WO2019216223A1 - Agent d'imagerie de diagnostic non invasif pour maladie cardiaque - Google Patents

Agent d'imagerie de diagnostic non invasif pour maladie cardiaque Download PDF

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WO2019216223A1
WO2019216223A1 PCT/JP2019/017441 JP2019017441W WO2019216223A1 WO 2019216223 A1 WO2019216223 A1 WO 2019216223A1 JP 2019017441 W JP2019017441 W JP 2019017441W WO 2019216223 A1 WO2019216223 A1 WO 2019216223A1
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compound
heart disease
imaging agent
diagnostic imaging
mmol
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PCT/JP2019/017441
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English (en)
Japanese (ja)
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啓史 眞矢
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日本メジフィジックス株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds

Definitions

  • the present invention relates to a noninvasive diagnostic imaging agent for heart disease.
  • RAAS renin-angiotensin-aldosterone system
  • Non-Patent Document 1 describes that blood collected by cardiac catheterization showed that aldosterone was synthesized and secreted in a human failing heart.
  • Non-Patent Document 2 reveals that the gene expression of CYP11B2, which is an aldosterone synthase, is enhanced by examination using an autopsy heart. And it has been shown that this increased expression of CYP11B2 gene is associated with myocardial fibrosis and cardiac dysfunction.
  • Non-Patent Document 6 Although not intended for cardiovascular diseases, various radioactive compounds having high selectivity for CYP11B2 have been developed for the purpose of depicting the lesions of the adrenal glands and enabling imaging diagnosis of primary aldosteronism ( (Patent Documents 4 to 11, Non-Patent Document 6)
  • Detecting the expression of CYP11B2 in the heart region of heart disease patients may lead to the evaluation of the progression of heart diseases such as heart failure.
  • heart diseases such as heart failure.
  • the lesion area gradually increases from a minute lesion of about several millimeters.
  • the timing of treatment intervention can be advanced, and the prognosis There is a possibility that it can contribute to improvement.
  • Nuclear medicine diagnosis using single photon tomography (SPECT) and positron emission tomography (PET) is one of the methods for detecting changes in the molecular level in vivo.
  • the present inventor has already created a heart failure model rat, confirmed that the expression of CYP11B2 is increased in the cardiac lesion, and further, nuclear medicine examination using a radiolabeled compound capable of binding to aldosterone synthase This shows that CYP11B2 expressed in the lesion can be detected (Patent Document 12). However, it is not clear whether the expression level of CYP11B2 is increased to a level detectable by a nuclear medicine examination using SPECT or PET in a minute lesion of heart disease.
  • a tracer that is applicable to a modality with excellent quantitativeness and has high ability to bind to a target is used, and after administration of a radiolabeled compound, There is a need to wait until the tracer accumulates in the heart lesion to such an extent that it can be detected by a nuclear medicine examination.
  • the exposure dose in the body produced by administering the radiolabeled compound into the living body increases in proportion to the exposure amount and the exposure time.
  • the exposure dose in the body increases, and the number of tests that can be performed may be limited due to the relationship with the threshold dose for organ damage caused by radiation. There is. Therefore, it has been desired to develop a tracer by PET that is superior in spatial resolution and quantitativeness for detection of minute lesions of heart disease and evaluation of the progression of the disease over time, and has a short waiting time after administration.
  • Radioactive fluorine (fluorine-18) has a half-life of 110 minutes and is a nuclide for PET that is widely used clinically.
  • Patent Document 12 shows SPECT and PET tracer data, but compared to SPECT tracer, PET, especially fluorine-18 tracer, is weakly accumulated in the cardiac lesion. The inventor's knowledge revealed that the image was not drawn.
  • the present invention has been made in view of the above circumstances, and has a high accumulation property in a cardiac lesion, and provides a compound suitable as a tracer for nuclear imaging examination of PET imaging. By using the compound, a cardiac lesion is obtained. Is to be detected in vivo.
  • a noninvasive diagnostic imaging agent for heart disease containing a radiolabeled compound represented by the following formula (1) or a salt thereof as an active ingredient.
  • X 1 represents a hydrogen atom or a halogen atom
  • X 2 represents a fluorine atom or a nitrile group
  • X 3 represents a radioactive fluorine atom.
  • the present invention it is possible to noninvasively detect a heart disease lesion, and in particular, it is possible to depict a heart lesion portion by PET imaging.
  • FIG. 1A and 1B are diagrams showing the results of autoradiography of compound [ 18 F] 101 and compound [ 18 F] 100 using ischemic heart disease model rat heart sections, respectively.
