[0155] It is possible to co-register representations in spatial space before processing them, as described in this specification. "Co-registration" (also called "image registration" in the prior art) serves to optimally align two or more spatial representations of the same examination area. One of the spatial representations is designated as the reference image, and the other is called the object image. To optimally adapt this image to the reference image, a compensating transformation is calculated.

[0156] In one embodiment of the present disclosure, a third representation in the spatial space is generated based on the first representation and the second representation in the spatial space. Such a third representation also represents at least a portion of the examination area in the spatial space.

[0157] However, it is also possible for the first representation and the second representation, which are received or generated in a first step, to be representations in the frequency domain. In other words, in one embodiment, the first representation and the second representation represent the examination area in the frequency domain.

[0158] The “frequency space” is a domain in which a signal is considered as the sum of its individual frequency components.

[0159] In a frequency-space representation, also referred to in this description as a frequency-space representation or frequency-space representation, the area under investigation is represented by a superposition of fundamental oscillations. For example, the area under investigation can be represented by a sum of sine and / or cosine functions with different amplitudes, frequencies, and phases. The amplitudes and phases can be plotted as a function of frequency, for example in a two- or three-dimensional representation. Typically, the lowest frequency (origin) is placed in the center. The further one moves away from this center, the higher the frequencies. Each frequency can be assigned an amplitude, with which the frequency is represented in the frequency-space representation, and a phase, which indicates the extent to which the respective oscillation is shifted compared to a sine or cosine oscillation.

[0160] The raw data generated during magnetic resonance imaging examinations (so-called k-space data) is an example of a representation in the frequency domain. Such raw data (k-space data) from magnetic resonance imaging examinations can be used directly as the first and / or second representation in the frequency domain within the meaning of the present disclosure.

[0161] Radiological images are usually obtained as a result of radiological examinations (particularly in the case of computed tomography and sonography) as representations in spatial space (also called image space). A representation in spatial space can be converted (transformed) into a representation in frequency space, for example using a Fourier transform. Conversely, a representation in frequency space can be converted (transformed) into a representation in spatial space, for example using an inverse Fourier transform. The term “generating a representation” therefore preferably means that a frequency representation of the examination area is generated from a spatial space representation of the examination area using a transformation, or that a spatial space representation of the examination area is generated from a frequency representation of the examination area using a transformation.

[0162] Details about position-space representations and frequency-space representations and their respective conversion into each other are described in numerous publications, see for example: https: / / see.stanford.edu / materials / lsoftaee261 / book-fall-07.pdf.

[0163] Thus, if the first representation and / or the second representation represent the area of ​​investigation in spatial space, the respective spatial representation can first be converted (converted, transformed) into a representation in frequency space through a transformation (e.g., a Fourier transform). In other words, a representation in frequency space can be generated from a spatial representation through a transformation (e.g., a Fourier transform).

[0164] It is also possible to co-register representations in frequency space. It should be noted that a translation in spatial space is represented by an additive linear phase ramp in frequency space. Scaling and rotation, however, are preserved during the Fourier and inverse Fourier transformations—scaling and rotation in frequency space also represent scaling and rotation in spatial space (see, for example, 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_l4 / Program / Syllabus / Skare.pdf).

[0165] It should be noted that co-registration in the frequency domain does not need to be very precise, since high frequencies, which represent image details and thus inaccuracies in registration, are attenuated by the frequency filter. This is an advantage of the approach described in this disclosure over approaches that perform operations in the spatial domain.

[0166] In a preferred embodiment of the present disclosure, the first representation and the second representation received or generated in a first step are representations in the frequency domain.

[0167] In one embodiment of the present disclosure, a third representation in frequency space is generated based on the first representation in frequency space and the second representation in frequency space. Such a third representation also represents at least a portion of the examination region in frequency space.

[0168] Regardless of whether the third representation represents at least part of the examination area in spatial space or in frequency space, the third representation represents the signal amplification caused by the second amount of contrast agent in the examination area. In other words, the third representation includes the differences in the second representation compared to the first representation caused by the second amount of contrast agent. In the third representation in frequency space, each frequency is represented with a higher amplitude value the more the frequency is influenced by the second amount of contrast agent. If the third representation is generated in frequency space - and not in spatial space - low frequencies can be weighted and thus the contrast of a fourth representation in spatial space can be emphasized.In a preferred embodiment, generating the third representation comprises subtracting the first representation from the second representation. In other words, in a preferred embodiment, the third representation is the difference between the first and second representations.

[0169] If the third representation is a frequency-domain representation of the examination area, a weighted third representation can be generated based on the third representation in a further step. By weighting the third representation, frequencies that contribute more to contrast are given a higher weight than frequencies that contribute less to contrast. The term "contrast" refers to the spatial representation corresponding to the frequency-domain representation. Contrast information is represented by low frequencies in a frequency-domain representation, while higher frequencies represent information about fine structures. Image noise is typically evenly distributed in the frequency domain representation.The weighted third representation can therefore be generated by applying a frequency-dependent weighting function to the third representation, with low frequencies being weighted more heavily than high frequencies. The frequency-dependent weighting function acts like a filter. The filter increases the signal-to-noise ratio by reducing the spectral noise density for high frequencies.

[0170] The weighting of the third frequency-space representation therefore has several advantages: firstly, a focus is placed on the contrast information, i.e., features in the resulting fourth frequency-space representation are highlighted that are attributable to a contrast enhancement by the second amount of contrast agent; secondly, it is possible to add the weighted third frequency-space representation several times to the third frequency-space representation in order to achieve a further contrast enhancement without interference and / or noise being amplified to the same extent as the contrast.

