JP2009133803A - Identifying technique of liver fibrotic level and carbohydrate medicine imagery molecule imaging agent therefor - Google Patents

Identifying technique of liver fibrotic level and carbohydrate medicine imagery molecule imaging agent therefor Download PDF

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JP2009133803A
JP2009133803A JP2007317959A JP2007317959A JP2009133803A JP 2009133803 A JP2009133803 A JP 2009133803A JP 2007317959 A JP2007317959 A JP 2007317959A JP 2007317959 A JP2007317959 A JP 2007317959A JP 2009133803 A JP2009133803 A JP 2009133803A
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JP4780799B2 (en
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Bikei O
美惠 王
Wu-Jr Lin
武智 林
Shui-Cheng Lee
瑞成 李
Lie-Hang Shen
立漢 沈
Kozen Chin
浩然 陳
Li-Fu Lin
立夫 林
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Institute of Nuclear Energy Research
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique capable of identifying liver fibrotic level with precision clinically. <P>SOLUTION: In the liver target carbohydrate medicine imagery molecule imaging technique, (a) a medicine imagery imaging agent containing galactose peptide is injected intravenously and (b) medicine imagery signal generated from unit liver volume is measured by means of a medicine imagery device in a specific period. Here, as the medicine imagery imaging agent is Tc-99 m-SOCTA-galactopeptide or Tc-99 m-DTPA-galactopeptide, γ radiant quantity emitted from unit liver volume is measured by means of a single photon emission computed tomographic instrument. Or, as the medicine imagery imaging agent is a magnetic imaging agent, electromagnetic signal generated from unit liver volume is measured by means of a nuclear magnetic resonance apparatus. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は、肝臓標的糖質医学イメージ分子造影方法及びその糖質造影剤に関し、特に、肝臓繊維化の程度を定量的且つ客観的に識別してクラス分けすることに適用する方法及びその糖質の医学イメージ分子造影剤に関する。   TECHNICAL FIELD The present invention relates to a liver target carbohydrate medical image molecular imaging method and a carbohydrate contrast agent thereof, and more particularly, a method applied to quantitatively and objectively identifying and classifying the degree of liver fibrosis and the carbohydrate thereof Medical imaging molecular contrast agent.

現在の臨床肝臓繊維化の検査は、肝生検により肝臓組織切片を採取した後、病理専門家により肉眼で識別する（図９参照）。この種の侵略的な方法は、潜在する危険性があり、患者の多くに望まれない。また、診断は主観的判断に頼ることになり、また肝生検サンプリングは誤差が大きいので、これは現在唯一の方法であるが、正確性は決して高くない。 The current clinical fibrosis test is performed by collecting a liver tissue section by liver biopsy and then visually identifying it by a pathologist (see FIG. 9). This type of invasive method is potentially dangerous and not desired by many patients. Also, diagnosis is dependent on subjective judgment, and because liver biopsy sampling is error prone, this is currently the only method, but accuracy is never high.

Ｌｅｅは、１９８３年に三鎖構造のガラクトースペプチドと肝臓細胞受容体の結合力は、単鎖のガラクトースペプチドの１０6倍であることを報告している。ガラクトースペプチドは受容体と結合後、飲み込まれて肝臓細胞に進入する。Ｋｗｏｎは、２００４年局所貧血肝臓細胞膜上のガラクトースペプチド受容体と内部に飲み込まれるガラクトースペプチド量はいずれも減少し、且つ減少する量と局所貧血程度は正比例関係を有することを報告している。 Lee reported in 1983 that the binding force between a three-chain galactose peptide and a liver cell receptor is 10 6 times that of a single-chain galactose peptide. After binding to the receptor, the galactose peptide is swallowed and enters the liver cells. Kwon reported in 2004 that the amount of galactose peptide receptors on the local anemia liver cell membrane and the amount of galactose peptide swallowed inside are both reduced, and the amount of decrease and the extent of local anemia are directly proportional.