  • FIG. 2 is a bar graph showing the signal intensity of the ischemia / reperfusion site relative to the signal intensity of the standard radiation source in the autoradiography of FIG.
  • FIG. 3A is a PET imaging image of an ischemic heart disease model rat administered with compound [ 18 F] 101
  • FIG. 3B is a PET imaging image of a normal rat administered with [ 18 F] 101
  • FIG. PET imaging images of ischemic heart disease model rats administered with compound [ 18 F] 100.
  • (a) is a short-axis cross-sectional image
  • (b) is a horizontal long-axis cross-sectional image
  • (c) is a vertical long-axis cross-sectional image.
  • the triangular arrowhead indicates the ischemic site of the heart
  • the arrow indicates the heart site
  • the pentagonal arrow indicates the liver.
  • the present invention is a noninvasive diagnostic imaging agent for heart disease, which contains a radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof as an active ingredient. According to the diagnostic imaging agent of the present invention, it is possible to depict a site where the fibrosis of the heart is progressing.
  • the “noninvasive diagnostic imaging agent” is used for nuclear medicine diagnosis, and more specifically, used for positron emission tomography (PET).
  • the “heart disease” includes ischemic heart disease and non-ischemic heart disease, preferably a disease caused by fibrosis of the heart, and an example is heart failure.
  • the “ischemic heart disease” is not limited as long as it is a heart disease caused by myocardial ischemia, and examples thereof include coronary heart disease angina, myocardial infarction, acute coronary syndrome, ischemic heart failure and the like.
  • non-ischemic heart disease includes myocarditis, hypertensive heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, non-ischemic heart failure, and the like.
  • X 1 when X 1 is a hydrogen atom, X 2 is preferably a fluorine atom. From the same viewpoint, in the above formula (1), when X 1 is a halogen atom, X 2 is preferably a fluorine atom or a nitrile group. From the same viewpoint, in the above formula (1), when X 1 is a fluorine atom, X 2 is preferably a fluorine atom or a nitrile group.
  • Preferred embodiments of the compound according to the present invention include three compounds represented by the following chemical formula.
  • the radioactive compound according to the present invention represented by the above formula (1) or a salt thereof can be produced, for example, according to the production method described in Patent Document 11 (International Publication No. 2015/199205). From the compound represented by the formula (2) or a salt thereof, it can be produced by a radiofluorination reaction.
  • X 1 represents a hydrogen atom or a halogen atom
  • X 2 represents a fluorine atom or a nitrile group
  • R 1 represents a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted aryl. A sulfonyloxy group is shown.
  • the substituted or unsubstituted alkylsulfonyloxy group is preferably an alkylsulfonyloxy group having 1 to 12 carbon atoms.
  • a hydrogen atom of the alkyl chain may be substituted with a halogen atom.
  • the substituted or unsubstituted arylsulfonyloxy group is preferably a substituted or unsubstituted benzenesulfonyloxy group, more preferably a substituted benzenesulfonyloxy group.
  • the hydrogen atom of the aryl ring is preferably substituted with an alkyl group having 1 to 12 carbon atoms or a nitro group.
  • substituted or unsubstituted alkylsulfonyloxy group and the substituted or unsubstituted arylsulfonyloxy group include a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, and trifluoromethane.
  • a sulfonyloxy group is mentioned.
  • radiohalide ions include radioactive fluoride ions (for example, [ 18 F] fluoride ions).
  • R 1 is a chlorine atom, a bromine atom, an iodine atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group.
  • the nucleophilic substitution reaction using radioactive fluoride ions is preferably performed in the presence of a base such as an alkali metal carbonate (for example, sodium carbonate or potassium carbonate).
  • a radioactive compound in which X 3 is a radioactive fluorine atom in the radioactive compound represented by the formula (1) can be obtained.
  • the radiofluorination reaction is preferably carried out in the presence of a base. 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8] -hexacosane (trade name: Cryptofix 222 ) And the like in the presence of various phase transfer catalysts.
  • radioactive compound represented by the above formula (1) or a salt thereof is used as a medicine
  • a column filled with unreacted radioactive fluorine and insoluble impurities with a membrane filter and various packing materials. Purification by HPLC or the like is desirable.
  • the “salt” may be anything that is pharmaceutically acceptable.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycol Acid, salicylic acid, pyranosidic acid (glucuronic acid, galacturonic acid, etc.), ⁇ -hydroxy acid (citric acid, tartaric acid, etc.), amino acid (aspartic acid, glutamic acid, etc.), aromatic acid (benzoic acid, cinnamic acid, etc.), sulfone Salts derived from organic acids such as acids (p-toluenesulfonic acid, ethanesulfonic acid, etc.) can be used.
  • the noninvasive diagnostic imaging agent of the present invention is a formulation containing the above-mentioned radioactive fluorine-labeled compound or a salt thereof in a form suitable for administration into a living body.
