Generation of artificial contrast-enhanced radiographic images

Abstract

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

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to the technical field of generating artificial contrast-enhanced radiological images. [Background technology]

[0002] WO 2019 / 074938 discloses a method for reducing the amount of contrast agent in the production of radiological images using an artificial neural network.

[0003] In the disclosed method, in a first step, a training dataset is created that includes a number of individuals and, for each individual, i) native radiographic images (zero contrast images), ii) radiographic images after administration of a small amount of contrast agent (low contrast images), and iii) radiographic images after administration of a standard amount of contrast agent (full contrast images).

[0004] In the second step, an artificial neural network is trained to predict, for each person in the training dataset, an artificial radiographic image showing the acquisition area after administration of a standard amount of contrast agent, based on the native image and the image after administration of a small amount of contrast agent. The radiographic image measured after administration of the standard amount of contrast agent serves in each case as a reference (ground truth) in the training.

[0005] In the third step, the trained artificial neural network can be used to predict for a new person, based on the native image and the radiological image after administration of a small amount of contrast agent, an artificial radiological image showing the acquired area as it would appear if a standard amount of contrast agent were administered.

[0006] The method disclosed in WO 2019 / 074938 has drawbacks.

[0007] For example, training data is needed to train an artificial neural network: to be able to train the network, a large number of radiological examinations must be performed on a large number of people to generate the training data.

[0008] The artificial neural network disclosed in WO 2019 / 074938 is trained to predict radiological images after administration of a standard amount of contrast agent. The artificial neural network is not configured or trained to predict radiological images after administration of amounts of contrast agent that are less than or greater than the standard amount. The method described in WO 2019 / 074938 could, in principle, be trained to predict radiological images after administration of amounts of contrast agent that differ from the standard amount. However, this requires additional training data and further training. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2019 / 074938 Brochure Summary of the Invention

[0010] It would be desirable to be able to generate radiological images with variable contrast enhancement without having to generate training data for each individual contrast enhancement and without having to train an artificial neural network. Furthermore, it would be desirable to be able to generate radiological images with variable contrast enhancement using a reproducible deterministic process to generate the variable contrast enhancement. This would facilitate the approval and use of corresponding medical procedures while minimizing false negative and false positive results. Machine learning methods typically use statistical models with limited generalizability because they are based on a limited selection of training data. Furthermore, it would be desirable to be able to generate radiological images with variable contrast enhancement using a wide variety of contrast agents. Furthermore, it would be desirable to be able to use a 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. Furthermore, it would be desirable to be able to use a method for generating radiological images with variable contrast enhancement using at least two different contrast agents with different properties, preferably an extracellular contrast agent and an intracellular contrast agent, so as to be able to fully utilize the imaging capabilities of different contrast agents. When different contrast agents are used in a method for generating radiological images with variable contrast enhancement, it would be particularly desirable if the different contrast agents were contained in a single composition and thus could be administered at once. [Means for solving the problem]

[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, the description and the drawings.

[0012] Thus, the present disclosure provides, in a first aspect, receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; A computer-implemented method for generating a contrast-enhanced radiological image is provided, comprising:

[0013] The present disclosure further comprises: processor and; A memory storing an application program configured to perform operations when executed by a processor, the operations including: receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; Including memory and A computer system is provided.

[0014] The present disclosure further provides a method for implementing a program loadable into a working memory of a computer system, the method comprising the steps of: receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; A computer program is provided to execute the above.

[0015] The present disclosure further provides the use of a composition comprising (i) an extracellular imaging agent and (ii) an intracellular imaging agent in a radiological examination, comprising: receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; Provide for use, including

[0016] The present disclosure further provides a composition for use in a radiological examination method, comprising: (i) an extracellular imaging agent; and (ii) an intracellular imaging agent, the composition comprising: receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; A composition comprising:

[0017] The present disclosure further provides a kit comprising a computer program product and a composition comprising (i) an extracellular imaging agent and (ii) an intracellular imaging agent, wherein the computer program product is loadable into a working memory of a computer system and causes the computer system to perform the following steps: receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation a times, where a is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; A kit is provided that includes a computer program for causing the

[0018] The subject matter of the present disclosure will be described in more detail below without distinguishing between the subject matter (method, computer system, computer program (product), use, composition for use, kit). Rather, the following descriptions are intended to apply by analogy to all subject matter, regardless of the context (method, computer system, computer program (product), use, composition for use, kit) in which they occur.

[0019] When steps are described in a sequence in this specification or claims, this does not necessarily mean that the present disclosure is limited to the sequence described. Instead, steps can be performed in a different sequence or in parallel with each other, except when one step is based on another step, thereby making it essential that the step building on the previous step be performed next (however, this will be clear in each individual case). Therefore, the sequence described constitutes a preferred embodiment.

[0020] The present disclosure describes a means for generating one or more artificial radiological images that can vary the contrast between contrast-enhanced and non-contrast-enhanced regions based on at least two representations of an examination region of an examination subject after the addition / administration / use of different amounts of contrast agent.

[0021] A "test subject" is typically an organism, preferably a mammal, most preferably a human.

[0022] An "examination area" is a part of an object under examination, for example an organ or part of an organ or organs or another part of an object under examination.

[0023] For example, the examination area may be the liver, kidney, heart, lung, brain, stomach, bladder, prostate, intestine or part thereof, or another part of the body of a mammal (eg, a human).

[0024] In one embodiment, the examination area comprises a liver or a portion of a liver, or the examination area is a liver or a portion of a liver of a mammal, preferably a human.

[0025] In a further embodiment, the examination area comprises a brain or part of a brain, or the examination area is a brain or part of a brain of a mammal, preferably a human.

[0026] 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.

[0027] In a further embodiment, the examination area comprises the chest or part of the chest, or the examination area is the chest or part of the chest of a mammal, preferably a human.

[0028] In a further embodiment, the examination area comprises a stomach or part of a stomach, or the examination area is a stomach or part of a stomach of a mammal, preferably a human.

[0029] In a further embodiment, the examination area comprises a pancreas or a portion of a pancreas, or the examination area is a pancreas or a portion of a pancreas of a mammal, preferably a human.

[0030] In a further embodiment, the examination area comprises a kidney or part of a kidney, or the examination area is a kidney or part of a kidney of a mammal, preferably a human.

[0031] In a further embodiment, the examination region comprises one or both lungs or portions of lungs of a mammal, preferably a human.

[0032] In a further embodiment, the examination area comprises a breast or a portion of a breast, or the examination area is a breast or a portion of a breast of a female mammal, preferably a human female.

[0033] In a further embodiment, the examination area comprises the prostate gland or a portion of the prostate gland, or the examination area is the prostate gland or a portion of the prostate gland of a male mammal, preferably a human male.

[0034] The examination region, also called the field of view (FOV), is in particular the volume that is imaged in a radiological image. The examination region is typically defined by a radiologist, for example on a localizer image. Of course, the examination region can alternatively or additionally be defined in an automated manner, for example based on a selected protocol.

[0035] The examination area is subjected to radiological examination.

[0036] "Radiology" is a branch of medicine related to the use of electromagnetic and mechanical waves (including, for example, ultrasound) for diagnostic, therapeutic, and / or scientific purposes. In addition to X-rays, other ionizing radiation, such as gamma rays or electrons, is also used. Imaging is an important application, and other imaging methods, such as ultrasound and magnetic resonance imaging (magnetic resonance imaging), also count as radiology, even though these methods do not use ionizing radiation. Thus, the term "radiology" in the context of this disclosure specifically encompasses the following examination methods: computed tomography, magnetic resonance imaging, and ultrasound.

[0037] In one embodiment of the present disclosure, the radiological examination is a magnetic resonance imaging examination.

[0038] In a further embodiment, the radiological examination is a computed tomography examination.

[0039] In one embodiment, the radiological examination is an ultrasound examination.

[0040] In radiological examinations, contrast agents are commonly used for contrast enhancement.

[0041] A "contrast agent" is a substance or mixture of substances that improves the depiction of body structures and functions in a radiological examination.

[0042] In computed tomography, iodine-containing solutions are usually used as contrast agents. In magnetic resonance imaging (MRI), superparamagnetic substances (e.g., iron oxide nanoparticles, superparamagnetic iron-platinum particles (SIPP)) or paramagnetic substances (e.g., gadolinium chelate, manganese chelate) are usually used as contrast agents. In ultrasound examinations, liquids containing gas-filled microbubbles are usually administered intravenously. Examples of contrast agents can be found in the literature (e.g., A.S.L. Jascinth et al.: Contrast Agents in Computed Tomography: A Review, Journal of Applied Dental and Medical Sciences, 2016, Vol. 2, No. 2, pp. 143-149; H. Lusic et al.: X-ray-Computed Tomography Contrast Agents, Chem. Rev. 2013, pp. 113-3, 1641-1666; https: / / www.radiology.wisc.edu / wp-content / uploads / 2017 / 10 / contrast-agents-tutorial.pdf; M.R. Nouh et al.: Radiographic and magnetic resonance contrast agents: Essentials and tips for safe practices, World J Radiol. 2017 Sept. 28; 9(9):339-349; L.C.A. Bonyi et al.: Intravascular Contrast Media in Radiography: Historical Development & Review of Risk Factors for Adverse Reactions). Reactions, South American Journal of Clinical Research, 2016, Vol. 3, No. 1, pp. 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).

