TW201909927A - LIVER CANCER IMAGING BY Fluciclovine - Google Patents

Abstract

Provided is an imaging agent of liver cancer or cancer that has occurred near the liver, the imaging agent containing radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (fluciclovine) or a pharmacologically acceptable salt thereof as an active ingredient.

Description

Application of fluciclovine for liver cancer imaging

The present invention relates to the use of trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (fluciclovine) for cancer imaging (cancer imaging) ).

Trans-1-amino-3- [18-fluoro] cyclobutane-fluoro-1-carboxylic acid (trans-1-amino-3- [18 F] fluorocyclobutane-1-carboxylic acid) "18 F-fluciclovine", has It is known as an agent for displaying amino acid metabolism of cancer cells; for 2-[fluoro18]-2-deoxy-D-glucose (2-[ ¹⁸ F]-2-deoxy-D which is metabolized by hyperthyroidism showing cancer cells -glucose, a prostate cancer which is difficult to describe, is known as a diagnostic agent for positron emission tomography (PET) which can describe the prostate cancer (Non-Patent Documents 1 to 4).

¹⁸ F-fluciclovine, because it can display the amino acid metabolism of cancer cells, in addition to depicting prostate cancer, it has also been suggested to be applied to metastatic brain tumors, early bone metastasis of cancer. Patent Documents 2 and 3".グへ Use of the が proposal (licensed documents 2, 3). [Patent Literature]

[Patent Document 1] International Publication No. WO 97/17092 [Patent Document 2] International Publication No. WO 2016/194372 (Patent Document 3) International Publication No. WO 2017/051519 (Non-Patent Document)

[Non-Patent Document 1] Shuster D. et al., J. Nucl. Med. (2007), Vol. 48, No. 1, pp. 56-63 [Non-Patent Document 2] Shuster D. et al., Radiology (2011), Vol. 259, No. 3, pp. 852-861 [Non-Patent Document 3] Oka S. et al., J. Nucl. Med. (2007), Vol. 48, No. 1, pp. 46-55 [Non-Patent Document 4] Inone Y. Et al, Asia Oceania J. Nucl. Med. Biol. (2004), Vol. 2, No. 2, pp. 87-94 [Non-Patent Document 5] Shuster D. et al., J. Nucl. Med. (2014), Vol. 55, Issue 12, page 1986-1992

However, regarding the liver, ¹⁸ F-fluciclovine has more normal liver and normal pancreas than other organs in the individuals who have been fasting for more than 4 hours. Therefore, the liver and liver are depicted by ¹⁸ F-fluciclovine. The cancer produced in a nearby location is considered to be difficult; for example, Non-Patent Document 5 discloses that ¹⁸ F-fluciclovine is used, and the normal liver is depicted as a hot spot "area with relatively high radioactivity". On the other hand, hepatic hematoma (hepatic hemangioma), which is a benign hepatic tumor, is depicted as a cold spot, a relatively low-radiation region. It is only such a report and does not reveal It is capable of depicting the malignant tumor "Cancer" produced in the vicinity of the liver and liver.

The present inventors focused on the feeding status of the examined individuals at the time of fluciclovine administration, and identified the radio-1-trans-3-amino-3-fluorocyclobutane-1-carboxylic acid (trans-1-amino-3- Fluoroclovine-carboxylic acid) "fluciclovine", which can image the cancer produced in the vicinity of the liver and the liver, has thus completed the present invention.

Accordingly, an aspect of the present invention provides a radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid "fluciclovine" or a pharmaceutically acceptable salt thereof as an active ingredient in the liver and An imaging agent for cancer produced at a location near the liver.

Further, another aspect of the present invention provides a method for photographing cancer, in which fluciclovine or its pharmaceutically acceptable trans--1-amino-3-fluorocyclobutane-1-carboxylic acid is labeled for radioactive fluorine. The test subject of the permissible salt is subjected to Postron Emission Tomography (PET), and includes a step of generating image data of a cancer-claw image generated by the liver or the liver near the site to be examined. The invention provides a method of photography for cancer.

Still another aspect of the present invention provides the use of radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid "fluciclovine" or a pharmaceutically acceptable salt thereof for use in the manufacture of An imaging agent for cancer produced in the vicinity of the liver and liver.