[0171] Fig. 1 shows examples of frequency-dependent weight functions that can be used to weight the third representation. For simplicity, the weight functions are depicted as two-dimensional graphs, with the weight factors wf (ordinate) plotted as a function of frequency f (abscissa).

[0172] Fig. 1 (a) shows a weight function in which the weight factors decrease exponentially from the center with increasing frequency.

[0173] Fig. 1 (b) shows a weight function in which the weight factors decrease linearly from the center with increasing frequency.

[0174] Fig. 1 (c) shows a weight function in which the weight factors decrease from the center with increasing frequency in the form of an inverted parabola.

[0175] Fig. 1 (d) shows a weight function in which the weight factors are constant over a defined range around the center and then decrease exponentially above a threshold frequency.

[0176] Fig. 1 (e) shows a weight function in which the weight factors are in the form of a cosine function around the center.

[0177] Fig. 1 (f) shows a weight function in which the weight factors run in the form of a staircase function around the center.

[0178] Fig. 1 (g) shows a weight function in which the weight factors are in the form of a Gaussian normal distribution function around the center.

[0179] Fig. 1 (h) shows a weight function in which the weight factors are arranged around the center in the form of a Hann function. Combinations of the weight functions shown and additional / other weight functions are possible. Examples of other weight functions can be found, for example, at https: / / de.wikipedia.org / wiki / Fensterfimktion#Beispiele_von_Fensterfunktionen; FJ 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; KM M Prabhu: Window Functions and Their Applications in Signal Processing, CRC Press, 2014, 978-1-4665-1583-3).

[0180] Weight functions that can be used are also referred to as window functions in the literature.

[0181] Preferably, weighting functions are used that have proven effective in MR imaging and spectroscopy for weighting k-space data, such as the Gaussian function or the Hann function (also known as the Hann window, see, for example, 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).

[0182] 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 spatial space, a third representation in frequency space, or a weighted third representation in frequency space. Through such a combination, information about the contrast enhancement induced by the second amount of contrast agent in the examination area is transferred to the first representation.

[0183] The combination to generate the fourth representation can, for example, be or include an addition of the first representation and the third representation (or the weighted third representation). However, it is also possible to carry out a multiplicative combination or a non-linear combination. In a preferred embodiment of the present disclosure, the generation of a fourth representation by combining the first representation with the (weighted) third representation is or includes adding the (weighted) third representation to the first representation a-fold, where a (gain factor) is a positive or negative real number, and where the third representation can be a third representation in the spatial domain, a third representation in the frequency domain, or a weighted third representation in the frequency domain.In other words, the (weighted) third representation is multiplied by a gain factor a and the result of the multiplication is added to the first representation.

[0184] In a preferred embodiment of the present disclosure, the fourth representation is generated or created (i) by adding a third representation in the spatial domain multiplied by a gain factor a to the first representation in the spatial domain, (ii) by adding a third representation in the frequency domain multiplied by a gain factor a to the first representation in the frequency domain, or (iii) by adding a weighted third representation in the frequency domain multiplied by a gain factor a to the first representation in the frequency domain. The mathematical methods (subtracting, adding, multiplying) typically relate to the tonal values ​​of the individual image elements (pixels, voxels) or the amplitude values ​​of the individual frequencies (in the case of frequency-domain representations).

[0185] The gain factor is a positive or negative real number.

[0186] The gain factor indicates the extent to which the contrast in the fourth representation is increased or decreased.

[0187] This means that the third (weighted) representation can also be added multiple times to the first representation to generate a higher contrast than the second representation in spatial space. Furthermore, by selecting the amplification factor a, it is possible to achieve an amplification that is greater than the contrast enhancement caused by a standard amount of contrast agent. Such contrast enhancement is not possible with the method described in WO2019 / 074938A1 without applying a quantity of contrast agent to individuals to generate the training data that is higher than the standard amount and thus outside the range approved by the regulatory authority.

[0188] It is also possible to choose an enhancement factor a that is less than 1, i.e. the contrast between areas with contrast agent and areas without contrast agent is then lower in the fourth representation than in the second representation.

[0189] It is also possible to further reduce the contrast by using negative values ​​of the enhancement factor a. This can be useful, for example, to generate a representation of the examination region without contrast agent based on a first representation representing the examination region with a first amount of the composition and a second representation representing the examination region with a second amount of the composition. If, for example, the second amount is twice as large as the first amount, an enhancement factor of a = -1 results in a fourth representation that looks as if no contrast agent had been applied, provided that the signal enhancements caused by the contrast agents increase linearly with their amount and that the first and second representations represent the examination region at the same time interval from the application of the first or second amount.

[0190] It is also possible to choose negative values ​​of a such that areas of the examination area that experience a contrast agent-induced signal enhancement in the metrologically generated representation are completely dark (black) in the artificially generated representations.

[0191] The gain factor can be selected by a user, ie be variable, or predefined, ie be specified.

[0192] It is also possible to determine the amplification factor automatically. For example, it is possible to define at least one area in a spatial representation of the first and / or the second representation and / or to have it selected by a user and to set the amplification factor such that a gray value in the spatial representation (or another tonal value in the case of a representation other than a gray value representation) assumes a defined value and / or lies above or below a threshold value and / or two gray values ​​in two different selected or defined areas are a defined distance from one another and / or have a distance from one another that is above or below a threshold value. It is also possible to apply other criteria to determine the amplification factor automatically.The basis for the criteria for automatically determining the gain factor can, for example, be the histogram of the first, second, third, weighted third, and / or fourth representation transformed into a spatial representation. Such a histogram can list the number of image elements with a defined tonal value or gray value.

[0193] If the fourth representation is a representation of the area under investigation in spatial space, it can be output, ie, displayed on a screen, printed out using a printer, and / or stored on a data storage device. It can also be transmitted to another computer system (e.g., via a network).

