Contrast agent for detecting cartilage damage, and method and program for inspecting cartilage damage using said contrast agent

Abstract

To provide new means useful for detecting damage to cartilage for image diagnosis of early osteoarthritis.SOLUTION: Using 17O-labeled water as an MRI contrast agent makes it possible to detect damage to cartilage, particularly minor damage to the surface layer of cartilage, which has been difficult to detect so far.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to 17 The present invention relates to a contrast agent containing O-labeled water for detecting cartilage damage, and a method and program for inspecting cartilage damage using the contrast agent. [Background technology]

[0002] Osteoarthritis is a disease that causes localized inflammation in the joints, including degeneration and destruction of articular cartilage, proliferative changes in the joint margins and subchondral bone, and synovitis. In patients with osteoarthritis, pain interferes with daily activities, including walking, leading to a decrease in quality of life (QOL).

[0003] Articular cartilage is composed of 70% water, which is maintained by approximately 10% of the proteoglycans present between cells. Osteoarthritis, which progresses due to excessive weight during exercise or trauma, is thought to be caused by the breakdown of the hydrostatic pressure maintenance mechanism in cartilage tissue early after injury, which induces apoptosis of chondrocytes. Therefore, diagnostic methods that focus on the water retention function of cartilage are important.

[0004] Various imaging sequences of MRI (magnetic resonance imaging) are often used for early imaging diagnosis of articular cartilage. T2 mapping is an imaging method that can evaluate collagen irregularity and increased water content, but in diagnosis, it is necessary to consider the difference in T2 value due to the different collagen arrangement direction in the superficial, middle, and deep layers of the cartilage surface. It is also necessary to be careful that normal cartilage may be interpreted as degenerated cartilage due to the extension of T2 value caused by the so-called magic angle effect. T1ρ mapping can detect the proteoglycan concentration that decreases with cartilage degeneration and is said to be less affected by the magic angle effect, but it is also affected by the water content. Delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), a contrast test, is an imaging method that uses gadolinium and is highly specific to changes in proteoglycan concentration in cartilage, but it requires the administration of twice the usual amount of gadolinium contrast agent, which is considered to be invasive.

[0005] None of the above methods have sufficient sensitivity or specificity to evaluate changes in the metabolic dynamics of the cartilage matrix, and an appropriate modality for diagnosing early osteoarthritis has yet to be developed.

[0006] On the other hand, the stable isotope of oxygen, oxygen-17( 17 O) labeled water (oxygen-17 stable isotope labeled water, H 2 - 17 O-containing water, 17 Also referred to as O-labeled water, 17 O-labeled water) is known as an active ingredient in nuclear magnetic resonance imaging diagnostic agents (Patent Document 1). 17 Development of an MRI imaging method for evaluating cerebral blood flow disorders using O-labeled water is also underway (Patent Document 2, Non-Patent Document 1). 17 Due to its safety, O-labeled water is expected to have further clinical applications. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] JP 2003-102698 A [Patent Document 2] JP 2013-255586 A [Non-patent literature]

[0008] [Non-Patent Document 1] Kudo K. et al., Magn Reson Med Sci 2018 17(3): 223-230. DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a new means that is useful for detecting cartilage damage and for imaging diagnosis of early stage osteoarthritis. [Means for solving the problem]

[0010] The present inventors 17 When O-labeled water was administered, the damaged area of ​​cartilage was rapidly 17 O concentration increases, but in normal areas, 17 They found that no increase in O concentration occurred and completed the following invention.