Further, still another aspect of the present invention provides a fluciclovine containing radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid by administration in a non-fasted condition. Or an pharmaceutically acceptable salt thereof as an active ingredient of a cancer imaging agent.

According to the present invention, focusing on the feeding condition of the examined individual at the time of administration of fluciclovine, enhancing the contrast of the cancer relative to the normal liver, and in particular, providing a depiction image of the cancer generated at a position near the liver and the liver, thereby providing A new form of imaging agent for cancer.

In the present invention, the term "imaging agent" means the purpose of administering a radiopharmaceutical to the body for the purpose of nuclear medicine examination.

The nuclear medicine examination in the present invention may be exemplified by positron emission tomography (PET), single photon emission computed tomography (SPECT), etc.; After being irradiated to the living body, the radiation emitted from the body can be detected and imaged by a positron emission tomography apparatus or a single photon computed tomography apparatus, and the non-invasive diagnosis of the disease state can be performed.

In the present invention, "hot spot" means a region where radiation energy is relatively high. Further, in the present invention, "cold spot" means a region in which radiation energy is relatively low.

The imaging agent of the present invention, which is contrast-enhanced with respect to the normal liver, can be used in a cancer "malignant tumor" which can be imaged, and can be applied to liver cancer. The "carcinoma caused by the location near the liver", for example, cholangiocarcinoma can be exemplified.

In the present invention, "hepatic cancer" refers to a malignant tumor of the liver, and is not only a primary liver cancer such as hepatocellular carcinoma or cholangiocarcinoma which is formed by hepatic cells or biliary cells due to canceration. (primary hepatic cancer) also includes metastatic liver cancer in which cancer cells of cancer cells other than the liver are moved to the liver and deeply implanted. Primary lesions of metastatic liver cancer, such as: stomach cancer, colorectal cancer, rectal cancer, breast cancer, renal cancer, thyroid Thyroid cancer, multiple myeloma, malignant lymphoma, prostate cancer, small cell lung cancer, pancreatic cancer, brain tumor Brain tumor) is an example. Further, in the present invention, "cholangiocarcinoma" includes gallbladder cancer and extrarahepatic bile duct carcinoma.

In the present invention, the "inspected individual" means a living body that is a subject of nuclear medicine examination, including humans and animals.

In the present invention, the term "non-fasting" means that there is no fasting, and the body of the individual to be examined who is administered fluciclovine is in a state of ingesting energy sources; when the individual to be inspected is a person, for example, starting Within 4 hours before the administration of the radioactive fluciclovine, it is also possible to take in a nutrient, an amino acid supplement, or the like by oral ingestion or by injection. On the other hand, the term "fasting" refers to a state in which the diet "feeding bait" that is usually ingested is stopped before the administration of radioactive fluciclovine is administered; when the individual being examined is a human, for example, before starting to administer radioactive fluciclovine Before 4 hours or more, no nutrition was taken through diet or the like.

The active ingredient of the imaging agent of the present invention is a radioactive fluciclovine or a pharmaceutically acceptable salt thereof. The so-called radioactive fluciclovine, if it is a radioisotope labeled trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (fluciclovine), There is no particular limitation. Representative imaging agents include ¹⁸ F-fluciclovine "trans-1-amino-3-[fluoro18]fluorocyclobutane-1-carboxylic acid labeled with radioactive fluorine. (trans-1-amino-3-[ ¹⁸ F]fluorocyclobutane-1-carboxylic acid).

The radioactive fluciclovine can be synthesized by a generally known method, for example, by the method described in Journal of Labelled Compounds and Radiopharmaceuticals, (1999), Vol. 42, pp. 215-225, WO 2008/75522.

In the present invention, the "salt" is not particularly limited as long as it is pharmaceutically acceptable. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, maleic acid, and succinic acid may be used. Mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid , pyranosidylic acid (glucuronic acid, galacturonic acid, etc.), α-hydroxy acid (citric acid), citric acid, tartaric acid ( Tartaric acid), amino acids, aspartic acid, glutamic acid, etc., aromatic acids, benzoic acid, cinnamic acid Acids, etc., organic acids such as sulfonic acids, p-toluenesulfonic acid, ethanesulfonic acid, etc. Amino acids "glycine, arginine, etc.", ammonia, primary amines, secondary amines, and tertiary amines "organic base" such as "tertiary amines" and cyclic amines "piperidine, morpholine, piperazine, etc."; or sodium hydroxide, Calcium hydroxide, potassium hydroxide, magnesium hydroxide, manganese hydroxide, iron hydroxide, copper hydroxide, zinc hydroxide, aluminum hydroxide, lithium hydroxide And other salts derived from inorganic bases.