[0194] If the fourth representation is a representation of the examination area in frequency space, the frequency space representation can be transformed into a position space representation (e.g., using an inverse Fourier transform). The position space representation can then be output, i.e., displayed on a screen, printed out using a printer, and / or stored on a data storage device. It can also be transmitted to another computer system (e.g., via a network). Fig. 2 shows, schematically in the form of an example, the generation of a third representation in position space and a fourth representation in position space based on a first representation in position space and a second representation in position space.

[0195] Fig. 2 shows an examination area of ​​an object under investigation in the form of various representations. The examination area shown in Fig. 2 includes the boars of a pig.

[0196] A first representation RI represents the examination area in spatial space without contrast agent. The first representation RI is a magnetic resonance imaging image.

[0197] A second representation R2 represents the same examination area of ​​the same examination object as the first representation RI, also in spatial space. The second representation R2 is also a magnetic resonance imaging image.

[0198] The second representation R2 represents the examination area after the application of a quantity of a composition comprising an extracellular contrast agent and an intracellular contrast agent. The intracellular contrast agent is a hepatobiliary contrast agent. The composition comprises 10 pmol per kg body weight of the extracellular contrast agent and 10 pmol per kg body weight of the intracellular contrast agent. The composition was administered intravenously to the subject. The second representation R2 represents the examination area in the so-called portal venous phase after the application of the contrast agent.

[0199] Based on the first representation RI and the second representation R2, a third representation R3 is generated. In the example shown in Fig. 2, the third representation R3 is the difference between the second representation R2 and the first representation RI.

[0200] In the third representation R3, negative tone values ​​that may arise when subtracting the first representation from the second representation can be set to zero (or another value) to avoid negative values.

[0201] The third representation R3 represents the contrast enhancement caused by the second amount of contrast agent in the examination area.

[0202] The third representation R3 is multiplied by the gain factor a, and the result of the multiplication is added to the first representation RI. This creates a fourth representation R4. In the example shown in Fig. 2, the gain factor a=3, meaning the third representation R3 is added three times to the first representation RI.

[0203] The fourth representation R4 can be subjected to normalization, i.e. the tonal values ​​can be multiplied by a factor so that the tonal value with the highest value is represented, for example, by the hue white and the tonal value with the lowest value is represented, for example, by the hue black.

[0204] Fig. 3 shows 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 schematically in the form of an example.

[0205] Fig. 3 shows an examination area of ​​an object under investigation in the form of various representations. The examination area shown in Fig. 3 includes a pig's liver.

[0206] A first representation RI 1 represents the examination area in spatial space without contrast agent. The first representation RI1 is a magnetic resonance imaging scan.

[0207] The first spatial representation RI 1 can be transformed by a transformation T, for example a Fourier transformation, into a first representation R1 F of the study area in the frequency domain. The first frequency domain representation R1 F represents the same investigation area - TI - of the same investigation object as the first spatial representation RI 1 , also without contrast agent.

[0208] The first frequency space representation R1 F can be transformed into the first position space representation RI by means of an inverse transformation T' 1 The inverse transformation 7 L| is the inverse transformation of the transformation T.

[0209] A second representation R2 1 represents the same area of ​​investigation of the same object of investigation as the first representation RI1 in the spatial space. The second representation R2 1 is also a magnetic resonance imaging image. The second spatial representation R2 1 represents the examination area after the application of a quantity of a composition comprising an extracellular contrast agent and an intracellular contrast agent. The intracellular contrast agent is a hepatobiliary contrast agent. The composition was administered intravenously to the subject. The composition comprised 10 pmol per kg body weight of the extracellular contrast agent and 10 pmol per kg body weight of the hepatobiliary contrast agent. The second representation R2 1 represents the examination area 15 minutes after injection of the compound in the so-called hepatobiliary phase. In the second spatial representation R2 1the contrast between the boar tissue and the surrounding tissue is increased due to the applied amount of the composition.

[0210] The second position space representation R2 1 can be transformed into a second representation R2 by transforming T F of the study area in the frequency domain. The second frequency domain representation R2 F represents the same investigation area of ​​the same investigation object as the second spatial representation R2 1 , also after application of the composition .

[0211] The second frequency space representation R2 F can be transformed into the second position space representation R2 by means of the inverse transformation 1 convert.

[0212] Based on the first frequency space representation R1 F and the second frequency space representation R2 F a third frequency space representation R3 FIn the example shown in Fig. 3, the third frequency space representation is R3 F the difference of the second frequency space representation R2 F and the first frequency space representation R1 F (R3 F = R2 F - R1 F ).

[0213] The third frequency space representation R3 F can be subjected to normalization, i.e. the amplitude values ​​can be multiplied by a factor so that the amplitude with the highest value is represented, for example, by the color white and the amplitude with the lowest value is represented, for example, by the color black.

[0214] It is also possible that in such a normalization, negative values ​​that may arise from subtracting the first representation from the second representation are set to zero (or another value) to avoid negative values. In Fig. 3, all frequency-space representations are shown on the same logarithmic grayscale.

[0215] The third frequency space representation R3 F represents the contrast enhancement caused by the applied amount of the composition in the examination area.

[0216] Fig. 3 further shows that the third frequency space representation R3 F a weight function WF is applied to obtain a weighted third representation R3 F w The weight function in this case is a Gaussian weight function.