[0043] MRI contrast agents exert their effects by altering the relaxation time of the structure in which they are incorporated. Two classes of substances can be distinguished: paramagnetic and superparamagnetic. Both classes of substances have unpaired electrons that induce a magnetic field around individual atoms or molecules. Superparamagnetic contrast agents primarily result in a shortening of T2, while paramagnetic contrast agents primarily result in a shortening of T1. The effect of such contrast agents is indirect, as they do not themselves emit a signal but instead only affect the intensity of signals in their vicinity. An example of a superparamagnetic contrast agent is iron oxide nanoparticles (SPIO, superparamagnetic iron oxide). 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®).

[0044] The present disclosure includes the use of compositions comprising (i) an extracellular imaging agent and (ii) an intracellular imaging agent. Imaging agents are classified as "extracellular" or "intracellular" according to their diffusion pattern in tissue.

[0045] The highly hydrophilic nature of extracellular contrast agents and their low molecular weight result in rapid diffusion into the interstitial space after intravenous administration. After a constant, relatively short period of circulation in the bloodstream, they are excreted via the kidneys.

[0046] Extracellular MRI contrast agents include, for example, the gadolinium chelates gadobutrol (Gadovist®), gadoteridol (Prohance®), gadoteric acid (Dotarem®), gadopentetic acid (Magnevist®), and gadodiamide (Omnican®). Additional extracellular gadolinium-containing contrast agents are described in WO 2016 / 193190 (gadoquatran).

[0047] Intracellular contrast agents are taken up to some extent into the cells of tissue and then excreted.Hepatobiliary contrast agents, for example, have the characteristic of being specifically taken up by liver cells (hepatocytes), accumulating in functional tissue (parenchyma), and enhancing the contrast of healthy liver tissue.An example of a hepatobiliary contrast agent is gadoxetic acid disodium salt (Gd-EOB-DTPA disodium), which is described in U.S. Patent No. 6,039,931 and is commercially available under the trade names Primovist® and Eovist®.Additional hepatobiliary contrast agents are described, inter alia, in International Publication No. WO 2022 / 194777.

[0048] The generation of the artificial radiological image with variable contrast enhancement is based on at least two representations of the examination region, a first representation and a second representation.

[0049] The first representation represents the examination region without contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0050] The second expression represents the test area after administration of a second amount of the composition. The second amount is greater than the first amount (which, as noted, may be zero). The expression "after a second amount of the composition" should not be understood to mean that the first and second amounts of the composition are summed in the test area (unless the first amount is zero). Thus, the expression "represents the test area after administration of a (first or second) amount" should rather be understood to mean "the expression represents the test area with a (first or second) amount" or "the expression represents the test area containing a (first or second) amount."

[0051] If the first amount is not equal to 0, the first and second representations preferably (but not necessarily) represent the examination region at the same time interval from the administration of the contrast agent. If the first amount is equal to 0, the time interval from the moment of administration of the contrast agent can be selected as desired for the second representation.

[0052] Preferably, both the first amount and the second amount of the composition are less than the standard amount. Preferably, the amounts of the individual components of the composition, i.e., the extracellular imaging agent and the intracellular imaging agent, in both the first amount and the second amount of the composition are less than the standard amount.

[0053] Preferably, the ratio of the molar amounts of the individual components of the composition in the first amount and the second amount is equal.

[0054] The standard amount is typically the amount recommended by the manufacturer and / or distributor of the composition and / or components of the composition, and / or the amount approved by a regulatory agency, and / or the amount stated on the package leaflet of the composition and / or components of the composition.

[0055] Thus, for example, the standard dose of Primovist® is 0.025 mmol Gd-EOB-DTPA disodium / kg body weight.

[0056] In one embodiment of the present disclosure, the composition comprises (i) an extracellular imaging agent and (ii) a hepatobiliary imaging agent.

[0057] 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.

[0058] In one embodiment of the present disclosure, the composition is a composition comprising (i) an extracellular imaging agent comprising a paramagnetic metal center and a macrocyclic chelator and (ii) a hepatobiliary imaging agent comprising a paramagnetic metal center and a macrocyclic chelator.

[0059] In one embodiment, the paramagnetic metal center of the extracellular and / or hepatobiliary contrast agent is a lanthanide. Preferably, the paramagnetic metal center of the extracellular and / or hepatobiliary contrast agent is Gd, particularly preferably Gd 3+ is.

[0060] In one embodiment, the extracellular imaging agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), wherein the compound of formula (I) is [ka] (In the formula, [ka] teeth [ka] It is the basis, * denotes R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, [ka] and [ka] is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) has the formula [ka] (In the formula, R 5 is a hydrogen atom, R 6 teeth, C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl), and phenyl is a group selected from the C1-C4 alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally mono-, di- or tri-substituted, identically or differently, by halogen atoms or groups selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The phenyl group is optionally mono-, di- or tri-substituted with, identically or differently, a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) has the formula [ka] It has.

[0061] In one embodiment, the hepatobiliary imaging agent is a compound of formula (IV) or a compound of formula (V), wherein the compound of formula (IV) is [ka] (In the formula, Ar is [ka] and [ka] is a group selected from # is the bond with X, X is a group selected from CH2 and (CH2)3; R 7 and R 9 are each independently a hydrogen atom or a -CHOH group, R 8 is a hydrogen atom, or a C1-C3 alkyl, -CH2OH, a group selected from -(CH2)2OH and -CH2OCH3, R 10 teeth, C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- wherein the C1-C3 alkoxy group and the C2-C5 alkoxy group are optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) has the formula [ka] (In the formula, Ar is [ka] and [ka] is a group selected from # is a bond with X, X is a group selected from CH2 and (CH2)2; R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, —CH2OH, —(CH2)2OH, and —CH2OCH3, R 12 teeth, C2-C5 alkoxy, (H3C-CHO)-(CH2)2-O-, (H3C-CHO)-(CH2)2-O-(CH2)2-O- and (H3C-CHO)-(CH2)2-O-(CH2)2-O-(CH2)2-O- is a group selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0062] In one embodiment of the disclosure, the composition comprises: (i) an extracellular imaging agent of formula (I), formula (II) or formula (III), wherein the compound of formula (I) is [ka] (In the formula, [ka] teeth [ka] It is the basis, * denotes R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, [ka] and [ka] is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) has the formula [ka] (In the formula, R 5 is a hydrogen atom, R 6 teeth, C1-C4 alkyl, C3-C5 cycloalkyl, (C1-C2 alkoxy)-(C2-C3 alkyl), and phenyl is a group selected from the C1-C4 alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally mono-, di- or tri-substituted, identically or differently, by halogen atoms or groups selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; The phenyl group is optionally mono-, di- or tri-substituted with, identically or differently, a halogen atom or a group selected from C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) has the formula [ka] an extracellular imaging agent comprising: and (ii) a hepatobiliary contrast agent of formula (IV) or formula (V), wherein the compound of formula (IV) is of the formula [ka] (In the formula, Ar is [ka] and [ka] is a group selected from # is the bond with X, X is a group selected from CH2 and (CH2)3; R 7 and R 9 are each independently a hydrogen atom or a -CHOH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, —CH2OH, —(CH2)2OH, and —CH2OCH3, R 10 teeth, C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- wherein the C1-C3 alkoxy group and the C2-C5 alkoxy group are optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) has the formula [ka] (In the formula, Ar is [ka] and [ka] is a group selected from # is a bond with X, X is a group selected from CH2 and (CH2)2; R 11 is a hydrogen atom or a group selected from C1-C3 alkyl, —CH2OH, —(CH2)2OH, and —CH2OCH3, R 12 teeth, C2-C5 alkoxy, (H3C-CHO)-(CH2)2-O-, (H3C-CHO)-(CH2)2-O-(CH2)2-O- and (H3C-CHO)-(CH2)2-O-(CH2)2-O-(CH2)2-O- is a group selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0063] In a preferred embodiment of the present disclosure, the composition comprises: (i) a compound of formula (I) [ka] (In the formula, [ka] teeth [ka] It is the basis, * denotes R 1 is a bond with; R 1 is R 3 It is a base; n=4, R 2 is a hydrogen atom, R 3 teeth, [ka] and [ka] is a group selected from * is the bond to the rest of the molecule, R4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, an extracellular imaging agent; and (ii) formula (IV) [ka] (In the formula, Ar is [ka] and [ka] is a group selected from # is the bond with X, X is a group selected from CH2 and (CH2)3; R 7 and R 9 are each independently a hydrogen atom or a -CHOH group, R 8 is a hydrogen atom or a group selected from C1-C3 alkyl, —CH2OH, —(CH2)2OH, and —CH2OCH3, R 10 is a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0064] The term "C1-C2 alkyl" denotes a straight-chain saturated monovalent hydrocarbon radical having one or two carbon atoms, e.g., methyl, ethyl.