It is desirable that the imaging agent of the present invention is administered via a parenteral method; as a dosage form, an injection is more desirable. It is desirable to use an aqueous solution, and may also contain a suitable acid-base regulator, a pharmaceutically acceptable solubilizing agent, a tonicity adjusting agent, a stabilizer, or an antioxidant. Additional components.

The content of the radioactive fluciclovine in the imaging agent of the present invention is not particularly limited as long as it has radiant energy which can be used for nuclear medical examination, and is, for example, 50 to 740 million Baker (MBq) when used. In the case of the radiant energy, the positron emission tomography is available for the adult.

Next, as an example of the developer of the present invention, a formulation containing ¹⁸ F-fluciclovine or a salt thereof to be permissible as an active ingredient is exemplified, and an example of the method of use thereof will be described below. First, an imaging agent of the above-described example is administered to an individual to be examined under fasting or non-fasting. Next, the individual to be examined is subjected to positron emission tomography. A device for positron emission tomography has been equipped with a radiation detector to detect two gamma rays generated by a proton emitted from radioactive fluorine due to decay in a 180-degree direction, and an electrical signal is changed. Therefore, image data including cancer generated in the vicinity of the liver or liver of the individual to be examined is generated from this electronic signal; as a result, imaging of cancer generated in the vicinity of the liver or liver of the individual to be examined can be performed; The image data can be processed according to the needs; for the unchecked individuals, the cancers in the liver or near the liver can depict hot spots; for the individuals under examination under fasting, Cancers in the liver or near the liver can depict cold spots. [Examples]

Hereinafter, the present invention will be described in further detail with reference to the examples, but the scope of the present invention is not limited by the examples.

[Example 1] Effect of ¹⁸ F-fluciclovine accumulation in acarcinoma rat (DU145: prostate cancer) on "in vivo distribution" 1. Material (1) Modulation of prostate cancer cell suspension Human prostate cancer cell DU145 "USA The culture of the American Type Culture Collection (ATCC) was performed using 5% fetal bovine serum "Hyclone" and as an antibiotic added as a culture medium. Penicillin penicillin 100 units/ml, streptomycin 100 μg/ml "Invitrogen"Dulbecco's modified eagle's medium "Invitrogen" The company (Invitrogen) performs subculture and maintenance in an incubator with an internal carbon dioxide (CO ₂ ) concentration of 5% and an internal temperature of 37 ° C. For the culture vessel, 175 cm ² (cm ^{2 ) is used.} ) Cell culture flask "Becton, Dickins, Japan" On and Company), subcultured twice a week. On the day of transplantation, the medium was removed from the cell culture flask and placed in an amount of 0.53 millimolar (mM) ethylenediaminetetraacetic acid tetrasodium. Salt; EDTA.4Na) 0.25% trypsin solution "37 ° C", in a 5% CO ₂ incubator at 37 ° C for about 5 minutes; cells once peeled from the cell culture flask, added to contain 0.53 Millogram of 0.25% trypsin solution of tetrasodium edetate and an equal amount of medium "37 ° C", carefully mixed; the obtained cell suspension was placed in a 15 ml centrifuge tube "Beckon, Japan" In Becton, Dickinson and Company, centrifuge at room temperature, 500 rpm, 5 minutes per minute; remove the supernatant, and place the medium "37 ° C" in the centrifuge tube to make the cells Suspension. After measuring the viable cell count under an inverted microscope, resuspend in the medium at a self-selected cell concentration; and an equal amount of basement membrane matrix ( Matrigel) "Becton, Dickinson and Company" was mixed to make a cell suspension for transplantation.