[0217] By weighting the third representation R3 FFrequencies that make a greater contribution to contrast are given a higher weight than frequencies that make a lower contribution. The term “contrast” refers to the spatial space representation corresponding to the frequency-domain representation. Contrast information is represented by low frequencies in a frequency-domain representation, while the higher frequencies represent information about fine structures. Image noise is typically evenly distributed in the frequency representation. The weighted third representation in the frequency domain can therefore be created by applying a frequency-dependent weighting function to the third representation in the frequency domain, with low frequencies being given a higher weight than high frequencies. The frequency-dependent weighting function has the effect of a filter. The filter increases the signal-to-noise ratio because the spectral noise density for high frequencies is reduced.

[0218] To generate the weighted third representation R3 F w the amplitude values ​​of the third frequency space representation R3 F multiplied by the weighting factors of the weighting function. The weighting factors are frequency-dependent, meaning the weighting factors are a function of frequency. For illustrative purposes, the weighting function WF is shown in two-dimensional form in Fig. 1. The weighting function WF shows the weighting factors wf as a function of frequency along one dimension.

[0219] The weight function WF determines the amplitudes of low frequencies (in the example shown, the frequencies decrease from the center of the representation R3 F outwards) are multiplied by a higher weighting factor than the amplitudes of higher frequencies (which are further from the center of the representation R3 Fremoved); ie, the low frequencies are weighted higher than the higher frequencies. This is in the weighted representation R3 F w This can be seen by the fact that grey 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 to the outside than in the representation R3 F .

[0220] In Fig. 3 it is further shown that a fourth representation R4 F of the examination area of ​​the object under investigation in the frequency space by combining the first frequency space representation R1 F with weighted third frequency space representation R3 F w The combination is done in the example by multiplying the weighted third frequency space representation R3 F w with an amplification factor a and adding the result to the first frequency space representation R1 F. In the example shown in Fig. 3, the gain factor is a=3, ie the weighted third frequency space representation R3 F w is three times to the first frequency space representation R1 F added.

[0221] It is possible to use the fourth representation R4 F to undergo normalization.

[0222] Fig. 3 further shows that the fourth representation R4 F of the examination area of ​​the object under investigation in the frequency space by a transformation into a representation R4 1 of the investigation area of ​​the object under investigation in the local area.

[0223] Fig. 4 shows exemplary and schematic representations of an examination area of ​​an object under investigation in spatial space. The representations differ in the amplification factor a, which in the present examples can assume the values ​​0, 1, 2, 3, and 4. The representations were generated using a method as described in relation to Fig. 3. This means that the subtraction and addition were performed in the frequency domain, and a weighting was applied.

[0224] A gain factor of a = 0 means that no contrast enhancement is applied to the first representation. Thus, the representation shows the original first representation in spatial space.

[0225] A gain factor of a = 1 means that the weighted third frequency-domain representation is added once to the first representation in the frequency domain. The contrast enhancement is similar to the contrast enhancement of the corresponding second spatial-domain representation, but exhibits less noise / interference due to the greater weighting of the low frequencies. A gain factor of a = 2, 3, or 4 means that the weighted third frequency-domain representation is added twice, three times, or four times to the first representation in the frequency domain. The contrast enhancement increases with increasing gain.

[0226] In the example shown in Fig. 4, an integer multiple of the weighted third frequency-space representation is always added to the first representation. As described, it is also possible to add a non-integer portion of the weighted third frequency-space representation to the first representation (e.g., a = 1.5 or a = 3.7 or a = 4.159). Thus, gain can be continuously increased.

[0227] Fig. 5 shows a preferred embodiment of an output of the artificial contrast-enhanced radiological image of an examination region by means of a computer system / computer program. The output is provided to a user of the computer system and / or computer program of the present disclosure.

[0228] The user is provided with an initial representation RI 1 an examination area of ​​an object under investigation, a second representation R2 1of the study area of ​​the object under investigation and a predicted fourth representation R4 1 of the examination area of ​​the object under examination (for example on a monitor).

[0229] The first representation RI 1 represents the examination area without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0230] The second representation R2 1 represents the test area after application of a second amount of the compound. The second amount is larger than the first amount.

[0231] The fourth representation R4 1 represents the examination area with enhanced contrast. The contrast between areas without contrast agent and areas with contrast agent is, in the case of the fourth representation, R4 1larger than the second representation R2 1 .

[0232] The fourth representation R4 1 was generated as described in relation to Fig. 3.

[0233] All displayed representations are representations of the study area in spatial space. In the example shown in Fig. 5, no frequency-space representations are displayed to the user. This is not typically intended, as many users are unfamiliar with frequency-space representations.

[0234] Below the displayed representations RI 1 , R2 1 and R4 1 The user is shown the histograms of the representations in an overlaid display.

[0235] Above the displayed representations RI 1 , R2 1 and R4 1Three virtual sliders are provided for the user to adjust settings. The first slider, a, allows the user to freely select the gain factor within a range of 1 to 10. The slider indicates that a continuous increase in the gain factor from 1 to 10 is possible.

[0236] Using a second slider, ß, and a third slider, y, the user can change parameters of the weighting function. These parameters can, for example, determine how much the weighting factors decrease with increasing frequency.

[0237] The output shown in Fig. 5 is preferably configured such that the display of the fourth representation R4 1is immediately updated when the user makes changes using one of the sliders. The user can then, for example, change the gain factor a and immediately see how a change in the gain factor affects the representation R4 1 This allows him to identify those settings that lead to a fourth representation R4 that is optimal for the user. 1 of the study area. Any change in one of the parameters a, ß and / or y causes the computer system to generate the fourth representation R4 based on the changed parameter(s). 1 is calculated and displayed only in the background. This also applies analogously to the histogram of the fourth representation R4 1 .

[0238] It is possible that the contrast enhancement in the frequency domain according to the present disclosure so far may cause a contrast enhancement that is undesirable for a user. This will be explained using an example. The example is shown schematically in Fig. 6.