  • This non-invasive diagnostic imaging agent is preferably administered parenterally, that is, by injection, and more preferably an aqueous solution.
  • Such compositions may optionally contain additional components such as pH adjusters, pharmaceutically acceptable solubilizers, stabilizers or antioxidants.
  • the molecular structure of each compound was identified by 1 H-NMR spectrum.
  • NMR apparatus AVANCE III (manufactured by Bruker) was used, the resonance frequency was 500 MHz, tetramethylsilane (TMS) was used as an internal standard, and TMS resonance was set to 0.00 ppm. All chemical shifts are in ppm on the delta scale ( ⁇ ), and for signal fine splitting, the abbreviations (s: singlet, d: doublet, t: triplet, dd: double doublet, dt: double triplet, m: (Multiplet, bs: broad singlet, quin: quintet).
  • room temperature is 25 ° C.
  • 6-chloro-5-fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] -1- [2- (p-toluenesulfonyloxy) ethyl] benzimidazole (Compound 12) ( A mixed solution (1.0 mL) of acetonitrile / dimethyl sulfoxide (9: 1) in which 5 mg, 0.0102 mmol) was dissolved was added and heated at 100 ° C. for 5 minutes.
  • Example 3 In Vitro Autoradiography Using Ischemic Heart Disease Model Rats Wistar rats (male) were thoracotomized under isoflurane anesthesia, the left coronary artery was ligated for 30 minutes, reperfused, thoraxed, and Bloody heart disease model rats were prepared. One week after the operation, the model rat was sacrificed under isoflurane anesthesia, and then the heart was removed and sliced into 5 ⁇ m and attached to a slide glass (stored at ⁇ 80 ° C. until use). The sections were returned from ⁇ 80 ° C. to room temperature, and immersed as pre-incubation in phosphate buffered saline (PBS) at 37 ° C.
  • PBS phosphate buffered saline
  • reaction human plasma containing compound [ 18 F] 101 (radioactivity concentration: about 40 kBq / mL) or compound [ 18 F] 100 (radioactivity concentration: about 40 kBq / mL) is prepared (hereinafter referred to as reaction).
  • reaction human plasma containing compound [ 18 F] 101 (radioactivity concentration: about 40 kBq / mL) or compound [ 18 F] 100 (radioactivity concentration: about 40 kBq / mL) is prepared (hereinafter referred to as reaction).
  • the pre-incubated section was immersed in the reaction solution at 37 ° C. for 10 minutes. Thereafter, the slices were washed by immersing in human plasma at 37 ° C. for 2 minutes and 5 times. The section after washing was sufficiently dried.
  • reaction solution a known amount was immersed in a slide glass pasted with a filter paper cut out in a circle, and the dried product was used as a standard radiation source.
  • the section after drying and the standard radiation source were exposed to an imaging plate (BAS-SR2040, manufactured by Fuji Film), and an autoradiogram was obtained with a fluoro image analyzer (Typhoon FLA 7000 IP, manufactured by GE Healthcare Japan).
  • FIG. 1A The result of compound [ 18 F] 101 is shown in FIG. 1A, and the result of compound [ 18 F] 100 is shown in FIG. 1B.
  • FIG. 1A accumulation of compound [ 18 F] 101 in the lesion area was confirmed.
  • FIG. 1B almost no accumulation of compound [ 18 F] 100 in the lesion area was observed.
  • FIG. 2 is a bar graph showing the signal intensity of the ischemia / reperfusion site relative to the signal intensity of the standard radiation source in the autoradiography of FIG. As shown in FIG. 2, accumulation of compound [ 18 F] 101 in the lesion area was confirmed, but accumulation of compound [ 18 F] 100 in the lesion area was hardly observed.
  • Example 4 PET imaging experiment using ischemic heart disease model rats Wistar rats (male) were thoracotomized under isoflurane anesthesia, and the left coronary artery was ligated for 30 minutes, then reperfused, closed, and ischemic.
  • a heart disease model rat was prepared.
  • Compound [ 18 F] 101 is administered to the model rat one week after surgery (approximately 40 MBq / animal), and imaging is performed for approximately 10 minutes using a PET apparatus (exploreVISTA, manufactured by GEHC) 60 minutes after administration. Carried out. The results are shown in FIG. 3A.
  • the same experiment was conducted using normal rats (control rats). The results are shown in FIG. 3B.
  • compound [ 18 F] 100 was administered to a model rat prepared in the same manner as described above one week after the operation (about 40 MBq / animal), and immediately after the administration, it was dynamic and used for 60 minutes after the administration using the PET apparatus. Imaging was performed, and the image of the last frame (10 minutes), that is, the image from 50 minutes to 10 minutes after administration, is shown in FIG. 3C.
  • FIG. 3C 3A to 3C, (a) is a short-axis cross-sectional image, (b) is a horizontal long-axis cross-sectional image, and (c) is a vertical long-axis cross-sectional image.
  • the triangular arrowhead indicates the ischemic site of the heart, the arrow indicates the heart site, and the pentagonal arrow indicates the liver.
  • the compound [ 18 F] 101 of the present invention was accumulated in the model rat lesion (ischemic site), and the lesion (ischemic site) could be depicted. Further, the comparison between FIG. 3A and FIG. 3C shows that the lesioned part of the compound [ 18 F] 101 of the present invention can be depicted more than the compound [ 18 F] 100.