本発明は、肝臓繊維化検査方法のボトルネックを突破し、肝臓繊維化レベルを正確に識別する非侵略的検査方法及び糖質造影剤を提供し、該造影剤は肝臓標的糖質医学イメージ分子造影方法に合わせて、定量的且つ客観的に肝臓繊維化の程度を識別でき、肝臓繊維化のクラス分けを行う根拠とし、特に、治療後の効果追跡及び疾病をクラス分けする精密な診断に適用する。
特表２００７−５２６３００号公報 The present invention provides a non-invasive test method and a carbohydrate contrast agent that breaks through the bottleneck of the liver fibrosis test method and accurately identifies the level of liver fibrosis, and the contrast agent is a liver target carbohydrate medical imaging molecule. Quantitatively and objectively identify the degree of liver fibrosis according to the imaging method, and is used as a basis for classification of liver fibrosis, especially for accurate diagnosis after effect tracking and disease classification To do.
Special table 2007-526300 gazette

本発明の目的は、肝臓繊維化レベルを臨床上正確に識別する方法を提供し、肝臓標的糖質医学イメージ分子造影方法を完成し、検査時、肝生検等の組織または体液のサンプリングを行う必要がないようにすることにある。 An object of the present invention is to provide a method for clinically accurately identifying the level of liver fibrosis, to complete a liver-targeted carbohydrate medical imaging molecular imaging method, and to sample a tissue or body fluid such as a liver biopsy at the time of examination There is no need to do so.

一実施例中、本発明は、肝臓繊維化レベルを臨床上正確に識別することができる方法を提供し、肝臓標的糖質医学イメージ分子造影技術の完成によって、検査時、肝生検で組織または体液のサンプリングを行う必要がなく、以下のステップ：（ａ）ガラクトースペプチドを含む医学イメージイメージング剤を静脈注射し、（ｂ）特定時間内に医学イメージ器具で単位肝臓体積が発生する医学イメージ信号を測定する。 In one embodiment, the present invention provides a method that allows clinically accurate identification of liver fibrosis levels, and the completion of liver-targeted glycomedical imaging molecular imaging technology allows for tissue or liver biopsy at the time of examination. There is no need to sample a body fluid, and the following steps are: (a) a medical image imaging agent containing a galactose peptide is injected intravenously; (b) a medical image signal that generates a unit liver volume with a medical imaging device within a specified time. taking measurement.

他の実施例中、本発明は、更に肝臓繊維化レベルの評価に適用する肝臓標的糖質医学イメージ分子造影剤を提供し、それは、双官能基結合剤によってガラクトースペプチドを結合した後、医学イメージ用金属と結合させて造影剤とし、その特徴は、該造影剤が必要な双官能基結合剤が室温保存で潮解し難く、保存期間が1年以上に達することである。   In another embodiment, the present invention further provides a liver-targeted carbohydrate medical imaging molecular contrast agent that is applied to the evaluation of liver fibrosis level, which is a medical image after conjugating a galactose peptide with a bifunctional binder. It is combined with a metal for use as a contrast agent, and the feature is that the bifunctional group binding agent that requires the contrast agent is difficult to deliquesce at room temperature storage, and the storage period reaches one year or more.

本発明は、肝臓繊維化レベルを臨床上精確に識別する方法を提供し、肝臓標的糖質医学イメージ分子造影方法を完成し、検査時、肝生検等の組織または体液のサンプリングを行う必要がない。 The present invention provides a method for clinically accurately identifying liver fibrosis level, completes a liver-targeted carbohydrate medical imaging molecular imaging method, and needs to perform sampling of tissue or body fluid such as liver biopsy at the time of examination. Absent.