[0239] Fig. 6 shows a first representation RI 1 and a second representation R2 1 of an examination area of ​​an examination object. The examination area includes the boar E and the gallbladder B of a pig. The first representation RI 1 represents the examination area without contrast agent in spatial space. The second representation R2 1 represents the examination area after application of the composition comprising an extracellular contrast agent and an intracellular contrast agent in spatial space. In the second representation R2 1it can be seen that the gallbladder has partially filled, for example with a fluid containing one or both contrast agents or another fluid that results in a high contrast between the partially filled gallbladder and the surrounding areas.

[0240] Contrast enhancement as described in the previous disclosure results in an artificial contrast-enhanced radiological image R4 1 of the examination area, the contrast between the partially filled gallbladder and the other areas is further enhanced. However, it is conceivable that a user might be more interested in contrast enhancement of the liver.

[0241] In a preferred embodiment, the computer system and the computer program of the present disclosure are configured to receive an input from the user. In the input, the user can specify one or more regions for which he does not wish to have contrast enhancement. The user can draw such a region in the first, second and / or fourth representation in spatial space, for example, using a mouse or another input device. Thus, in the example shown in Fig. 6, the user can draw the gallbladder in the first representation RI 1 , the second representation R2 1 and / or the fourth representation R4 1 select and / or mark. The computer system and the computer program can be configured to set the tonal values ​​or gray values ​​of all image elements (pixels, voxels) representing the (marked) gallbladder to zero. The result is the representation R2 1*, in which the gallbladder is represented by black image elements. If the contrast enhancement is carried out as described in this disclosure based on the representations RI 1 and R2 1 * (or on the basis of their corresponding frequency space representations), the artificial contrast-enhanced radiological image R4 is obtained 1 *, in which the contrast between the liver L and the other areas is now particularly enhanced, but the partially filled gallbladder is no longer shown with contrast enhancement.

[0242] In a preferred embodiment, regions that are not (supposed to be) contrast-enhanced are determined automatically. Preferably, for all pairwise corresponding (ie having the same coordinates) image elements of the first spatial representation RI 1 and the second position space representation R2 1 the quotient of the tonal values ​​is determined:

[0243] Q = g2(x, y, z) / gl(x, y, z)

[0244] Where Q is a quotient of tonal values, g2(x, y, z) is the tonal value of the image element with the coordinates x, y, z in the second representation R2 1 and gl(x, y, z) is the tone value of the image element with the same coordinates x, y, z in the first representation RI 1The quotient Q of the tonal values ​​is a measure of how much brighter the image element with the coordinates x, y, z is represented in the second representation compared to the corresponding image element in the first representation. It indicates the contrast enhancement caused by the second set of the composition in the examination area represented by image elements with the coordinates x, y, z. The computer system and the computer program can be configured to compare the quotient of the tonal values ​​for all image elements with a predefined threshold value. The predefined threshold value indicates a maximum contrast enhancement to be expected from the contrast agents contained in the composition.

[0245] If a quotient of the tonal values ​​of corresponding image elements is greater than the predefined threshold, the tonal values ​​of the corresponding image elements can be set to zero.

[0246] Fig. 7 shows an exemplary and schematic illustration of a computer system according to the present disclosure.

[0247] A "computer system" is an electronic data processing system that processes data using programmable computing instructions. Such a system typically includes a "computer," the unit that includes a processor for performing logical operations, and peripherals.

[0248] In computer technology, "peripherals" refers to all devices connected to a computer that serve to control the computer and / or act as input and output devices. Examples include monitors, printers, scanners, mice, keyboards, drives, cameras, microphones, speakers, etc. Internal connectors and expansion cards are also considered peripherals in computer technology.

[0249] The computer system (1) shown in Fig. 7 comprises an input unit (10), a control and computing unit (20) and an output unit (30).

[0250] The control and computing unit (20) serves to control the computer system (1), to coordinate the data flows between the units of the computer system (1) and to carry out calculations.

[0251] The control and computing unit (20) is configured to: cause the receiving unit (10) to receive a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, cause the receiving unit (10) to receive a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount, generate a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,to generate a fourth representation based on the first representation and the third representation, wherein generating the fourth representation comprises adding the third representation to the first representation a-fold, where a is a positive or negative real number, to cause the output unit (30) to output the representation of the examination area and / or to store it and / or to transmit it to a separate computer system.

[0252] Fig. 8 shows an exemplary and schematic illustration of another embodiment of the computer system of the present disclosure.

[0253] The computer system (1) comprises a processing unit (21) connected to a memory (22). The processing unit (21) and the memory (22) form a control and computing unit, as shown in Fig. 7. The processing unit (21) may comprise one or more processors alone or in combination with one or more memories. The processing unit (21) may be conventional computer hardware capable of processing information such as digital image recordings, computer programs, and / or other digital information. The processing unit (21) typically consists of an arrangement of electronic circuits, some of which may be embodied as an integrated circuit or as several interconnected integrated circuits (an integrated circuit is sometimes also referred to as a "chip").The processing unit (21) may be configured to execute computer programs that may be stored in a working memory of the processing unit (21) or in the memory (22) of the same or another computer system.

[0254] The memory (22) may be ordinary computer hardware capable of storing information such as digital image recordings (e.g. representations of the examination area), data, computer programs and / or other digital information either temporarily and / or permanently. The memory (22) may comprise volatile and / or non-volatile memory and may be permanently installed or removable. Examples of suitable memories are RAM (Random Access Memory), ROM (Read-Only Memory), a hard disk, flash memory, a removable computer diskette, an optical disc, magnetic tape or a combination of the above. Optical discs may include read-only compact discs (CD-ROM), read / write compact discs (CD-R / W), DVDs, Blu-ray discs and the like.