[0065] The term "C1-C3 alkyl" denotes a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms, for example methyl, ethyl, n-propyl or isopropyl.

[0066] The term "C1-C4 alkyl" denotes a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3 or 4 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

[0067] The term "C2-C4 alkyl" denotes a linear or branched saturated monovalent hydrocarbon radical having 2, 3, or 4 carbon atoms.

[0068] The term "C1-C2 alkoxy" denotes a straight-chain saturated monovalent group of the formula (C1-C2 alkyl)-O-, where the term "C1-C2 alkyl" is as defined above.

[0069] The term "C1-C3 alkoxy" denotes a linear or branched saturated monovalent radical of the formula (C1-C3 alkyl)-O-, where the term "C1-C3 alkyl" is as defined above.

[0070] The term "C2-C4 alkoxy" denotes a linear or branched saturated monovalent radical of the formula (C2-C4 alkyl)-O-, where the term "C2-C4 alkyl" is as defined above, for example, a methoxy, ethoxy, n-propoxy, or isopropoxy group.

[0071] The term "C2-C5 alkoxy" denotes a linear or branched saturated monovalent radical of the formula (C2-C5 alkyl)-O-, where the term "C2-C5 alkyl" is as defined above.

[0072] The term "C3-C5 cycloalkyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbyl ring containing 3, 4, or 5 carbon atoms. The "C3-C5 cycloalkyl" group is, for example, a monocyclic hydrocarbyl ring, such as a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0073] The term "C1-C3 haloalkyl" refers to a linear or branched saturated monovalent hydrocarbon group in which the term "C1-C3 alkyl" is as defined above and in which one or more hydrogen atoms are replaced by the same or different halogen atoms. Preferably, the halogen atoms are fluorine atoms. The "C1-C3 haloalkyl" group is, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropan-2-yl group.

[0074] In a preferred embodiment of the present disclosure, the composition comprises a compound of formula (i) [ka] or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, and (ii) an extracellular imaging agent of formula [ka] or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

[0075] In one embodiment, the molar amounts of the extracellular contrast agent and the hepatobiliary contrast agent in the composition are the same, or an excess of hepatobiliary contrast agent is present. 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, and more preferably in the range of 1:1 to 1:3.

[0076] In further embodiments, the molar amounts of the extracellular contrast agent and the hepatobiliary contrast agent are the same, or an excess of the extracellular contrast agent is used. Thus, in preferred embodiments, the molar ratio of the extracellular contrast agent to the hepatobiliary contrast agent is in the range of 1:1 to 10:1, preferably in the range of 1:1 to 5:1, and more preferably in the range of 1:1 to 3:1.

[0077] Preferably, the extracellular contrast agent is 3 L·mmol, measured at 1.5 T in plasma or water at 37°C. -1 ·s -1 Preferably, the hepatobiliary contrast agent has a relaxivity of 4 L mmol / L, measured at 1.5 T in plasma or water at 37°C. -1 ·s -1 It has a degree of relaxation of over 100%.

[0078] In a preferred embodiment of the present disclosure, the composition has (i) at least 3 L·mmol as measured at 1.5 T in plasma or water at 37°C. -1 ·s -1 and (ii) an extracellular contrast agent with a relaxivity of at least 4 L·mmol, measured at 1.5 T in plasma or water at 37°C. -1 ·s -1 and a composition comprising a hepatobiliary contrast agent having a relaxivity of 1000 nm or less.

[0079] In a first step, a first representation and a second representation are received or generated.

[0080] The term "receive" encompasses both retrieval of a representation and acceptance of a representation transmitted, for example, to a computer system of the present disclosure. The representation may be received from a computed tomography system, a magnetic resonance imaging system, or an ultrasound scanner. The representation may be read from one or more data memories and / or transmitted from a separate computer system.

[0081] Representations may also be generated as described below.

[0082] Radiological images obtained from radiological examinations (particularly in the case of computed tomography and ultrasound examinations) are typically obtained as representations in real space (also called image space).

[0083] "Real space" is the ordinary three-dimensional Euclidean space that corresponds to the space that humans experience and move through. Therefore, representations of real space are more familiar to people.

[0084] In one embodiment of the present disclosure, the first and second representations received or generated in the first step are representations in real space.

[0085] In a representation in real space, also referred to herein as a real space depiction or real space representation, the examination area is typically represented by a number of image elements (pixels or voxels), which may be, for example, in a raster arrangement, where each image element represents a portion of the examination area and where each image element may be assigned a color or gray value. A format widely used in radiology for storing and processing representations in real space 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 representations in real space are also possible.

[0086] It is possible to perform co-registration of the representations in real space before they are processed as described herein. "Co-registration" (also known in the prior art as "image registration") is used to bring two or more real-space representations of the same examination area into the best possible alignment with one another. One of the real-space representations is defined as the reference image, the other is called the object image. To best fit it to the reference image, a compensatory transformation operation is calculated.

[0087] In one embodiment of the present disclosure, a third representation in real space is generated based on the first and second representations in real space, such third representation also representing at least a portion of the inspection area in real space.

[0088] However, it is also possible that the first and second representations received or generated in the first step are representations in frequency space, in other words, in one embodiment the first and second representations represent the examination region in frequency space.

[0089] "Frequency space" is the domain in which a signal is considered to be the sum of its individual frequency components.

[0090] In a representation in frequency space, also referred to herein as a frequency space representation or frequency space representation, the examination region is represented by a superposition of fundamental frequencies. For example, the examination region can be represented by a sum of sine and / or cosine functions with different amplitudes, frequencies, and phases. The amplitude and phase can be plotted as a function of frequency, for example, in a two-dimensional or three-dimensional representation. Typically, the lowest frequency (the origin) is located in the center. The further away from this center, the higher the frequency. Each frequency can be assigned an amplitude that represents the frequency in the frequency space representation, and a phase that indicates the degree of shift of the respective wave relative to the sine or cosine wave.

[0091] Raw data obtained in a magnetic resonance imaging study (so-called k-space data) is an example of a representation in frequency space. Such raw data (k-space data) from a magnetic resonance imaging study can be directly used as the first and / or second representation in frequency space in the context of the present disclosure.

[0092] Radiological images obtained from radiological examinations (particularly in the case of computed tomography and ultrasound examinations) are typically obtained as representations in real space (also called image space).

[0093] A representation in real space can be transformed into a representation in frequency space, for example by a Fourier transform. Conversely, a representation in frequency space can be transformed into a representation in real space, for example by an inverse Fourier transform. Thus, the term "generating a representation" preferably means that a frequency space representation of the examination area is generated from a real space representation of the examination area by a transform operation, or that a real space representation of the examination area is generated from a frequency space representation of the examination area by a transform operation.

[0094] Details regarding real space and frequency space representations and their respective conversions to and from each other are provided in numerous publications, see for example https: / / see.stanford.edu / materials / lsoftaee261 / book-fall-07.pdf.

[0095] Thus, if the first representation and / or the second representation represent the examination region in real space, the respective real space representation may first be transformed (altered, converted) into a representation in frequency space by a transformation operation (e.g., Fourier transform). In other words, the representation in frequency space may be generated from the representation in real space by a transformation operation (e.g., Fourier transform).

[0096] It is also possible to coregistrate representations in frequency space. Note that the transformation to real space constitutes an additive linear phase ramp in frequency space. However, scaling and rotation are preserved in the Fourier and inverse Fourier transforms, and scaling and rotation in frequency space are also scaling and rotation in real space (see, e.g., S. Skare: Rigid Body Image Realignment in Image Space vs. k-Space, ISMRM SCIENTIFIC WORKSHOP on Motion Correction, 2014, https: / / cds.ismrm.org / protected / Motion_14 / Program / Syllabus / Skare.pdf).

[0097] It should be noted that the coregistration in frequency space does not need to be very accurate, since the high frequencies that map image details and therefore alignment inaccuracies are attenuated by the frequency filter, which is an advantage of the approach described in this disclosure over approaches where the operation is performed in real space.

[0098] In a preferred embodiment of the present disclosure, the first and second representations received or generated in the first step are representations in frequency space.

[0099] 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 third representation also representing at least a portion of the examination region in frequency space.

[0100] Whether the third representation represents at least a portion of the examination region in real space or frequency space, the third representation represents the signal enhancement caused by the second amount of contrast agent in the examination region. In other words, the third representation includes the difference between the second representation and the first representation caused by the second amount of contrast agent. In the third representation in frequency space, each frequency is represented by an amplitude value, and the more strongly a frequency is affected by the second amount of contrast agent, the larger this value becomes. If the third representation is generated in frequency space and not in real space, low frequencies can be weighted, thus enhancing the contrast of the fourth representation in real space.