[0011] (1) 17 An MRI contrast agent containing O-labeled water for detecting cartilage damage. (2) 17 MRI images of cartilage taken before and after administration of an MRI contrast agent containing O-labeled water were taken of subjects. 17 and obtaining a signal value derived from O, the signal value or a signal value calculated from the signal value. 17 To compare the O concentration before and after administration of contrast agent, and to evaluate the change in signal value or17 2. A method for testing for cartilage damage comprising determining an elevated O concentration. (3) The method according to (2), wherein the cartilage is articular cartilage. (4) The method according to (2) or (3), wherein the contrast agent is administered into the subject's joint cavity. (5) The method according to any one of (2) to (4), wherein the MRI image is a T2-weighted image taken by a proton MRI device. (6) 17 MRI images of cartilage taken before and after administration of an MRI contrast agent containing O-labeled water were taken of subjects. 17 A process for obtaining a signal value derived from O, optionally from the signal value 17 A process for calculating the O concentration, and a process for calculating the signal value or the O concentration calculated from the signal value 17 A program to test for cartilage damage, to carry out a process to compare O concentrations before and after contrast administration. (7) The program according to (6), wherein the cartilage is articular cartilage. (8) The program according to (6) or (7), wherein the contrast agent is administered into the subject's joint cavity. (9) The program according to any one of (6) to (8), wherein the MRI image is a T2 weighted image taken by a proton MRI device. Effect of the Invention

[0012] According to the present invention, 17 By using O-labeled water as a contrast agent, a highly safe imaging diagnostic method is provided that can detect cartilage damage, particularly minor damage to the cartilage surface layer, which is an early stage lesion of osteoarthritis that has been difficult to detect in the past. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1A is a photograph of the external appearance of both femoral condyles of a rabbit 4 weeks after anterior cruciate ligament resection after staining with India ink, FIG. 1B is an HE-stained image of a slice specimen of both femoral condyles, and FIG. 1C is an image stained with Safranin-O. [Diagram 2]Figure 2A shows the positions of the imaging sections of both femoral condyles of a rabbit taken 4 weeks after anterior cruciate ligament resection, with five dotted lines. Figure 2B shows a T2-weighted image of the imaging section (before administration of 17O-labeled water). Figure 2C shows a 17O concentration map of the articular cartilage based on the T2-weighted image superimposed on a proton density-weighted image (anatomical image). [Diagram 3] Figure 3A shows the position of the ROI (Region of Interest) analyzed in the T2 weighted image, and Figure 3B shows the time course of the 17O concentration in each ROI. The phase on the horizontal axis corresponds to the number of MRI scans, and the time interval between scans is 3 minutes 39 seconds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The following description of the present invention may be based on a representative embodiment or specific example, but the present invention is not limited to such an embodiment or specific example. In this specification, the upper and lower limit values ​​of each numerical range can be arbitrarily combined. In addition, in this specification, a numerical range expressed using "~" or "-" means a range including the numerical values ​​at both ends as the upper and lower limits, unless otherwise specified.

[0015] MRI contrast agents The present invention relates to 17 An MRI contrast agent for detecting cartilage damage is provided, which contains O-labeled water.

[0016] 17 O-labeled water contains a higher concentration of H than naturally occurring water. 2 - 17 It is water containing O. 17 H in O-labeled water 2 - 17 The concentration of O should be sufficient for MRI detection at the site of cartilage damage that is required to be examined. 2 - 17 Any concentration that can supply O 2 is sufficient, but a high concentration is preferable in order to reduce the amount of solution administered to the subject. 17 H in O-labeled water 2 -17 The O concentration is, for example, 5 mol% or more, preferably 10 mol% or more, and more preferably 15 mol% or more. 17 H in O-labeled water 2 - 17 There is no upper limit to the O concentration, and theoretically it can be as high as 100 mol%. 17 H in O-labeled water 2 - 17 The mol% O concentration is synonymous with atom% (oxygen atomic ratio).

[0017] 17 O-labeled water can be prepared in advance by a method known to those skilled in the art, for example, as described in JP-A-2000-218134. 17 By low-temperature distillation of raw oxygen containing O 17 It can be produced by concentrating O, adding hydrogen to the concentrate, and reacting them. 17 As O-labeled water, commercially available products such as those sold by Taiyo Nippon Sanso Corporation can also be used.