[0255] In addition to the memory (22), the processing unit (21) can also be connected to one or more interfaces (11, 12, 31, 32, 33) for displaying, transmitting, and / or receiving information. The interfaces can comprise one or more communication interfaces (32, 33) and / or one or more user interfaces (11, 12, 31). The one or more communication interfaces can be configured to send and / or receive information, e.g., to and / or from an MRI scanner, a CT scanner, an ultrasound camera, other computer systems, networks, data storage devices, or the like. The one or more communication interfaces can be configured to transmit and / or receive information via physical (wired) and / or wireless communication connections.The one or more communication interfaces may include one or more interfaces for connecting to a network, e.g., using technologies such as cellular, Wi-Fi, satellite, cable, DSL, fiber optic, and / or the like. In some examples, the one or more communication interfaces may include one or more short-range communication interfaces configured to connect devices using short-range communication technologies such as NFC, RFID, Bluetooth, Bluetooth LE, ZigBee, infrared (e.g., IrDA), or the like.

[0256] The user interfaces may comprise a display (31). A display (31) may be configured to display information to a user. Suitable examples include a liquid crystal display (LCD), a light-emitting diode display (LED), a plasma display (PDP), or the like. The user input interface(s) (11, 12) may be wired or wireless and may be configured to receive information from a user into the computer system (1), e.g., for processing, storage, and / or display. Suitable examples of user input interfaces include a microphone, an image or video capture device (e.g., a camera), a keyboard or keypad, a joystick, a touch-sensitive surface (separate from or integrated with a touchscreen), or the like.In some examples, the user interfaces may include automatic identification and data capture (AIDC) technology for machine-readable information. This may include barcodes, radio frequency identification (RFID), magnetic stripes, optical character recognition (OCR), integrated circuit cards (ICC), and the like. The user interfaces may further include one or more interfaces for communicating with peripheral devices such as printers and the like.

[0257] One or more computer programs (40) can be stored in the memory (22) and executed by the processing unit (21), which is thereby programmed to perform the functions described in this description. The retrieval, loading, and execution of instructions of the computer program (40) can occur sequentially, such that one instruction is retrieved, loaded, and executed at a time. However, the retrieval, loading, and / or execution can also occur in parallel.

[0258] The computer system of the present disclosure may be embodied as a laptop, notebook, netbook and / or tablet PC, and may also be a component of an MRI scanner, a CT scanner or an ultrasound diagnostic device.

[0259] Fig. 9 shows an exemplary and schematic embodiment of the computer-implemented method of the present disclosure in the form of a flow chart.

[0260] The method (100) comprises the steps:

[0261] (110) Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent,

[0262] (120) receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after application of a second quantity of the composition, wherein the second quantity is greater than the first quantity,

[0263] (130) generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation,

[0264] (150) generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number,

[0265] (170) Outputting and / or storing the representation of the examination area and / or transmitting the representation of the examination area to a separate computer system.

[0266] The present invention can be used for various purposes. Some examples of application are described below, without intending to limit the invention to these examples.

[0267] A first application example concerns magnetic resonance imaging examinations for the delineation of intra-axial tumors such as intracerebral metastases and malignant gliomas. Due to the infiltrative growth of these tumors, a precise demarcation between tumor and healthy tissue is difficult. However, determining the extent of a tumor is crucial for surgical removal. The differentiation between tumors and healthy tissue is facilitated by the application of an extracellular contrast agent; after intravenous administration of a standard dose of 0.1 mmol / kg body weight of the extracellular MRI contrast agent gadobutrol, intra-axial tumors can be delineated much better. 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 dose of contrast agent (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).

[0268] A single triple dose or a second follow-up dose up to a total dose of 0.3 mmol / kg body weight can be administered. This exposes the patient and the surrounding area to additional gadolinium, and in the case of a second scan, additional costs will be incurred.

[0269] The present invention can be used to avoid a contrast agent dose that exceeds the standard amount. A first MRI image can be generated without contrast agent or with a smaller amount than the standard amount, and a second MRI image with the standard amount. Based on these generated MRI images, a synthetic MRI image can be generated, as described in this disclosure, in which the contrast between lesions and healthy tissue can be varied within wide limits by changing the enhancement factor a. Contrasts can be achieved that can otherwise only be achieved by applying an amount of contrast agent that is higher than the standard amount.

[0270] Another application example involves reducing the amount of MRI contrast agent used in a magnetic resonance imaging examination. Gadolinium-containing contrast agents such as gadobutrol are used for a variety of examinations. They enhance contrast in examinations of the skull, spine, breast, and other examinations. In the central nervous system, gadobutrol highlights areas with a disrupted blood-brain barrier and / or abnormal vessels. In breast tissue, gadobutrol visualizes the presence and extent of malignant breast disease. Gadobutrol is also used in contrast-enhanced magnetic resonance angiography to diagnose strokes, detect tumor perfusion, and detect focal cerebral ischemia.

[0271] Due to increasing environmental pollution, the cost burden on the healthcare system, and concerns about acute side effects and potential long-term health risks, particularly with repeated and long-term exposure, a dose reduction of gadolinium-containing contrast agents is being sought. This can be achieved by the present invention.

[0272] A first MRI image can be generated without contrast agent and a second MRI image can be generated with a contrast agent quantity that is less than the standard quantity. Based on these generated MRI images, a synthetic MRI image can be generated, as described in this disclosure, in which the contrast can be varied within wide limits by changing the amplification factor a. A contrast corresponding to the contrast after application of the standard quantity can be achieved with a contrast agent quantity less than the standard quantity.