[0101] In a preferred embodiment, the step of 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 representation and the second representation.

[0102] If the third representation is a representation of the examination region in frequency space, a further step can generate a weighted third representation based on the third representation. As a result of the weighting of the third representation, frequencies that contribute more to contrast are weighted more heavily than frequencies that contribute less to contrast. The term "contrast" refers to the real-space representation corresponding to the frequency-space representation. Contrast information is represented in the frequency-space representation by low frequencies, while higher frequencies represent information about fine structure. Image noise is typically uniformly distributed in the frequency representation. Therefore, the weighted third representation can be generated by applying a frequency-dependent weighting function to the third representation, in which low frequencies are weighted more heavily than high frequencies. The frequency-dependent weighting function has the effect of a filter. The filter increases the signal-to-noise ratio by reducing the spectral noise density at high frequencies.

[0103] Therefore, weighting the third frequency space representation has several advantages. First, the focus is on contrast information, i.e., the features that are emphasized in the resulting fourth frequency space representation are those that result from the increase in contrast due to the second amount of contrast agent. Second, the weighted third frequency space representation can be added multiple times to the third frequency space representation to achieve further increases in contrast without interference and / or noise being emphasized to the same extent as the contrast. [Brief explanation of the drawings]

[0104] [Figure 1] FIG. 10 illustrates an example of a frequency-dependent weighting function that can be used to weight the third representation. [Figure 2] FIG. 10 is a diagram illustrating, in an example form, generating a third representation in real space and a fourth representation in real space based on a first representation in real space and a second representation in real space. [Figure 3]FIG. 10 is a diagram illustrating, in an example form, generating a third representation in frequency space and a fourth representation in frequency space based on a first representation in frequency space and a second representation in frequency space. [Figure 4] 1A-1C are schematic diagrams illustrating various exemplary representations of an examination area of ​​an examination object in real space; [Figure 5] FIG. 1 illustrates a preferred embodiment of the output of an artificial contrast-enhanced radiological image of an examination area by a computer system / computer program. [Figure 6] 1A shows a first representation R1I and a second representation R2I of an examination area of ​​an examination object; [Figure 7] FIG. 1 is an exemplary schematic diagram of a computer system according to the present disclosure. [Figure 8] FIG. 10 is a schematic, exemplary illustration of a further embodiment of a computer system of the present disclosure. [Figure 9] FIG. 1 illustrates, by way of example only, an embodiment of a computer-implemented method of the present disclosure in the form of a flowchart. DETAILED DESCRIPTION OF THE INVENTION

[0105] Figure 1 shows an example of a frequency-dependent weighting function that can be used to weight the third representation. For simplicity, the weighting function is represented as a two-dimensional graph plotting the weighting factor wf (vertical axis) as a function of frequency f (horizontal axis).

[0106] Figure 1(a) shows a weighting function in which the weighting factor decreases exponentially from the center as the frequency increases.

[0107] Figure 1(b) shows a weighting function in which the weighting coefficient decreases linearly from the center as the frequency increases.

[0108] Figure 1(c) shows a weighting function in which the weighting factor decreases in the form of an inverse parabola from the center as the frequency increases.

[0109] FIG. 1(d) shows a weighting function in which the weighting coefficients are constant over a specified range around the center and then decrease exponentially from a threshold frequency.

[0110] FIG. 1(e) shows a weighting function in which the weighting coefficients have a cosine progression around the center.

[0111] FIG. 1(f) shows a weighting function in which the weighting coefficients have a step function transition around the center.

[0112] FIG. 1(g) shows a weighting function whose weighting coefficients have a Gaussian normal distribution function progression around the center.

[0113] FIG. 1(h) shows a weighting function in which the weighting coefficients have a Hann function progression around the center.

[0114] Combinations of the shown weighting functions and further / other weighting functions are possible. Examples of other weighting functions can be found, for example, in: https: / / de.wikipedia.org / wiki / Fensterfunktion#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.

[0115] The weighting functions that can be used are also called window functions in the literature.

[0116] It is preferred to use weighting functions that have proven useful for weighting k-space data in MR imaging and spectroscopy, such as Gaussian or Hann functions (also called Hann or Hanning windows; see, e.g., 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).

[0117] In a further step, a fourth representation is generated by combining the first representation with the third representation, which may be a third representation in real space, a third representation in frequency space, or a weighted third representation in frequency space. Such a combination transfers information about the contrast enhancement provided by the second amount of contrast agent in the examination region to the first representation.

[0118] The combination to generate the fourth representation may be or may include, for example, the addition of the first representation and the third representation (or a weighted third representation). However, multiplicative or nonlinear combinations are also possible. In a preferred embodiment of the present disclosure, generating the fourth representation by combining the first representation with the (weighted) third representation may include adding the (weighted) third representation to the first representation α times, where α (gain factor) is a positive or negative real number, and the third representation may be a third representation in real space, a third representation in frequency space, or a weighted third representation in frequency space. In other words, the (weighted) third representation is multiplied by the gain factor α, and the multiplication result is added to the first representation.

[0119] In a preferred embodiment of the present disclosure, the fourth representation is generated or created by (i) adding the third representation in real space multiplied by a gain factor α to the first representation in real space, (ii) adding the third representation in frequency space multiplied by a gain factor α to the first representation in frequency space, or (iii) adding the weighted third representation in frequency space multiplied by a gain factor α to the first representation in frequency space. The mathematical methods (subtraction, addition, multiplication) typically involve tonal values ​​of individual image elements (pixels, voxels) or amplitude values ​​of individual frequencies (in the case of frequency space representation).

[0120] The gain factor is a real number that can be positive or negative.

[0121] The gain factor indicates the degree to which contrast is enhanced or reduced in the fourth representation.

[0122] This means that a third (weighted) representation can also be added multiple times to the first representation to produce a higher contrast than is shown by the second representation in real space.

[0123] By selecting the gain factor α, it is also possible to achieve contrast enhancement greater than that provided by a standard amount of contrast agent, which is not possible with the method described in WO 2019 / 074938 unless training data is generated by administering to people amounts of contrast agent that are greater than the standard amount and therefore outside the range approved by regulatory authorities.

[0124] It is also possible to choose a gain factor α less than 1, ie the contrast between regions with and without contrast agent is lower in the fourth representation than in the second representation.

[0125] It is also possible to further reduce the contrast by using a negative gain factor α. 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. For example, if the second amount is twice the first amount, and the signal enhancement provided by the contrast agent increases linearly with the amounts, and the first and second representations represent the examination region at the same time intervals from the administration of the first and second amounts, a gain factor of α=−1 will result in a fourth representation that appears as if no contrast agent had been administered.

[0126] It is also possible to select a negative α value so that areas of the examination region that experience contrast agent-induced signal enhancement in the representation generated by the measurement are completely dark (black) in the artificially generated representation.

[0127] The gain factors may be user-selected, i.e., variable, or may be pre-defined, i.e., predetermined.

[0128] It is also possible to determine the gain factors in an automated manner. For example, at least one region within the real-space representation of the first and / or second representations can be defined and / or selected by a user, and the gain factors can be set so that gray values ​​(or different tonal values, in the case of representations other than gray value representations) within the real-space representation have a specified value and / or are above or below a threshold, and / or so that two gray values ​​within two different selected or defined regions are at a specified distance from each other and / or are at a distance from each other that is above or below a threshold. Other criteria can also be used for the automatic determination of the gain factors. The criteria for the automatic determination of the gain factors can be based, for example, on histograms of the first, second, third, weighted third, and / or fourth representations converted to the real-space representations. Such histograms can indicate the number of image elements having a specified tonal or gray value.

[0129] If the fourth representation is a representation of the inspection area in real space, it can be output, i.e., displayed on a screen, printed using a printer, and / or stored in a data memory. It can also be transmitted (e.g., over a network) to another computer system.

[0130] If the fourth representation is a representation of the examination region in frequency space, the frequency space representation can be converted to a real space representation (e.g., by an inverse Fourier transform). The real space representation can then be output, i.e., displayed on a screen, printed using a printer, and / or stored in a data memory. It can also be transmitted (e.g., over a network) to another computer system.

[0131] FIG. 2 illustrates, in an example form, the generation of a third representation in real space and a fourth representation in real space based on a first representation in real space and a second representation in real space.

[0132] Figure 2 shows various representations of the examination area to be examined. The examination area shown in Figure 2 includes a pig liver.

[0133] The first representation R1 represents the examination region in real space without contrast agent. The first representation R1 is a magnetic resonance image.

[0134] The second representation R2 represents the same examination region of the same object as the first representation R1, also in real space. The second representation R2 is also a magnetic resonance image.