[0018] The contrast agent is 17 In addition to O-labeled water, the contrast medium may contain components such as isotonicity agents such as sodium chloride, potassium chloride, glucose, D-sorbitol, and glycerin, preservatives such as benzyl alcohol, parahydroxybenzoic acid esters, and chlorobutanol, antioxidants such as ascorbic acid, α-tocopherol, and sulfites, and buffers such as phosphates, carbonates, acetates, and citrates. A contrast medium containing these components may also be referred to as a contrast composition.

[0019] The contrast agent may be administered to a subject requiring examination for cartilage damage by any administration route as long as the administered contrast agent is accessible to the cartilage in the subject's body, but it is preferably administered locally near the cartilage in order to perform the examination with a smaller amount of contrast agent. When the cartilage to be examined is articular cartilage, it is particularly preferable to administer the contrast agent locally into the joint cavity.

[0020] The amount of contrast agent administered was H 2 - 17 O concentration, e.g., H in the joint cavity in the case of local administration into the joint cavity 2 - 17 The amount of the agent to be administered is such that the H O concentration in the contrast agent is 0.5 mol% or more, preferably 0.8 mol% or more, for example, approximately 1 mol%. 2 - 17 This can be appropriately determined by those skilled in the art, taking into consideration factors such as O concentration, volume of the joint cavity, and route of administration.

[0021] How to test for cartilage damage To examine cartilage damage, subjects are subjected to MRI imaging of cartilage before and after administration of a contrast agent, and MRI images are obtained. 17 A direct method utilizing the nuclear magnetic resonance phenomenon of O itself may be used. 2 - 17 An indirect method using T2 shortening caused by protons in the O molecule may be used. The indirect method uses the nuclear magnetic resonance phenomenon of protons, so it is possible to use proton MRI devices currently in clinical use, and it has higher sensitivity than the direct method. 17 O can be detected. Below, we will use the indirect method as an example. 17 The O detection method will be further described.

[0022] In the indirect method, in order to detect T2 shortening with high sensitivity, it is preferable to acquire a T2 weighted image (T2WI) by adopting a fast spin echo method or a spin echo method, especially a T2 weighted sequence by the fast spin echo method. Imaging parameters such as repetition time (TR) and echo time (TE) may be appropriately set within a range normally used for acquiring a T2 weighted image according to the imaging sequence. In the case of the fast spin echo method, for example, a good image can be acquired in one phase of 3 minutes and 39 seconds by setting TR 1600 ms, TE 129 ms, FA 150°, echo train (ETL) 12, and the number of additions 6 times.

[0023] Imaging (scanning) is performed once or multiple times before and after administration of the contrast agent. Imaging before administration of the contrast agent may be performed at any time before administration, and imaging after administration of the contrast agent may be performed at any time between immediately after administration and 3 days after administration. In a preferred embodiment, imaging before administration of the contrast agent is performed at any time between 30 minutes before administration and immediately before administration, and imaging after administration of the contrast agent is performed at any time between immediately after administration and 60 minutes after administration. In a more preferred embodiment, imaging before administration of the contrast agent is performed immediately before administration, and imaging after administration of the contrast agent is performed continuously between immediately after administration and 10 minutes after administration.

[0024] Next, signal values ​​(signal intensity) are obtained from the acquired MRI images by image analysis, and the signal values ​​before and after administration of a contrast agent are compared.

[0025] In one embodiment, an arbitrary region of interest (ROI) is set in a region of the MRI image corresponding to the cartilage, and a signal value is obtained from each pixel included in the ROI. The cartilage in the MRI image may be identified by referring to other images such as a proton density weighted image. The signal values ​​before and after the administration of the contrast agent can be compared using the average value of the signal values ​​of each pixel included in the ROI.

[0026] In the indirect method, H 2 - 17 The protons in the O molecule cause T2 shortening, resulting in a decrease in signal value. Therefore, in the ROIs where the average signal value decreased after administration compared to before administration of the contrast agent, the administration of H 2 - 17 The O concentration is increased, and the cartilage included in the ROI can be evaluated as having or likely having damage.