[0273] Another application example concerns the detection, identification and / or characterization of lesions in the liver using a hepatobiliary contrast agent such as Primovist®.

[0274] Primovist® is administered intravenously (iv) 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 for extracellular MR contrast agents. Compared to contrast-enhanced MRI with extracellular gadolinium-containing contrast agents, Primovist® enables dynamic TLV multiphase imaging. However, due to the lower dose of Primovist® and the observation of transient motion artifacts that may occur shortly after intravenous administration, the contrast enhancement of Primovist® in the arterial phase is perceived by radiologists as lower than that of extracellular MRI contrast agents. However, the assessment of contrast enhancement in the arterial phase and the vascularity of focal liver lesions is crucial for accurate lesion characterization.

[0275] With the aid of the present invention, the contrast can be increased, particularly in the arterial phase, without the need to administer a higher dose.

[0276] A first MRI image without contrast agent and a second MRI image during the arterial phase can be generated after the application of an amount of contrast agent corresponding to the standard amount. Based on these generated MRI images, a synthetic MRI image can be generated, as described in this disclosure, in which the contrast in the arterial phase can be varied within wide limits by changing the enhancement factor a. Contrasts can be achieved that can otherwise only be achieved by applying an amount of contrast agent that is higher than the standard amount.

[0277] Another application example concerns the use of MRI contrast agents in computed tomography examinations. MRI contrast agents typically have a lower contrast-enhancing effect in a CT examination than CT contrast agents. Nevertheless, it can be advantageous to use an MRI contrast agent in a CT examination. One example is a minimally invasive intervention in a patient's body, in which a surgeon monitors the procedure using a CT scanner. Computed tomography (CT) has the advantage over magnetic resonance imaging that, while CT images of an examination area of ​​a subject are being generated, surgical interventions are possible on a larger scale in the examination area. However, there are only a few interventional instruments and surgical devices that are MRI-compatible. In addition, access to the patient is limited by the magnets used in MRI.While a surgeon is performing an operation in the area being examined, he or she can use the CT to create an image of the area being examined and follow the procedure on a monitor.

[0278] For example, if a surgeon wishes to perform an intervention on a patient's liver, e.g., to perform a biopsy of a liver lesion or to remove a tumor, the contrast between a liver lesion or tumor and healthy liver tissue in a CT scan of the liver will not be as pronounced as in an MRI scan following the application of a hepatobiliary contrast agent. Currently, no hepatobiliary CT-specific contrast agents are known and / or approved for CT. The use of an MRI contrast agent, particularly a hepatobiliary MRI contrast agent in computed tomography, therefore combines the ability to differentiate between healthy and diseased liver tissue with the ability to perform an intervention while simultaneously visualizing the liver.

[0279] The comparatively low contrast enhancement achieved by the MRI contrast agent can be increased with the help of the present invention without having to administer a higher dose than the standard dose.

[0280] A first CT image can be generated without MRI contrast agent and a second CT image can be generated after the application of an MRI contrast agent whose amount corresponds to the standard amount. Based on these generated CT images, a synthetic CT image can be generated, as described in this disclosure, in which the contrast induced by the MRI contrast agent can be varied within wide limits by changing the amplification factor a. Contrasts can be achieved that can otherwise only be achieved by applying an amount of MRI contrast agent that is higher than the standard amount.

Claims

Patent claims 1. Computer-implemented method comprising: Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount, Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number, Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

2. The method according to claim 1, wherein the first representation and the second representation represent the examination area in the spatial space.

3. The method of claim 1, wherein the first representation and the second representation represent the examination area in the frequency domain.

4. The method of claim 3, wherein generating the fourth representation comprises: Transform the result of adding the third representation to the first representation a-fold into the position space.

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

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

7. Method according to one of claims 1 to 6, further comprising: Receiving a first spatial representation, wherein the first spatial representation represents the examination area of ​​the examination object without contrast agent or after the application of the first amount of the composition in the spatial space, Transforming the first spatial representation into the first representation of the examination area of ​​the object under investigation in the frequency domain, Receiving a second spatial representation, wherein the second spatial representation represents the examination area of ​​the examination object after the application of the second set of the composition in the spatial space, Transforming the second spatial representation into the second representation of the examination area of ​​the object under investigation in the frequency domain.

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

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

10. The method according to any one of claims 5 to 8, wherein, when applying the frequency-dependent weighting function to the third representation, amplitude values ​​are multiplied by a window function, wherein the window function is a Gaussian distribution function or a Hann function or a Poisson function.

11. Method according to one of claims 1 to 10, further comprising: Receive one or more values ​​for a from a user.

12. The method according to any one of claims 1 to 10, further comprising: Receiving a first tone value of a first image element of a spatial representation of the first representation or the second representation, Receiving a second tone value of a second image element of a spatial representation of the first representation or the second representation, Determining a value for a for which the difference between the first tone value and the second tone value takes on a predefined value or lies above or below a predefined threshold.

13. The method according to any one of claims 3 to 10, further comprising: Receiving a marking of an area within a position space representation of the second representation, Setting the tonal values ​​of the area in the spatial representation of the second representation to zero, thereby generating a modified second spatial representation, Generating the second representation in frequency space from the modified second position space representation.

14. Method according to one of claims 3 to 10, further comprising: for all image elements of a first spatial representation of the first representation: determining a first tone value, for all image elements of a second spatial representation of the second representation: determining a second tone value, for all corresponding image elements of the first and second spatial representation: determining a quotient of the second tone value and the first tone value, Setting those tonal values ​​of the second spatial representation to zero for which the quotient is greater than a predefined threshold, thereby generating a modified second spatial representation, Generating the second representation in frequency space from the modified second position space representation.