[0135] The second representation R2 represents the examination region after administration 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 μmol / kg body weight of the extracellular contrast agent and 10 μmol / kg body weight of the intracellular contrast agent. The composition was administered intravenously to the subject. The second representation R2 represents the examination region in the so-called portal venous phase after administration of the contrast agent.

[0136] A third representation R3 is generated based on the first representation R1 and the second representation R2. In the example shown in Figure 2, the third representation R3 is the difference between the second representation R2 and the first representation R1.

[0137] In the third representation R3, negative tonal values ​​that may result when subtracting the first representation from the second representation may be set to 0 (or another value) to avoid negative values.

[0138] A third representation R3 represents the contrast enhancement provided in the examination region by the second amount of contrast agent.

[0139] The third representation R3 is multiplied by a gain factor α and the result is added to the first representation R1, thereby generating the fourth representation R4. In the example shown in Figure 2, the gain factor α=3, i.e., the third representation R3 is added to the first representation R1 three times.

[0140] The fourth representation R4 may be subjected to normalization, i.e., the tonal values ​​may be multiplied by a factor so that the tonal values ​​with the highest values ​​are represented, for example, by the hue "white" and the tonal values ​​with the lowest values ​​are represented, for example, by the hue "black".

[0141] FIG. 3 illustrates, in an example form, the generation of a third representation in frequency space and a fourth representation in frequency space based on a first representation in frequency space and a second representation in frequency space.

[0142] Figure 3 shows various representations of the examination area to be examined. The examination area shown in Figure 3 includes a pig liver.

[0143] First Representation R1 I represents the examination region in real space without contrast agent. I is a magnetic resonance image.

[0144] First real space representation R1 Iis a first representation R1 of the examination region in frequency space by a transformation operation T, e.g., a Fourier transform. F The first frequency space representation R1 F is the first real space representation R1, also without contrast agent. I represents the same inspection area of ​​the same inspection object.

[0145] First frequency space representation R1 F is the inverse transformation operation T -1 The first real space representation R1 I The inverse transformation operation T -1 is the inverse transform of the transform operation T.

[0146] Second representation R2 I is the first representation in real space R1 I The second expression R2 represents the same test area of ​​the same test object. I is also a magnetic resonance image. The second real-space representation R2 I represents the examination area after administration 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 contained 10 μmol / kg body weight of the extracellular contrast agent and 10 μmol / kg body weight of the hepatobiliary contrast agent. A second expression R2 I represents the examined area 15 minutes after injection of the composition in the so-called hepatobiliary phase. I In this case, the contrast between the liver tissue and the surrounding tissue is enhanced as a result of the amount of composition administered.

[0147] Second real space representation R2 I is the second representation R2 of the test region in frequency space by the transformation operation T. F The second frequency space representation R2 F Similarly, after administration of the composition, the second real space representation R2 I represents the same inspection area of ​​the same inspection object.

[0148] The second frequency space representation R2 F is the inverse transformation operation T -1The second real space representation R2 I can be converted to

[0149] First frequency space representation R1 F and the second frequency space representation R2 F The third frequency space representation R3 is based on F In the example shown in FIG. 3, a third frequency space representation R3 F is the second frequency space representation R2 F and the first frequency space representation R1 F is the difference between (R3 F =R2 F -R1 F ).

[0150] The third frequency space representation R3 F may be subjected to normalization, i.e. the amplitude values ​​may be multiplied by a factor so that the amplitude with the highest value is represented, for example, by the hue "white" and the amplitude with the lowest value is represented, for example, by the hue "black".

[0151] Such normalization also allows for avoiding negative values ​​that may arise when subtracting the first representation from the second representation by setting them to 0 (or another value).In Figure 3, all frequency space representations are shown in the same logarithmic grayscale.

[0152] The third frequency space representation R3 F represents the contrast enhancement provided in the examination area by the administered amount of composition.

[0153] In Figure 3, the weighting function WF is expressed as a third frequency space representation R3 F to obtain the weighted third expression R3 F,w It is further shown that the weighting function in this case is a Gaussian weighting function.

[0154] Third Representation R3 FAs a result of this weighting, frequencies that contribute more to contrast are weighted more heavily than frequencies that contribute less to contrast. The term "contrast" refers to the real-space representation that corresponds to the frequency-space representation. Contrast information is represented in the frequency-space representation by low frequencies, while higher frequencies represent information about fine structure. Image noise is typically uniformly distributed in the frequency representation. Therefore, a weighted third representation in frequency space can be generated by applying a frequency-dependent weighting function to the third representation in frequency space, in which low frequencies are weighted more heavily than high frequencies. The frequency-dependent weighting function has the effect of a filter. The filter increases the signal-to-noise ratio by reducing the spectral noise density at high frequencies.

[0155] Weighted third representation R3 F,w To generate the third frequency space representation R3 F The amplitude values ​​of are multiplied by the weighting factors of a weighting function. The weighting factors are frequency dependent, i.e., they are functions of frequency. For illustrative purposes, the weighting function WF is shown in two-dimensional form in Figure 1. The weighting function WF shows the weighting factors wf as a function of frequency along one dimension.

[0156] The WF weighting function is the amplitude of the low frequencies (in the example shown, the frequency is expressed as R3 F The amplitude of the high frequency (expressed as R3) increases from the center to the outside. F This means that gray values ​​towards the edge of the representation are weighted higher than those towards the center of the representation R3. F The overall brightness is darker than in the R3 F The weighted representation R3 F,w It can be recognized in.

[0157] In FIG. 3, a fourth representation R4 of the test area of ​​the test object in frequency space is F is the first frequency space representation R1 Fand the weighted third frequency space representation R3 F,w In this example, this combination is shown to be generated by a weighted third frequency space representation R3 F,w is multiplied by a gain factor α and the result is expressed as a first frequency space representation R1 F In the example shown in FIG. 3, the gain factor α=3, i.e., the weighted third frequency space representation R3 F,w is the first frequency space representation R1 F is added three times.

[0158] Fourth Representation R4 F can be subjected to normalization.

[0159] In FIG. 3, a fourth representation R4 of the test area of ​​the test object in frequency space is F is the representation of the inspection area of ​​the inspection object in real space R4 I It has further been shown that

[0160] 4 shows, by way of example, various representations of the examination area of ​​the examination object in real space. The representations differ by a gain factor α, which in this example can take the values ​​0, 1, 2, 3, and 4. The representations were generated in the manner described in connection with FIG. 3. This means that subtractions and additions were performed in frequency space, and weighting was performed.

[0161] A gain factor of α=0 means that no contrast enhancement is performed in the first representation, so the representation shows the original first representation in real space.

[0162] A gain factor of α=1 means that the weighted third frequency-space representation is added once to the first representation in frequency space. The contrast enhancement is similar to that in the corresponding second real-space representation, but with less noise / interference due to the stronger weighting given to low frequencies.

[0163] A gain factor of α=2, 3, or 4 means that the weighted third frequency-space representation is added two, three, or four times to the first representation in frequency space. Contrast enhancement increases as the gain factor increases.

[0164] In the example shown in Figure 4, in all cases, an integer weighted third frequency space representation is added to the first representation. As will be described, it is also possible to add a non-integer weighted third frequency space representation to the first representation (e.g., α = 1.5 or α = 3.7 or α = 4.159). This means that the emphasis can be continuously increased.

[0165] 5 illustrates a preferred embodiment of the output of an artificial contrast-enhanced radiological image of an examination region by a computer system / computer program, the output being provided to a user of the computer system and / or computer program of the present disclosure.

[0166] a first representation R1 of the inspection area of ​​the inspection object; I , a second representation R2 of the inspection area of ​​the inspection object I , and a predicted fourth representation R4 of the test region of interest I is displayed to the user (e.g., on a monitor).

[0167] First Representation R1 I represents the examination area without contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent.

[0168] Second representation R2 I represents the test area after administration of a second amount of the composition, the second amount being greater than the first amount.

[0169] Fourth Representation R4 I represents the examination region with enhanced contrast. The contrast between the region without contrast and the region with contrast is given by the second expression R2 I In the case of the fourth expression R4 IIn this case, it is large.

[0170] Fourth Representation R4 I was generated as described in connection with FIG.

[0171] All displayed representations are representations of the examination area in real space. In the example shown in Figure 5, the frequency space representation is not displayed to the user. This is usually not expected, as many users are unfamiliar with frequency space representations.

[0172] Displayed representation R1 I , R2 I and R4 I Below, a histogram of the representation is displayed to the user as an overlaid histogram.

[0173] Displayed representation R1 I , R2 I and R4 I Above the slider, the user is provided with three virtual sliders that the user can adjust. The first slider, α, allows the user to freely select a gain factor in the range of 1 to 10. The slider indicates that the gain factor can be increased continuously from 1 to 10.

[0174] The second slider β and the third slider γ allow the user to change the parameters of the weighting function, which can determine, for example, how much the weighting factor decreases with increasing frequency.