[0027] In another embodiment, a signal value is acquired from each pixel in an MRI image, and the difference in signal value before and after administration of a contrast agent is displayed as a map. In the area displayed on the map where the signal value has decreased due to administration of a contrast agent, H 2 - 17The O concentration is elevated, and the cartilage contained in the region can be assessed as having or likely to have damage.

[0028] In addition, instead of comparing the signal values ​​before and after the administration of the contrast agent, 17 O concentrations may be compared. 17 The O concentration was calculated based on the previously obtained signal value. 17 For example, if the signal value is a signal value of a T2 weighted image, 17 The O concentration can be calculated using the formula below:

number

[0029] Specifically, in one embodiment, the average signal value of each pixel included in the ROI is subtracted from the average signal value of the ROI. 17 The O concentration was calculated and averaged before and after contrast administration. 17 The O concentrations in the ROI after administration are compared. 17 If the O concentration is elevated, the cartilage contained in the ROI can be evaluated as having or likely having damage.

[0030] In another embodiment, the signal value of each pixel in the MRI image is 17 The O concentration was calculated before and after contrast administration. 17 The difference in O concentration is displayed on a map. 17Cartilage contained within areas of elevated O concentrations can be assessed as having or likely to have damage.

[0031] When setting ROIs in an MRI image, in addition to the ROI (subject ROI) that specifies the region to be examined, a control ROI (control ROI) may be set in the normal cartilage area. 17 The O concentration was compared before and after contrast agent administration, and the degree of decrease in signal value due to administration or 17 If the degree of increase in O concentration is greater in the test ROI than in the control ROI, or if the rate of decrease in the signal value due to administration or 17 When the rate of increase in O concentration is greater in the test ROI compared to the control ROI, it can be assessed that the cartilage contained in the test ROI has or is likely to have damage.

[0032] The above explanation was given using an indirect MRI scan as an example. 17 Similarly, when MRI imaging is performed using a direct method that detects O itself, 17 A signal value derived from O is obtained, and a change in the signal value or a signal value calculated from the signal value is obtained. 17 Cartilage damage can be assessed based on elevated O concentrations.

[0033] Thus, the present invention provides 17 MRI images of cartilage taken before and after administration of an MRI contrast agent containing O-labeled water were taken in subjects. 17 and obtaining a signal value derived from O, the signal value or a signal value calculated from the signal value. 17 To compare the O concentration before and after administration of contrast agent, and to evaluate the change in signal value or 17 The present invention also provides a method for testing for cartilage damage, comprising determining an increase in O concentration. The above testing method can also be expressed as a method for detecting cartilage damage or a method for evaluating the possibility of cartilage damage. 17 MRI images of cartilage taken before and after administration of an MRI contrast agent containing O-labeled water were taken in subjects. 17Also provided is a method of collecting data for diagnosing cartilage damage, comprising obtaining a signal value derived from O.

[0034] A program for the examination of cartilage damage The present invention further comprises: 17 MRI images of cartilage taken before and after administration of an MRI contrast agent containing O-labeled water were taken in subjects. 17 A process for obtaining a signal value derived from O, optionally from the signal value 17 A process for calculating the O concentration, and a process for calculating the signal value or the O concentration calculated from the signal value 17 The present invention provides a program for inspecting cartilage degeneration or damage, which causes a computer to execute a process of comparing O concentrations before and after administration of a contrast agent. This program can be used to implement the above-mentioned inspection method, and the details of each process are as described in the explanation of the inspection method. The present invention also provides a computer-readable storage medium storing the program. Examples of the storage medium include a hard disk, a flash memory, a CD, and a DVD.

[0035] Test subject As shown in the following examples, 17 After administration of O-labeled water, the damaged area of ​​cartilage was rapidly 17 Therefore, according to the present invention, the O concentration is increased in subjects who need to be examined for cartilage damage. 17 A contrast agent containing O-labeled water was administered to detect the 17 By detecting the change in the signal value derived from O using MRI imaging, it is possible to perform image diagnosis of cartilage damage.