(2) Preparation of disease model rat The nude rat "F344/N Jcl-rnu, male, 8 weeks old" was anesthetized with diethyl ether, and was placed in a lateral position. Lying down, the transplant site was shaved and sterilized with 70% ethanol. The cell suspension containing the DU145 "0.1 ~ 1.0 Í ^{10 7} " was taken by a 1 ml syringe (syringe) equipped with a 27-gauge needle (27G needle) for subcutaneous inoculation; once the basement membrane matrix was solidified, the needle was removed. The naked rats are returned to the cage and these become donor rats. At the 8th week of transplantation, a mixture of ketamine 40 mg/ml/xylazine 4 mg/ml was administered to donor mice by intramuscular injection of 2 ml/kg. general anesthesia. The subcutaneous tumor was removed after shaving the site where the subcutaneous tumor had been formed and disinfecting the skin with 70% ethanol. The subcutaneous tumor was taken out, and the tumor was cut out to an appropriate size "4 to 5 mm angle" using a new razor blade for a cryostat as a tumor block for transplantation. The transplanted tumor mass was immersed in a solution of the cooled basement membrane matrix and Phosphate buffered saline (PBS) in equal amounts, and was cooled until transplantation. The nude rat "F344/N Jcl-rnu, male, 8 weeks old" as a recipient was general anesthetized with diethyl ether, lie down in a lateral position, shaved on the left lumbar region, and treated with 70% ethanol. Skin disinfection; Surgical scissors were used to cut 0.5 to 1.0 cm of skin, and 1.0 to 1.5 cm of subcutaneous tissue was peeled off to prepare a transplanting pocket. In this transplantation pocket, transplantation was performed for each nude rat. 2 tumor masses. The cut wounds were adhered with medical AA Alpha, and each naked rat was placed back in the cage for the 15th day after transplantation.

(3) trans-1-amino-3-[fluoro18]fluorocyclobutane-1-carboxylic acid (trans-1-amino-3-[ ¹⁸ F]fluorocyclobutane-1-carboxylic acid) ¹⁸ F-fluciclovine The modulation of the administration solution was prepared by the method described in WO2008/75522. The administration system was adjusted as follows, that is, ¹⁸ F-fluciclovine "185 million Baker / 2 ml / vial" 0.5 ml "46.25 million Baker" and physiological saline 14.5 ml were mixed to make a dosing solution "3.08 Wanbeck/ml.

2. Methods The nude rats of DU145 were transplanted subcutaneously with the disease model rat produced in the above 1, (2), and divided into fasting "more than 18 hours, free water supply, N = 5" and non-fasting "free feeding. Bait, free water, N=3". 15 minutes before the administration of ¹⁸ F-fluciclovine, a mixture of ketamine "40 mg / ml" / xylazine "4 mg / ml" was prepared using a disposable sterile insulin syringe "Myjector" with a 27-gauge needle. Intramuscular injection of "2 ml / kg" for general anesthesia. ¹⁸ F-fluciclovine administration solution "The administration solution prepared in the above 1, (3)" was injected from the tail vein with a Myjector with a 27-gauge needle in an amount of 1.0 kg of a naked rat weighing 1 kg. ¹⁸ F-fluciclovine 60 minutes after administration, using a heparin-treated 10 ml syringe equipped with a 18-gauge needle, blood was drawn from the abdominal aorta whole blood, and then the naked rat was killed; The surgical scissors were dissected, and organs such as liver and muscles and subcutaneous tumors were taken out, and the tail was cut out from the rats, and the rest was left as a residual body. After measuring the weight of each organ and tissue "except bladder and urine", the radioactivity of each organ, tissue, and residual whole body was measured by a single channel analyzer "Apply Guangyan Industry Co., Ltd.". For each organ, tissue, and residual whole body, at the time of self-selection, the attenuation correction radioactivity "% of injected dose (% ID)" is calculated, and the weight from each organ and tissue is further The attenuation corrected radioactivity "% of injected dose (% ID)" per gram was determined, and the mean value ± standard deviation was calculated.

3. The results are shown in Figure 1. From Figure 1, the accumulation of ¹⁸ F-fluciclovine in the liver under non-fasting, about 37% relative to the accumulation under fasting; the accumulation of ¹⁸ F-fluciclovine in the tumor under non-fasting, only Dropped to 60% of the accumulation under fasting. Therefore, when there is liver cancer in the liver, if it is not fasted, ¹⁸ F-fluciclovine can be used to describe liver cancer as a hot spot, which is shown in Fig. 1. In addition, the ¹⁸ F-fluciclovine of the fasting tumor has a liver accumulation ratio of 0.6. Therefore, when there is liver cancer in the liver, if it is fasted, it is thought that: using ¹⁸ F-fluciclovine, Liver cancer is depicted as a cold spot.