15. The method according to any one of claims 1 to 14, wherein the first representation and the second representation are the result of a magnetic resonance imaging examination and / or have been generated from magnetic resonance images.

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

17. The method according to any one of claims 1 to 15, wherein the examination area comprises a liver, a kidney, a heart, a lung, a brain, a stomach, a bladder, a prostate gland, an intestine and / or a part thereof and / or another / further part of the body of a human being.

18. A 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), wherein the compound of formula (I) has the formula e ne ruppe-represented, where * is the connection to R 1 represents, R 1 a group R 3 represents, n = 4, R 2 represents a hydrogen atom, R 3 represents a group consisting of where * represents the linkage to the rest of the molecule, R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula (II), where R 5 represents a hydrogen atom, R 6 a group selected from C1-C4-alkyl, C5-C8-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, wherein the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula, and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), wherein the compound of formula (IV) has the formula has, whereby Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CH2)s, R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 10 represents a group consisting of C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times with a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CEE and (CH2)2, R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12 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-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

19. A computer system comprising a processor; and a memory storing an application program configured to perform an operation when executed by the processor, the operation comprising: Receiving or generating a first representation, wherein the first representation represents an examination region of an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount, Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number, Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

20. A computer program product comprising a data carrier on which a computer program is stored, wherein the computer program can be loaded into a working memory of a computer system and causes the computer system to perform the following steps: Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent, Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount, Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number, Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area 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 comprising: Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after an application of a second amount of the composition, wherein the second amount is greater than the first amount, Generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number, Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area 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), wherein the compound of formula (I) has the formula e ne ruppc-rcpräscnticrt. where * is the connection to R 1 represents, R 1 a group R 3 represents, n = 4, R 2 represents a hydrogen atom, R 3 represents a group consisting of where * represents the link to the rest of the molecule, R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula (II), where R5 represents a hydrogen atom, R 6 a group selected from Ci-C4-alkyl, Cs-Cs-cycloalkyl, (Ci-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, where the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, where the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from Ci-Cs-alkyl, Ci-Cs-haloalkyl and Ci-Cs-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, by a halogen atom or a group selected from Ci-Cs-alkyl, Ci-Cs-haloalkyl and Ci-Cs-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula, and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), wherein the compound of formula (IV) has the formula (IV), where Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CH2)s, R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 10 represents a group consisting of C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times with a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CH2)2, R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12 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-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

23. A composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent for use in a radiological examination procedure comprising: Receiving or generating a first representation, wherein the first representation represents an examination area of ​​an examination object without contrast agent or after the application of a first amount of the composition, Receiving or generating a second representation, wherein the second representation represents the examination area of ​​the examination object after application of a second amount of the composition, wherein the second amount is greater than the first amount, generating a third representation based on the first representation and the second representation, wherein generating the third representation comprises subtracting the first representation from the second representation, Generating a fourth representation, wherein generating the fourth representation comprises adding the third representation to the first representation, where a is a positive or negative real number, Outputting and / or storing the fourth representation of the examination area and / or transmitting the fourth representation of the examination area to a separate computer system.

24. A contrast agent for use according to claim 23, 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), wherein the compound of formula (I) has the formula e ne ruppe-represented, where * is the connection to R 1 represents, R 1 a group R 3 represents, n = 4, R 2 represents a hydrogen atom, R 3 represents a group consisting of where * represents the link to the rest of the molecule, R 4 represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula (II), where R5 represents a hydrogen atom, R 6 a group selected from C1-C4-alkyl, C5-C8-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, wherein the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from C1-C8-alkyl, C1-C8-haloalkyl and C1-C8-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula, and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), wherein the compound of formula (IV) has the formula (IV), where Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CTR); R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 10 represents a group consisting of C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times with a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula has, whereby Are a group selected from where # represents the connection to X, X represents a group selected from CH2 and (CH2)2, R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12 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-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

25. A kit comprising a computer program product according to claim 20 and a composition comprising an extracellular contrast agent and an intracellular contrast agent.

26. Kit according to 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), wherein the compound of formula (I) has the formula where: e ne group-represents, where * is the link to R 1 represents, R 1 a group R 3 represents, n = 4, R 2 represents a hydrogen atom, R 3 represents a group consisting of where * represents the link to the rest of the molecule, R 4represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; wherein the compound of formula (II) has the formula (II), where R 5 represents a hydrogen atom, R 6 a group selected from Ci-C4-alkyl, Cs-Cs-cycloalkyl, (Ci-C2-alkoxy)-(C2-C3-alkyl)- and phenyl, where the C1-C4-alkyl group is optionally substituted, identically or differently, with a phenyl group, where the phenyl group is optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from Ci-Cs-alkyl, Ci-Cs-haloalkyl and Ci-Cs-alkoxy, and wherein the phenyl group is optionally substituted one, two or three times, identically or differently, by a halogen atom or a group selected from Ci-Cs-alkyl, Ci-Cs-haloalkyl and Ci-Cs-alkoxy, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (III) has the formula, and (ii) the intracellular contrast agent is a compound of formula (IV) or a compound of formula (V), wherein the compound of formula (IV) has the formula wherein Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CH2)s, R 7 and R 9 independently represent a hydrogen atom or a -CTROH- group, R 8is a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 10 represents a group consisting of C2-C5-alkoxy, (Ci-C3-alkoxy)-(CH2)2-O-, (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (Ci-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein the Ci-C5-alkoxy and C2-C5-alkoxy groups are optionally substituted one, two, three or four times with a fluorine atom, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; and the compound of formula (V) has the formula Are a group selected from and represents, where # represents the connection to X, X represents a group selected from CH2 and (CH2)2, R 11 represents a hydrogen atom or a group selected from Ci-Cs-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 12a 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-, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

Images