[0036] 17 The increase in O concentration is due to the H 2 - 17 This is believed to be because O molecules penetrate into the cartilage through the damaged area of ​​the cartilage. Since it is believed that water molecules can penetrate into the cartilage even if the degree of cartilage damage is slight, the present invention makes it possible to detect even slight damage such as degeneration of the cartilage surface layer, which is an early stage lesion of osteoarthritis that has been particularly difficult to detect in the past.

[0037] The present invention is applicable to subjects that require examination of cartilage damage. The subjects are mammals, such as rodents including mice, rats, hamsters, guinea pigs, and rabbits, primates including humans, chimpanzees, and rhesus monkeys, livestock including pigs, cows, goats, horses, and sheep, and pets including dogs and cats. The preferred subjects are humans.

[0038] A subject who needs to be examined for cartilage damage is a subject who has or may have some kind of damage to cartilage. For example, the subject may have or may have a disease or condition accompanied by or caused by cartilage damage, and examples of such diseases or conditions include osteoarthritis (knee joint, elbow joint, ankle joint, shoulder joint, etc.), autoimmune arthritis such as rheumatoid arthritis, intra-articular fracture, meniscus injury, knee ligament injury, patellar dislocation, chronic knee injury due to sports, intervertebral disc injury, osteochondritis dissecans (knee joint, elbow joint, ankle joint, etc.), etc.

[0039] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. EXAMPLES

[0040] Working Example 17 Evaluation of articular cartilage damage in an anterior cruciate ligament transection (ACLT) model using O-labeled water (1) Materials and methods · Creating an ACLT model To induce cartilage damage in the knee joint, an ACLT model was created using 14-week-old male Japanese white rabbits. Anesthesia was induced in the rabbits using intravenous anesthesia (pentobarbital 30 mg / kg + ketamine 50 mg / kg), followed by inhalation anesthesia (isoflurane 1-4%) for maintenance anesthesia. The anterior surface of the knee joint on the operated side was shaved and disinfected with povidone-iodine, and an analgesic (buprenorphine 0.02 mg / kg) was injected subcutaneously. A 5 cm skin incision was made on the medial side of the patella, and the joint capsule was incised at the same position. The patella was laterally dislocated, the knee joint was deeply flexed, and the anterior cruciate ligament in the femoral intercondylar region was exposed and dissected using a No. 11 scalpel. The inside of the joint was washed with saline, and the joint capsule and skin were closed using 3-0 nylon thread. During breeding, animals were euthanized if wound infection was observed or if they were unable to stand.

[0041] It has been previously reported that in the ACLT model, degeneration of the cartilage surface begins 4 weeks after surgery, and degeneration of the entire cartilage occurs from 8 weeks after surgery (Makoto Yoshioka et al. Characterization of a model of osteoarthritis in the rabbit knee. Osteoarthritis and Cartilage, 1996, 4 (2):87-98). Therefore, 5 rabbits were euthanized (pentobarbital 200 mg / kg) at 4 and 8 weeks after surgery, and cartilage damage was evaluated by MRI, as well as macroscopically and histologically.

[0042] MRI imaging The rabbit's knee joint on the operated side was imaged using a 3T-MRI device (MAGNETOM Prisma, Siemens). The affected leg of the rabbit was amputated at the thigh and fixed in the knee joint extension position to prevent body movement during imaging. A 24G Surflow needle was inserted from the front of the knee joint through the patellar tendon and left in the joint. The lock connector side of the extension tube was cut, and the inner cavity of the cut surface was connected to a thin-diameter polyethylene tube (PE50) with hardening resin (Shofu Quick Resin) to create a homemade administration route with a thin inner cavity, which was connected to the placed Surflow needle.