[0175] The output shown in FIG. 5 preferably changes as the user makes changes via one of the sliders to a fourth representation R4 I As a result, if the user changes the gain coefficient α, for example, the change in the gain coefficient is reflected in the display R4. I This allows the user to select the optimal fourth representation R4 of the inspection area. I It is possible to identify settings that result in

[0176] Any change to one of the parameters α, β and / or γ can be expressed as a fourth expression R4 I The fourth expression R4 is obtained by using one or more parameters modified for the sole purpose of background calculation and display of the fourth expression R4. I The same is true for the histogram of

[0177] Contrast enhancement in frequency space according to this disclosure so far may result in contrast enhancement that is undesirable for the user. This is illustrated by an example, which is shown schematically in FIG. 6.

[0178] FIG. 6 shows a first representation R1 of the inspection area of ​​the object to be inspected. I and the second representation R2 I The examination area includes the pig liver L and gallbladder B. The first representation R1 I represents the examination region without contrast agent in real space. The second representation R2 I represents the examination region after administration of the composition comprising the extracellular and intracellular contrast agents in real space. I , it can be seen that the gallbladder is partially filled, for example, with a fluid containing one or both contrast agents or another fluid, resulting in high contrast between the partially filled gallbladder and the surrounding area.

[0179] The contrast enhancement described in the previous disclosure is an artificial contrast-enhanced radiographic image R4 of the examination area. I , further enhancing the contrast between the partially filled gallbladder and other areas, however, the user may be more interested in contrast enhancement of the liver.

[0180] In a preferred embodiment, the computer system and computer program of the present disclosure are configured to receive input from a user. In the input, the user can specify one or more regions where contrast enhancement is not desired. The user can draw such regions in the first, second, and / or fourth representation in real space, for example, using a mouse or another input means. For example, in the example shown in FIG. 6, the user can draw a region in the first representation R1 I , the second representation R2 I and / or the fourth representation R4 I The gallbladder can be selected and / or highlighted in the representation R2. The computer system and computer program can be configured to set the tonal or grey value of all image elements (pixels, voxels) representing the (highlighted) gallbladder to 0. The result is a representation R2 where the gallbladder is represented by black image elements. I* As described in this disclosure, the expression R1 I and R2 I* (or their corresponding frequency space representations), this results in an artificial contrast-enhanced radiographic image R4 I* , where there is increased contrast especially between the liver L and other areas, but the partially filled gallbladder is no longer shown with enhanced contrast.

[0181] In a preferred embodiment, the regions where contrast is not (is) enhanced are determined in an automated manner. Preferably, the quotient of the tonal values ​​is calculated based on the first real space representation R1 I and the second real space representation R2 I is determined for all pairs of corresponding image elements (i.e., having the same coordinates): Q=g2(x,y,z) / g1(x,y,z) where Q is the quotient of the tonal values ​​and g2(x,y,z) is the second representation R2 I is the tonal value of the image element with coordinates x, y, z in the first representation R1, and g1(x,y,z) is the tonal value of the image element with coordinates x, y, z in the first representation R1. I(The quotient Q of the tonal values ​​is a measure of how brightly the image element with coordinates x, y, z appears in the second representation compared to the corresponding image element in the first representation. This specifies the contrast enhancement provided by the second amount of the composition in the examination area represented by the image element with coordinates x, y, z.)

[0182] The computer system and computer program may be configured to compare the quotient of the tonal values ​​of all image elements with a predetermined threshold value that specifies the maximum contrast enhancement expected due to the contrast agent present in the composition.

[0183] If the quotient of the tonal values ​​of the corresponding image elements is greater than a predetermined threshold, the tonal value of the corresponding image element can be set to zero.

[0184] FIG. 7 illustrates an exemplary schematic of a computer system according to the present disclosure.

[0185] A "computer system" is an electronic data processing system that processes data according to programmable computational rules. Such a system typically includes a "computer," which is a unit that includes a processor and peripheral devices for performing logical operations.

[0186] In computer technology, a "peripheral" refers to any device that is connected to a computer and used to control the computer and / or as an input / output device. Examples are monitors (screens), printers, scanners, mice, keyboards, drives, cameras, microphones, speakers, etc. Internal ports and expansion cards are also considered peripherals in computer technology.

[0187] The computer system (1) shown in FIG. 7 comprises an input unit (10), a control and calculation unit (20) and an output unit (30).

[0188] The control and calculation unit (20) is used to control the computer system (1), coordinate the data flow between the units of the computer system (1), and perform calculations.

[0189] The control and calculation unit (20) causing the receiving unit (10) to receive a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; causing the receiving unit (10) to receive a second representation representing the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, and subtracting the first representation from the second representation; generating a fourth representation based on the first representation and the third representation, and adding the third representation to the first representation α times, where α is a positive or negative real number; causing the output unit (30) to output the representation of the inspection area and / or store it and / or transmit it to a separate computer system; It is configured as follows.

[0190] FIG. 8 illustrates, by way of example, a further embodiment of a computer system of the present disclosure.

[0191] 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 calculation unit, as shown in FIG.

[0192] The processing unit (21), alone or in combination with one or more memories, may constitute one or more processors. The processing unit (21) may be standard computer hardware capable of processing information such as digital images, computer programs, and / or other digital information. The processing unit (21) typically consists of an arrangement of electronic circuits, some of which may be designed as an integrated circuit or as multiple integrated circuits connected together (integrated circuits are sometimes called "chips"). The processing unit (21) may be configured to execute computer programs, which may be stored in the working memory of the processing unit (21) or in memory (22) of the same or a different computer system.

[0193] The memory 22 may be conventional computer hardware capable of temporarily and / or permanently storing information, such as digital images (e.g., representations of an examination area), data, computer programs, and / or other digital information. The memory 22 may comprise volatile and / or nonvolatile memory and may be non-removable or removable. Examples of suitable memory are RAM (random access memory), ROM (read-only memory), hard disk, flash memory, removable computer floppy disk, optical disk, magnetic tape, or combinations of the foregoing. Optical disks may include compact disks with read-only memory (CD-ROM), compact disks with read / write capability (CD-R / W), DVDs, Blu-ray disks, etc.

[0194] The processing unit (21) may be connected to one or more interfaces (11, 12, 31, 32, 33) as well as the memory (22) for displaying, transmitting, and / or receiving information. The interfaces may include one or more communication interfaces (32, 33) and / or one or more user interfaces (11, 12, 31). The one or more communication interfaces may be configured to transmit and / or receive information to and / or from, for example, an MRI scanner, a CT scanner, an ultrasound camera, another computer system, a network, a data memory, etc. The one or more communication interfaces may 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 using technologies such as cellular, Wi-Fi, satellite, cable, DSL, fiber optics, etc. In some examples, the one or more communication interfaces may include one or more short-range communication interfaces configured to connect devices with short-range communication technologies such as NFC, RFID, Bluetooth, Bluetooth LE, ZigBee, infrared (e.g., IrDA), etc.

[0195] The user interface may include a display (31). The 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 panel (PDP), etc. The user input interfaces (11, 12) may be wired or wireless and may be configured to receive information from a user, for example, for processing, storage, and / or display within the computer system (1). Suitable examples of user input interfaces include a microphone, an image or video recording device (e.g., a camera), a keyboard or keypad, a joystick, a touch-sensitive surface (separate from or integrated within a touchscreen), etc. In some examples, the user interface may include automatic identification and data capture technology (AIDC) for machine-readable information. This may include barcodes, radio frequency identification (RFID), magnetic strips, optical character recognition (OCR), integrated circuit cards (ICC), etc. The user interface may also include one or more interfaces for communicating with peripheral devices, such as a printer.

[0196] One or more computer programs (40) may be stored in memory (22) and executed by processing unit (21), thereby programmed to perform the functions described herein. Retrieval, loading, and execution of instructions in computer programs (40) may be performed sequentially, such that instructions are retrieved, loaded, and executed, respectively. However, retrieval, loading, and / or execution may also occur in parallel.

[0197] The computer system of the present disclosure may be designed as a laptop, notebook, netbook, and / or tablet PC, which may also be a component of an MRI scanner, a CT scanner, or an ultrasound machine.

[0198] FIG. 9 illustrates, by way of example, an embodiment of a computer-implemented method of the present disclosure in the form of a flowchart.

[0199] The method (100) comprises the following steps: (110) receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; (120) receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; (130) generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; (150) generating a fourth representation, the fourth representation including adding the third representation to the first representation α times, where α is a positive or negative real number; (170) outputting and / or storing the representation of the inspection area and / or transmitting the representation of the inspection area to a separate computer system; Includes.

[0200] The present invention can be used for a variety of purposes, some examples of which are described below, but which are not intended to limit the invention to these examples.