[Example 2] trans-1-amino-3-fluorocyclobutane-1-[carbon 14]carboxylic acid (trans-1-amino) in a squamous cell carcinoma nude mouse (GL-261 cell: brain tumor) -3-fluorocyclobutane-1-[ ¹⁴ C]carboxylic acid) ¹⁴ C-fluciclovine accumulation of food effects "autoradiography" 1. Materials (1) Preparation of brain tumor cell suspension Dalber containing fetal bovine serum Dulbecco's Modified Eagle's Medium "DMEM, pH 7.4, Sigma-Aldrich" in 5 ml, suspended 5.0 Í ^{10 5} GL-261 cells From the American Model Culture Collection, seeded in a 75 square centimeter (cm ² ) tissue culture flask "Nalgene-Nunc", an incubator with an internal temperature of 37 ° C and an internal carbon dioxide (CO ₂ ) concentration of 5% ( Incubator) was cultured for 7 days. On the day of transplantation, the medium was removed from the tissue culture flask and placed in a 0.25% trypsin solution containing 0.53 millimoles (mM) of ethylenediaminetetraacetic acid tetrasodium salt (EDTA.4Na). At 37 ° C, it was allowed to stand at 37 ° C for about 5 minutes in a 5% CO ₂ incubator; once the cells were peeled off from the tissue culture flask, 0.25% trypsin containing 0.53 mmol of tetrasodium ethylenediaminetetraacetate was added. The solution and the same amount of medium "37 ° C" were carefully mixed; the obtained cell suspension was placed in a 15 ml centrifuge tube "IWAKI" for centrifugation; the supernatant was removed, and the tube was placed in a centrifuge tube. The medium was "37 ° C" to suspend the cells. The viable cell count was measured by a cell counter, and then resuspended in a medium at a concentration of 2.0 Í ^{10 8} cells per ml to prepare a cell suspension for transplantation.

(2) Preparation of disease model mouse 150 μL (μL) of a cell suspension for transplantation containing about 3.0Í10 ⁷ GL-261 cells was inoculated with a 1 ml syringe equipped with a 21-gauge needle, and subcutaneously inoculated. The nude mice were placed in the cage on the back of nude mice "Japan SLC, KSN-slc, male, 4 weeks old". In the two weeks after the tumor diameter became 5 mm to 10 mm, general feeding was carried out.

(3) Preparation of ¹⁴ C-fluciclovine is based on the method described in Nucl. Med. Biol., Vol. 39, pp. 109-119, and the synthesized aqueous solution of ¹⁴ C-fluciclovine "18.5 million Baker/ml" with 0.9 The physiological saline solution "Otsuka Pharmaceutical" was diluted to prepare a 185 kilobeck/50 microliter (kBq/μL) administration solution.

2. Methods The nude mice transplanted with GL-261 cells subcutaneously (the disease model mice prepared in the above 1, (2)" were divided into fasting "more than 20 hours, free water supply, N = 1" and non-fasted " Free feeding, free water, N=1". ¹⁴ C-fluciclovine "administration solution prepared in the above 1, (3)" was administered from the tail vein at a dose of 185 kilobakers per 50 microliters. At the 30-minute point of the head and the back, the nude mice were subjected to deep anesthesia by inhaling ether, and a heparin-treated 1 ml syringe equipped with a 23-gauge needle was used to extract whole blood from the abdominal aorta. Blood was drawn, and then the nude mice were sacrificed; after freezing the nude mice whole body with liquid nitrogen, the animals were embedded in 1.5% carboxymethyl cellulose and fixed in a freezer. The microtome stage, after rough-planed, was made into a subcutaneous tumor, kidney, and median slice of 15 micron, placed in a freezer for about 1 week. dry. The dried slice is transferred to a container with a desiccant. After returning to normal temperature, the protective film "4 micron" is coated, adhered to the imaging plate, and after exposure, image analysis is performed. An image analysis system bio-imaging analyzer "BAS5000, manufactured by Fuji Film Co., Ltd.", obtained an autoradiogram. For liver and subcutaneous tumors, three regions of interest were circled individually to find photo-stimulated luminescence per square millimeter minus correction in the background ((PSL-BKG) ) / mm ² ) "1 square millimeter equivalent light stimulating luminescence, background correction", and the mean value ± standard deviation was calculated. The analysis of the soft system uses TINA version 2.09 "Raytest Company".