[0043] To evaluate both femoral condyles, five slices were set as MRI sections, with the most distal part of both femoral condyles as the central slice in a coronal section tilted 45 degrees forward relative to the bone axis (indicated by five dotted lines in Fig. 2A). First, proton density weighted images (PDWIs) were acquired as reference images to identify the articular cartilage under the following conditions (TE, 21 ms; TR, 1600; FOV, 60×80 mm; matrix, 269×448; slice thickness, 2 mm; slice gap, 2.6 mm; number of excitations, 6; scan time, 3 min 39 s). Then, T2-weighted images were continuously taken using 2D-fast spin echo under the following conditions (TE, 129 ms; TR, 1600; echo train length, 12; FOV, 60×80 mm; matrix, 269×448; slice thickness, 2 mm; slice gap, 2.6 mm; number of excitations, 6; scan time, 3 min 39 s; number of repetitions, 18; total scan time, 65 min 42 s). The first three of the 18 consecutive images were used as baseline images before administration. Immediately after the third image was completed, 20 mol% of 1000 mg ... 17 0.5 ml of physiological saline containing 0-labeled water (Taiyo Nippon Sanso Corporation) was rapidly administered, followed by a booster flush with 0.5 ml of physiological saline.

[0044] MRI image evaluation The articular cartilage was identified in each slice section from the proton density weighted images, and multiple small regions of interest (ROIs) were set in the articular cartilage of both condyles. 17 The O concentration was calculated using the following formula using the signal value of the T2 weighted image. 17 The time course of changes in O concentration was compared with the histological grade of cartilage damage, which will be described later.

number

[0045] Macroscopic and histological evaluation After MRI, the rabbit knee joints were opened and exposed, and cartilage damage in the femoral condyle was evaluated macroscopically and histologically according to the MRI slices (Gabriel GN et al. Evaluation of multiphase implants for repair of focal osteochondral defects in goats. Biomaterials, 2000, 21(24):2561-74).

[0046] For macroscopic evaluation, the presence or absence of cartilage damage was evaluated using the Osteoarthritis Research Society International (OARSI) score using Indian ink (S. Laverty et al. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthritis and Cartilage, 2010, 18 Suppl 3:S53-S65). An OARSI score of 2 or higher, in which accumulation of Indian ink was observed on the joint surface, was defined as "macroscopic cartilage damage present," and an OARSI score of 1, in which no accumulation was observed, was defined as "no macroscopic cartilage damage present."

[0047] For histological evaluation, both femoral condyles were fixed in 10% formalin for 24 hours, and decalcified with formic acid (5 parts formic acid, 1 part formalin solution, 15 parts distilled water) for 20 days. To match the slice width of MRI, the most distal part of both femoral condyles was set as the central slice in a coronal section tilted 45 degrees forward from the bone axis, and three slices including 2.6 mm anterior and posterior slices were prepared and evaluated. Safranin-O staining was performed, and the degree of cartilage damage was evaluated using OARSI grading (HJ Mankin et al. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg, 1971, 53(3):523-37). OARSI grade 1 or higher, in which fibrosis of the cartilage surface is observed, was defined as "histological cartilage damage present," and OARSI grade 0, which indicates normal cartilage, was defined as "no histological cartilage damage." Scoring was performed twice by two examiners independently, and inter-examiner and intra-examiner errors were evaluated.

[0048] ·Research approval All animal experiments were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee of the Hokkaido University Graduate School of Medicine.

[0049] (2) Results Figure 1A shows a representative case 4 weeks after surgery, with an external photograph after India ink staining. Macroscopic evaluation revealed OARSI score 3 cartilage damage on the lateral side of the medial condyle and OARSI score 2 cartilage damage on the medial side of the lateral condyle. HE-stained and Safranin-O-stained images of the slice specimen are shown in Figures 1B and 1C, respectively. Histological evaluation revealed OARSI grade 3 cartilage damage on the lateral side of the medial condyle (cracks from the cartilage surface to the middle layer, black arrow in the figure) and OARSI grade 2 cartilage damage on the medial side of the lateral condyle (cracks in the middle layer of the cartilage, white arrow in the figure), which were consistent with the damage observed in the macroscopic evaluation, in both the HE-stained and Safranin-O-stained images.