[0201] The first use case concerns magnetic resonance imaging (MRI) for distinguishing between intracerebral metastases and intraparenchymal tumors, such as malignant gliomas. The infiltrative growth of these tumors makes it difficult to accurately distinguish tumor tissue from healthy tissue. However, determining the extent of the tumor is crucial for surgical resection. The distinction between tumor and healthy tissue is facilitated by the administration of an extracellular MRI contrast agent; after intravenous administration of the extracellular MRI contrast agent gadobutrol at a standard dose of 0.1 mmol / kg body weight, intraparenchymal tumors can be distinguished much more easily. Higher doses further increase the contrast between lesions and healthy brain tissue. The detection rate of brain metastases increases linearly with the dose of the 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).

[0202] A single triple dose or two subsequent doses may now be administered up to a total dose of 0.3 mmol / kg body weight, exposing the patient and environment to additional gadolinium and incurring further additional costs in the case of a second scan.

[0203] The present invention can be used to avoid exceeding the standard dose of contrast agent. A first MRI image can be generated without contrast agent or with a lower-than-standard dose, and a second MRI image can be generated with the standard dose. Based on these generated MRI images, a synthetic MRI image can be generated in which the contrast between the lesion and healthy tissue can be varied within a wide range by changing the gain coefficient α, as described in this disclosure. This makes it possible to achieve contrast that would otherwise be achievable only by administering a higher-than-standard dose of contrast agent.

[0204] Another use case involves reducing the amount of MRI contrast agents used in magnetic resonance imaging (MRI). Gadolinium-containing contrast agents, such as gadobutrol, are used in numerous examinations. They are used for contrast enhancement in skull, spine, breast, and other examinations. In the central nervous system, gadobutrol highlights areas where the blood-brain barrier is compromised and / or blood vessels are abnormal. 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 stroke, detect tumor blood perfusion, and detect focal cerebral ischemia.

[0205] Due to concerns about increased environmental impact, costs to the healthcare system, and potential acute side effects and long-term health risks, a reduction in the dose of gadolinium-containing contrast agents is desirable, especially in the case of repeated, prolonged exposure, which can be achieved by the present invention.

[0206] A first MRI image can be generated without contrast agent and a second MRI image can be generated with a substandard amount of contrast agent. Based on these generated MRI images, a composite MRI image can be generated in which the contrast can be varied within a wide range by varying the gain factor α, as described in this disclosure. This allows the same contrast to be achieved with a substandard amount of contrast agent as that obtained after administration of a standard amount.

[0207] Another example use relates to the detection, identification and / or characterization of liver lesions using hepatobiliary contrast agents such as Primovist®.

[0208] Primovist® is administered intravenously (iv) at a standard dose of 0.025 mmol / kg body weight, which is lower than the standard dose of 0.1 mmol / kg body weight for extracellular MRI contrast agents. Unlike contrast-enhanced MRI using extracellular gadolinium-containing contrast agents, Primovist® allows dynamic multiphase T1w imaging. However, the low dose of Primovist® and the observation of transient motion artifacts that can occur immediately after intravenous administration mean that contrast enhancement with Primovist® in the arterial phase is perceived by radiologists as less effective than that with extracellular MRI contrast agents. However, assessment of arterial phase contrast enhancement and the vascularity of focal liver lesions is crucial for accurate characterization of the lesions.

[0209] With the aid of the present invention it is possible to increase the contrast, especially in the arterial phase, without the need to administer higher doses.

[0210] A first MRI image without contrast agent and a second MRI image during the arterial phase after administration of an amount of contrast agent equivalent to the standard amount can be generated. Based on these generated MRI images, a synthetic MRI image can be generated in which the contrast in the arterial phase can be varied within a wide range by changing the gain coefficient α, as described in this disclosure. This makes it possible to achieve contrast that would otherwise be achievable only by administering a larger amount of contrast agent than the standard amount.

[0211] Another example use relates to the use of MRI contrast agents in computed tomography examinations.

[0212] In CT examinations, MRI contrast agents typically have a lower contrast-enhancing effect than CT contrast agents. However, using MRI contrast agents in CT examinations can be advantageous. One example is minimally invasive interventions in a patient's liver, where the surgeon monitors the procedure using a CT scanner. Computed tomography (CT) has the advantage over magnetic resonance imaging (MRI) in that it allows for larger surgical interventions in the examined area while generating CT images of the area. In contrast, few surgical instruments and devices are MRI-compatible. Furthermore, access to the patient is limited by the magnets used in MRI. Therefore, the surgeon can visualize the examination area using CT and follow the procedure on a monitor while performing the procedure in the examination area.

[0213] For example, when a surgeon wants to perform a procedure on a patient's liver, for example, to perform a biopsy on a liver lesion or to remove a tumor, the contrast between liver lesions or tumors and healthy liver tissue is not as pronounced in the CT image of the liver as in the MRI image after administering a hepatobiliary contrast agent.Currently, there is no known and / or approved CT-specific hepatobiliary contrast agent for CT.Therefore, the use of MRI contrast agents in computed tomography, more particularly hepatobiliary MRI contrast agents, combines the possibility of distinguishing between healthy liver tissue and diseased liver tissue and the possibility of performing surgery with simultaneous visualization of the liver.

[0214] The relatively low contrast enhancement achieved by MRI contrast agents can be increased with the aid of the present invention without the need to administer higher than standard doses.

[0215] A first CT image can be generated without the MRI contrast agent and a second CT image can be generated after administering an amount of the MRI contrast agent equivalent to the standard amount. Based on these generated CT images, a composite CT image can be generated in which the contrast produced by the MRI contrast agent can be varied over a wide range by varying the gain factor α, as described in this disclosure. This makes it possible to achieve contrast that would otherwise be achievable only by administering an amount of the MRI contrast agent that is greater than the standard amount. [Explanation of symbols]

[0216] 1. Computer Systems 10 Input unit, receiving unit 11 User Input Interface 12 User Input Interface 20 Control and Computation Unit 21 Processing Unit 22 Memory 30 output units 31 Display 32 Communication Interface 33 Communication Interface 40 Computer Programs 100 ways

Claims

1. receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation α times, where α is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; 11. A computer-implemented method comprising:

2. The method of claim 1 , wherein the first representation and the second representation represent the examination region in real space.

3. The method of claim 1 , wherein the first and second representations represent the examination region in frequency space.

4. said step of generating said fourth representation further comprising: adding the third representation to the first representation α times and transforming the result into real space; 4. The method of claim 3, comprising:

5. said generating said third representation further comprising: applying a frequency dependent weighting function to the result of subtracting the first representation from the second representation.

5. The method of claim 3 or 4, comprising:

6. said generating said third representation further comprising: generating a weighted third representation by applying a frequency dependent weighting function to the result of subtracting the first representation from the second representation; 5. The method of claim 3 or 4, comprising:

7. receiving a first real-space representation of the examination region of the examination subject in real space without a contrast agent or after administration of the first amount of the composition; transforming the first real space representation into the first representation of the test area of ​​the test object in frequency space; receiving a second real-space representation of the test area of ​​the test subject in real space after administration of the second amount of the composition; transforming the second real space representation into the second representation of the test area of ​​the test object in frequency space; 7. The method of claim 1, further comprising:

8. 8. The method of claim 1, wherein α is greater than 1.

9. 9. The method of claim 5, wherein applying the frequency-dependent weighting function to the third representation causes amplitude values ​​having low frequencies to be multiplied by a larger weighting factor than amplitude values ​​having high frequencies.

10. 9. The method of claim 5, wherein applying the frequency-dependent weighting function to the third representation comprises multiplying amplitude values ​​by a window function, the window function being a Gaussian distribution function, a Hann function, or a Poisson function.

11. receiving one or more values ​​of α from a user; 11. The method of any one of claims 1 to 10, further comprising:

12. receiving a first tonal value of a first image element of the first representation or a real space depiction of the second representation; receiving second tonal values ​​of a second image element of the first representation or a real space depiction of the second representation; determining a value of α such that the difference between the first tonal value and the second tonal value is a predetermined value or is above or below a predetermined threshold; 11. The method of any one of claims 1 to 10, further comprising:

13. receiving a highlight of an area within the real space depiction of the second representation; setting the tonal values ​​of the regions in the real space representation of the second representation to zero, thereby generating a modified second real space representation; generating said second representation in frequency space from said modified second real space representation; 11. The method of claim 3, further comprising:

14. determining first tonal values ​​for all image elements of a first real space depiction of said first representation; determining second tonal values ​​for all image elements of a second real space depiction of said second representation; determining a quotient of the second tonal value and the first tonal value for all corresponding image elements of the first real space representation and the second real space representation; setting the tonal values ​​of the second real space representations where the quotient is greater than a predetermined threshold to zero, thereby generating a modified second real space representation; generating said second representation in frequency space from said modified second real space representation; 11. The method of claim 3, further comprising:

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

16. 16. The method according to any one of claims 1 to 15, wherein the test subject is an organism, preferably a mammal, most preferably a human.