3. Results The results are shown in Table 1 and Figures 2 and 3.

Table 1

From Table 1, the accumulation of fluciclovine in the liver, under fasting, is relatively high in the cancer site; in contrast, under non-fasting, the accumulation in the cancer site is relatively low. Therefore, it is considered that, under non-fasting, fluciclovine can be used to describe liver cancer as a hot spot. Also, under fasting, it is considered that fluciclovine can be used to describe liver cancer as a cold spot.

[Example 3] Effect of ¹⁴ C-fluciclovine accumulation in subcutaneously transplanted nude mice (HepG2 cells: liver cancer cells) "Autoradiogram" 1. Materials (1) Preparation of liver cancer cell suspension in a cell culture flask , Dulbecco's Modified Eagle's Medium containing 10% fetal calf serum and L-Glutamine "3.5 millimoles""DMEM, pH 7.4, Sigma-Aldrich" 20 ml, each seeded HepG2 cells "taken from: Institute of Physical Chemistry, Bio Resource Center Cell Materials Development Room" 1.8Í10 ⁶ The cells were cultured for 5 days in an incubator set to an internal temperature of 37 ° C and an internal carbon dioxide (CO ₂ ) concentration of 5%. On the day of transplantation, DMEM medium was removed from the tissue culture flask, and washed with Phosphate buffered saline (PBS), Sigma-Aldrich, and 0.02% ethylenediaminetetraacetic acid. 4 ml of a 0.05% trypsin solution of ethylenediamine tetraacetic acid (EDTA) was run in, removed by about 2/3, left to stand in the same incubator for about 5 minutes, and the cells were peeled off. Milled PBS (-) "Sigma-Aldrich" pipetting to obtain a cell suspension. After measuring the cell number "4.47 Í ^{10 7} cells" with a Coulter counter, centrifugation "room temperature, 1500 rpm, 4 minutes", remove PBS (-), and use 0.3 ml of PBS (- The cells were loosened to prepare a cell suspension for transplantation "8.94 Í ^{10 7} cells/ml".

(2) Preparation of disease model mouse (1) The liver cancer cell suspension prepared by (1) nude mouse "Japan SLC company, KSN-slc, male, 4 weeks old" was injected subcutaneously every back. Only 0.1 ml of "8.94Í10 ⁶ /piece" was transplanted, and general feeding was carried out for 2 to 5 weeks.

(3) Trans-1-amino-3-fluorocyclobutane-1-[ ¹⁴ C]carboxylic acid ¹⁴ C-fluciclovine The preparation was carried out in the same manner as in Example 2.

2. Method The same method as in Example 2 was carried out, except for the nude mice in which the HepG2 cells were subcutaneously transplanted, the disease model mice produced in the above (1).

3. Results The results are shown in Table 2 and Figures 4 and 5.

Table 2

As shown in Table 2 and Figures 4 and 5, in the animal model of subcutaneous transplantation of HepG2 cells, the accumulation of fluciclovine in the liver, under non-fasting, is relatively low in the cancer site, and therefore, it is considered to be non-fasted. If you use fluciclovine, you can use liver cancer as a hot spot.

[Example 4] Effect of ¹⁴ C-fluciclovine accumulation in nude mice (HepG2 cells: liver cancer cells) in the liver. "Autoradiography" 1. Materials (1) Preparation and examples of liver cancer cell suspension 3 The same method is used to modulate it.

(2) Production of disease model mouse (1) Adjusted liver cancer cell suspension in the liver of nude mice "Japan SLC, KSN-slc, male, 5 to 6 weeks old" Each transplanted 0.032 ml "2.50 Í ^{10 6} ~ 2.60 Í ^{10 6} / only", in the 13 weeks, the general feeding.

(3) Trans-1-amino-3-fluorocyclobutane-1-[ ¹⁴ C]carboxylic acid ¹⁴ C-fluciclovine The preparation was carried out in the same manner as in Example 2.

2. Method The same method as in Example 2 was carried out, except for the nude mice in which the HepG2 cells were transplanted in the liver, "the disease model mice produced in the above (1) (2)".