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Abstract

La présente invention concerne des composés qui s'accumulent à un niveau élevé dans des lésions cardiaques et qui sont appropriés en tant que traceur de médecine nucléaire dans l'imagerie TEP. L'invention porte en outre sur la détection in vivo de lésions cardiaques à l'aide desdits composés, et sur la fourniture d'un agent d'imagerie diagnostique non invasive pour une maladie cardiaque contenant en tant que principe actif un composé radiomarqué représenté par la formule (1) ou son sel. [Dans la formule, X1 représente un atome d'hydrogène ou un atome d'halogène, X2 représente un atome de fluor ou un groupe nitrile, et X3 représente un atome de fluor radioactif.]
PCT/JP2019/017441 2018-05-08 2019-04-24 Agent d'imagerie de diagnostic non invasif pour maladie cardiaque WO2019216223A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015199205A1 (fr) * 2014-06-26 2015-12-30 日本メジフィジックス株式会社 Composé dérivé de 2-(3-pyridinyl)-1h-benzimidazole et médicament le contenant
WO2017213247A1 (fr) * 2016-06-10 2017-12-14 日本メジフィジックス株式会社 Agent d'imagerie de diagnostic non invasif pour maladie cardiaque

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015199205A1 (fr) * 2014-06-26 2015-12-30 日本メジフィジックス株式会社 Composé dérivé de 2-(3-pyridinyl)-1h-benzimidazole et médicament le contenant
WO2017213247A1 (fr) * 2016-06-10 2017-12-14 日本メジフィジックス株式会社 Agent d'imagerie de diagnostic non invasif pour maladie cardiaque

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ABE, T. ET AL.: "A Novel CYP11B2-Specific Imaging Agent for Detection of Unilateral Subtypes of", PRIMARY ALDOSTERONISM, J CLIN ENDOCRINOL METAB, vol. 101, no. 3, 2016, pages 1008 - 15, XP055456963, ISSN: 0021-972X, DOI: 10.1210/jc.2015-3431 *

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