[0050] In addition, for a representative case 4 weeks after surgery, a T2-weighted image of both femoral condyles in a coronal section taken along the central dotted line of the five dotted lines shown in Figure 2A is shown in Figure 2B. 17 From the signal values ​​of individual pixels of the T2-weighted image taken approximately 11 minutes after administration of O-labeled water (the sixth time), 17 O concentrations were calculated and mapped. 17 The O map is shown in FIG. 2C, superimposed on the proton density weighted image. In the area where cartilage damage was observed, 17 High O concentrations were observed.

[0051] Two ROIs were set in each area corresponding to cartilage damage and normal cartilage in the T2-weighted image, and the average signal value in each ROI was used. 17 The O concentration was calculated. The ROI setting positions are shown in Fig. 3A. 17 The time course of the O concentration is shown in Figure 3B. In ROI1 and ROI2, which were set within the cartilage damage area, 17 Immediately after administration of O-labeled water (fourth imaging session) 17 The O concentration in the normal cartilage region was increased in ROI3 and ROI4. 17 Administration of O-labeled water 17 No trend toward an increase in O concentration was observed.

Claims

1. 17 An MRI contrast agent containing O-labeled water for detecting cartilage damage.

2. The agent described in claim 1, wherein the H 2 - 17 O concentration in the 17 O-labeled water is 5 mol% or more.

3. The agent according to claim 1 or 2, wherein the amount administered to a subject is an amount that brings the H 2 - 17 O concentration around the cartilage to 0.5 mol% or more.

4. An MRI contrast composition for detecting cartilage damage, comprising 17 O-labeled water.

5. The composition described in claim 4, wherein the H 2 - 17 O concentration in the 17 O-labeled water is 5 mol% or more.

6. The composition according to claim 4 or 5, wherein the amount administered to a subject is an amount that results in an H 2 - 17 O concentration around the cartilage of 0.5 mol % or more.

7. 17 From MRI images of cartilage taken before and after administration of an MRI contrast agent or contrast composition containing O-labeled water in a subject administered with the contrast agent or contrast composition, 17 obtaining a signal value derived from O; Signal value or calculated from signal value 17 Comparing the O concentration before and after administration of the contrast agent or composition; and The cartilage in the area where the 17 O concentration is increased by administration of a contrast agent or a contrast composition is judged to have damage.

16. A method for examining cartilage for damage, comprising:

8. The method of claim 7, wherein the cartilage is articular cartilage.

9. 9. The method of claim 7 or 8, wherein the imaging agent or composition is administered into the subject's joint cavity.

10. The method according to any one of claims 7 to 9, wherein the MRI image is a T2 weighted image taken by a proton MRI device.

11. A method for collecting data for diagnosing cartilage damage, comprising obtaining signal values ​​derived from 17O from MRI images of cartilage taken before and after administration of an MRI contrast agent or contrast composition containing 17O-labeled water in a subject administered the contrast agent or contrast composition.

12. The method of claim 11, wherein the cartilage is articular cartilage.

13. The method of claim 11 or 12, wherein the contrast agent or composition is administered into the subject's joint cavity.

14. The method according to any one of claims 11 to 13, wherein the MRI image is a T2-weighted image taken by a proton MRI device.

15. 17 From MRI images of cartilage taken before and after administration of an MRI contrast agent or contrast composition containing O-labeled water in a subject administered with the contrast agent or contrast composition, 17 obtaining signal values ​​derived from O; Optionally from the signal value 17 Processing to calculate O concentration, and Signal value or calculated from signal value 17 A process for comparing O concentrations before and after administration of a contrast agent or contrast composition. A program to test for cartilage damage to perform the procedure.

16. The program of claim 15 , wherein the cartilage is articular cartilage.

17. 17. The method of claim 15 or 16, wherein the imaging agent or imaging composition is administered into the subject's joint cavity.

18. The program according to any one of claims 15 to 17, wherein the MRI image is a T2 weighted image taken by a proton MRI device.

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