3. Results The results are shown in Figure 6.

In this example, although HepG2 cells were transplanted intrahepatically, no tumor was formed in the liver, but a tumor was formed in the peritoneal cavity adjacent to the liver. Fig. 6, tissue section, fluciclovine accumulation in the abdominal cavity, whether it is forbidden Under the condition of eating or not fasting, it is visually the same degree, but it is visually significantly lower in terms of liver accumulation and non-fasting. Therefore, if it is a non-fasting situation, it is considered to use fluciclovine, which can describe liver cancer as a hot spot.

As a result of the foregoing, it was revealed that liver cancer can be drawn by administering radioactive fluciclovine.

The present application claims priority on the basis of Japanese Patent Application No. 2017-150433 filed on August 3, 2017, the entire disclosure of which is incorporated herein.

Fig. 1 shows trans-1-amino-3-[fluoro18]fluorocyclobutane-1 using the model of cancer-bearing rat "DU145: prostate cancer" obtained in Example 1. - distribution pattern in vivo ^"18 F-fluciclovine" carboxylic acid (trans-1-amino-3- [18 F] fluorocyclobutane-1-carboxylic acid). Regarding each organ, the black column on the left indicates the amount of accumulation under fasting (unit: percentage of the injected dose per gram of tissue mass), the right white column system Indicates the amount of stock that has not been fasted. Unit: Percentage of injected dose per gram (%ID/g). Fig. 2 shows a trans--1-amino-3 model of the GL-261 cell: brain tumor model obtained by using the nude mouse obtained in Example 2. Autoradiogram of in vivo distribution of ^-14- C-fluciclovine of trans-1-amino-3-fluorocyclobutane-1-[ ^14C ]carboxylic acid ). Fig. 3 shows the distribution of ¹⁴ C-fluciclovine under non-fasting using the nude mouse "GL-261 cell: brain tumor" model obtained in Example 2. Autoradiogram. Fig. 4 is a diagram showing the autoradiogram of the distribution of ¹⁴ C-fluciclovine in the fasting of the subcutaneously transplanted nude mouse "HepG2 cells: liver cancer cells" model obtained in Example 3. Fig. 5 is a graph showing the autoradiogram of the distribution of ¹⁴ C-fluciclovine under non-fasting using the subcutaneously transplanted nude mouse "HepG2 cells: liver cancer cells" model obtained in Example 3. Fig. 6 is a diagram showing the autoradiogram of the distribution of ¹⁴ C-fluciclovine in fasted and non-fasted mice using the model of intrahepatic nude mice "HepG2 cells: liver cancer cells" obtained in Example 4. And its tissue slice.

Claims (9)

An imaging agent containing trans-1-amino-3-fluorocyclobutane-1-carboxylic acid "fluciclovine" An imaging agent for cancer produced at a position near the liver and the liver as an active ingredient or a pharmaceutically acceptable salt thereof. The imaging agent according to claim 1, wherein the liver cancer is primary liver cancer. The imaging agent according to claim 1, wherein the liver cancer is a metastatic liver cancer. The use of the imaging agent as described in claim 1 or 2 of the patent application is by non-fasting administration. The developer according to claim 1 or 2, wherein the radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid is a compound represented by a fluorine element. The imaging agent described in the first or second aspect of the patent application is used for positron emission tomography (PET). A method for photographing cancer, which is administered with trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (trans-1-amino-3-fluorocyclobutane-1-carboxylic acid) or its pharmacy The test subject of the salt to be examined is a method of imaging a cancer including a step of generating image data of a cancer-carrying image generated by a position near the liver or the liver of the test subject by performing a photon tomography "PET". In order to produce an imaging agent for cancer occurring in the vicinity of the liver or liver, radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (trans-1-amino-3-fluorocyclobutane-1-carboxylic acid) is used. Acid) "fluciclovine" or a pharmaceutically acceptable salt thereof. Use of a cancer imaging agent by transpending under non-fasting to contain radioactive trans-1-amino-3-fluorocyclobutane-1-carboxylic acid (trans-1-amino-3-fluorocyclobutane) 1-carboxylic acid) An imaging agent for cancer of fluciclovine or a pharmaceutically acceptable salt thereof as an active ingredient.