17. 16. The method according to any one of claims 1 to 15, wherein the examination area comprises the liver, kidneys, heart, lungs, brain, stomach, bladder, prostate, intestines and / or parts thereof, and / or another / further part of the human body.

18. (i) The extracellular imaging agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), and the compound of formula (I) is 【Chemistry 1】 (In the formula, 【Chemistry 2】 teeth 【Transformation 3】 It is the basis, * indicates R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, 【Chemistry 4】 and 【Transformation 5】 is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) is represented by the formula 【Transformation 6】 (In the formula, R 5 is a hydrogen atom, R 6 teeth, C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl, (C 1 ~C 2 Alkoxy)-(C 2 ~C 3 alkyl) and phenyl is a group selected from Said C 1 ~C 4 The alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally substituted, identically or differently, by halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 alkoxy; The phenyl groups may optionally be the same or different and may be halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkoxy is mono-, di- or trisubstituted with groups selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) is represented by the formula 【Transformation 7】 and (ii) the intracellular imaging agent is a compound of formula (IV) or a compound of formula (V), and the compound of formula (IV) is 【Transformation 8】 (In the formula, Ar is 【Chemistry 9】 and 【Chemistry 10】 is a group selected from ＃ is the bond with X, X is CH 2 and (CH 2 ) 3 is a group selected from R 7 and R 9 are each independently a hydrogen atom or -CH 2 is an OH group, R 8 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 10 teeth, C 2 ~C 5 Alkoxy, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- wherein C is a group selected from 1 ~C 3 Alkoxy groups and C 2 ~C 5 The alkoxy group is optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) is represented by the formula 【Chemistry 11】 (In the formula, Ar is 【Chemistry 12】 and 【Chemistry 13】 is a group selected from # is a bond with X, X is CH 2 and (CH 2 ) 2 is a group selected from R 11 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 12 teeth, C 2 ~C 5 Alkoxy, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- is a group selected from 18. The method of any one of claims 1 to 17, wherein the compound has a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

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

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

21. receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation α times, where α is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; 1. Use of a composition comprising (i) an extracellular contrast agent and (ii) an intracellular contrast agent in a radiological examination method comprising:

22. The radiological examination method is magnetic resonance imaging, (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), and the compound of formula (I) is 【Chemistry 14】 (In the formula, 【Chemistry 15】 teeth 【Chemistry 16】 It is the basis, * indicates R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, 【Chemistry 17】 and [Chemistry 18] is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) is represented by the formula 【Chemistry 19】 (In the formula, R 5 is a hydrogen atom, R 6 teeth, C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl, (C 1 ~C 2 Alkoxy)-(C 2 ~C 3 alkyl) and phenyl is a group selected from Said C 1 ~C 4 The alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally substituted, identically or differently, by halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 alkoxy; The phenyl groups may optionally be the same or different and may be halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkoxy is mono-, di- or trisubstituted with groups selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) is represented by the formula 【Chemistry 20】 and (ii) the intracellular imaging agent is a compound of formula (IV) or a compound of formula (V), and the compound of formula (IV) is 【Chemistry 21】 (In the formula, Ar is 【Chemistry 22】 and 【Chemistry 23】 is a group selected from ＃ is the bond with X, X is CH 2 and (CH 2 ) 3 is a group selected from R 7 and R 9 are each independently a hydrogen atom or -CH 2 is an OH group, R 8 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 10 teeth, C 2 ~C 5 Alkoxy, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- wherein C is a group selected from 1 ~C 3 Alkoxy groups and C 2 ~C 5 The alkoxy group is optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) is represented by the formula 【Chemistry 24】 (In the formula, Ar is 【Chemistry 25】 and 【Chemistry 26】 is a group selected from # is a bond with X, X is CH 2 and (CH 2 ) 2 is a group selected from R 11 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 12 teeth, C 2 ~C 5 Alkoxy, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- is a group selected from 22. The use according to claim 21, wherein the compound has a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

23. receiving or generating a first representation of an examination region of an examination subject without a contrast agent or after administration of a first amount of a composition; receiving or generating a second representation of the test area of ​​the test subject after administration of a second amount of the composition, the second amount being greater than the first amount; generating a third representation based on the first representation and the second representation, the third representation comprising subtracting the first representation from the second representation; generating a fourth representation comprising adding the third representation to the first representation α times, where α is a positive or negative real number; outputting and / or storing the fourth representation of the inspection area and / or transmitting the fourth representation of the inspection area to a separate computer system; 1. A composition comprising (i) an extracellular imaging agent and (ii) an intracellular imaging agent for use in a radiological examination method comprising:

24. The radiological examination method is magnetic resonance imaging, (i) the extracellular contrast agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), and the compound of formula (I) is 【Chemistry 27】 (In the formula, 【Chemistry 28】 teeth 【Chemistry 29】 It is the basis, * indicates R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, 【Transformation 30】 and 【Chemistry 31】 is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) is represented by the formula 【Chemistry 32】 (In the formula, R 5 is a hydrogen atom, R 6 teeth, C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl, (C 1 ~C 2 Alkoxy)-(C 2 ~C 3 alkyl) and phenyl is a group selected from Said C 1 ~C 4 The alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally substituted, identically or differently, by halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 alkoxy; The phenyl groups may optionally be the same or different and may be halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkoxy is mono-, di- or trisubstituted with groups selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) is represented by the formula 【Transformation 33】 and (ii) the intracellular imaging agent is a compound of formula (IV) or a compound of formula (V), and the compound of formula (IV) is 【Transformation 34】 (In the formula, Ar is 【Chemistry 35】 and 【Transformation 36】 is a group selected from ＃ is the bond with X, X is CH 2 and (CH 2 ) 3 is a group selected from R 7 and R 9 are each independently a hydrogen atom or -CH 2 is an OH group, R 8 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 10 teeth, C 2 ~C 5 Alkoxy, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- wherein C is a group selected from 1 ~C 3 Alkoxy groups and C 2 ~C 5 The alkoxy group is optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) is represented by the formula 【Chemistry 37】 (In the formula, Ar is 【Transformation 38】 and 【Chemistry 39】 is a group selected from # is a bond with X, X is CH 2 and (CH 2 ) 2 is a group selected from R 11 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 12 teeth, C 2 ~C 5 Alkoxy, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- is a group selected from 24. The composition for use according to claim 23, having a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

25. 21. A kit comprising the computer program product of claim 20 and a composition comprising an extracellular imaging agent and an intracellular imaging agent.

26. (i) The extracellular imaging agent is a compound of formula (I), a compound of formula (II), or a compound of formula (III), and the compound of formula (I) is 【Chemistry 40】 (In the formula, 【Chemistry 41】 teeth 【Chemistry 42】 It is the basis, * indicates R 1 It is a combination with R 1 is R 3 It is the basis, n=4, R 2 is a hydrogen atom, R 3 teeth, 【Chemistry 43】 and 【Chemistry 44】 is a group selected from * is the bond to the rest of the molecule, R 4 is a hydrogen atom or a methyl group) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (II) is represented by the formula 【Chemistry 45】 (In the formula, R 5 is a hydrogen atom, R 6 teeth, C 1 ~C 4 Alkyl, C 3 ~C 5 Cycloalkyl, (C 1 ~C 2 Alkoxy)-(C 2 ~C 3 alkyl) and phenyl is a group selected from Said C 1 ~C 4 The alkyl groups are optionally substituted, identically or differently, by phenyl groups, and the phenyl groups are optionally substituted, identically or differently, by halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 alkoxy; The phenyl groups may optionally be the same or different and may be halogen atoms or C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkoxy is mono-, di- or trisubstituted with groups selected from or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (III) is represented by the formula 【Chemistry 46】 and (ii) the intracellular imaging agent is a compound of formula (IV) or a compound of formula (V), and the compound of formula (IV) is 【Chemistry 47】 (In the formula, Ar is 【Chemistry 48】 and 【Chemistry 49】 is a group selected from ＃ is the bond with X, X is CH 2 and (CH 2 ) 3 is a group selected from R 7 and R 9 are each independently a hydrogen atom or -CH 2 is an OH group, R 8 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 10 teeth, C 2 ~C 5 Alkoxy, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 Alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- wherein C is a group selected from 1 ~C 3 Alkoxy groups and C 2 ~C 5 The alkoxy group is optionally mono-, di-, tri- or tetra-substituted with fluorine atoms. or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof; The compound of formula (V) is represented by the formula [Transformation 50] (In the formula, Ar is 【Chemistry 51】 and 【Chemistry 52】 is a group selected from # is a bond with X, X is CH 2 and (CH 2 ) 2 is a group selected from R 11 is a hydrogen atom or C 1 ~C 3 Alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 is a group selected from R 12 teeth, C 2 ~C 5 Alkoxy, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- is a group selected from 26. The kit of claim 25, having: or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof.

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