図１は、本発明の肝臓繊維化レベルを臨床上精確に識別することが可能な方法のフロー説明図である。図２は、本発明の肝臓標的糖質医学イメージ分子造影法の概念説明図である。本実施例中、該方法１は、肝臓標的糖質医学イメージ分子造影技術によって完成され、検査時、肝生検で組織または体液のサンプリングを行う必要がなく、それは、以下のステップからなる：先ず、ステップ１０を行い、１つの生物体上でガラクトースペプチドを含む医学イメージ造影剤(Galactopeptide imaging agent for liver targeting)を静脈注射する。続いて、ステップ１１を行い、特定時間内に医学イメージ機器で単位肝臓体積が発生する医学イメージ信号を測定する。そのうち、該医学イメージ造影剤は、放射性薬剤または磁性造影剤等の試剤を選択できる。１つの実施例中、該医学イメージ造影剤がTc-99m-SOCTA-galactopeptideまたはTc-99m-DTPA-galactopeptideである時、該医学イメージ機器は単光子放射コンピュータ断層測定機器で肝臓組織のγ放射量を収集し、その単位肝臓体積が放出するγ放射量を測定する。もう１つの実施例中、該医学イメージ造影剤が磁性造影剤である時、核磁気共振器で単位肝臓体積が発生する電磁信号を測定する。また、本実施例のステップ１１中、該特定時間の長さは、6時間以内である。   FIG. 1 is a flow explanatory diagram of a method capable of clinically accurately identifying the liver fibrosis level of the present invention. FIG. 2 is a conceptual explanatory diagram of the liver-targeted carbohydrate medical image molecular imaging method of the present invention. In this example, the method 1 is completed by the liver-targeted carbohydrate medical imaging molecular imaging technique, and at the time of examination, it is not necessary to perform tissue or body fluid sampling by liver biopsy, which consists of the following steps: Step 10 is performed, and a medical imaging contrast agent (Galactopeptide imaging agent for liver targeting) containing a galactose peptide is intravenously injected on one organism. Subsequently, step 11 is performed to measure a medical image signal in which a unit liver volume is generated in the medical image device within a specific time. Among them, as the medical image contrast agent, a reagent such as a radiopharmaceutical agent or a magnetic contrast agent can be selected. In one embodiment, when the medical imaging contrast agent is Tc-99m-SOCTA-galactopeptide or Tc-99m-DTPA-galactopeptide, the medical imaging device is a single photon emission computed tomography device and the amount of γ radiation of liver tissue. And measure the amount of γ radiation released by the unit liver volume. In another embodiment, when the medical image contrast agent is a magnetic contrast agent, an electromagnetic signal generated by a unit liver volume is measured by a nuclear magnetic resonator. Further, in step 11 of this embodiment, the length of the specific time is within 6 hours.

本発明が提示するTc-99m-SOCTA-galactopeptideは、肝臓繊維化レベルを識別するために用いられ、その基礎は、肝臓繊維化した肝臓が貧血状況にあり、局所貧血肝臓細胞が飲み込む医学イメージ造影剤剤量が貧血の程度に従い減少するので、図３のようなTc-99m-SOCTA-galactopeptide造影剤は図２の肝臓標的糖質の医学イメージ分子造影の概念に適合し、肝臓繊維化レベルの識別に用いることができる。医学イメージ分子造影の検査技術は従来技術に属するので、ここに記載しない。   The Tc-99m-SOCTA-galactopeptide presented by the present invention is used to identify the level of liver fibrosis, and the basis thereof is a medical imaging method in which the liver with fibrosis in the liver is in an anemia state and the local anemia liver cells are swallowed Since the amount of the drug decreases according to the degree of anemia, the Tc-99m-SOCTA-galactopeptide contrast agent as shown in FIG. 3 is compatible with the concept of medical image molecular imaging of liver target carbohydrate in FIG. Can be used for identification. Since the medical image molecular imaging examination technique belongs to the prior art, it is not described here.

図３の実施例中、SOCTAは、succinimidyl-3,6-diaza-5-oxo-3- [2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)-thio]octanoateの略記であり、その構造は、図４に示すとおりである。   In the example of FIG. 3, SOCTA is an abbreviation for succinimidyl-3,6-diaza-5-oxo-3- [2-((triphenylmethyl) thio) ethyl] -8-[(triphenylmethyl) -thio] octanoate The structure is as shown in FIG.

図２において、検査時、肝生検等で組織または体液のサンプリングを行う必要が無く、放射性薬剤Tc-99m-SOCTA-galactopeptideまたはTc-99m-DTPA-galactopeptideを人体に静脈注射し、Tc-99m-SOCTA-galactopeptideまたはTc-99m-DTPA-galactopeptideが標的として肝臓細胞受容体(Hepatic lectinまたはhepatic GalNAc receptorと証する)と結合し、中性子医学単光子放射コンピュータ断層測定機器で、肝臓細胞中Tc-99mが放射するγ射線と肝臓体積を測定し、単位肝臓体積が放出するγ射線量を算出し、この単位体積の医学イメージ数値が肝臓繊維化の程度を識別することに用い、肝臓繊維化程度のクラス分けの根拠することができる。磁性造影剤、例えば、Mn-DTPA-galactopeptideまたはGd-DTPA-galactopeptideを人体に静脈注射する場合、核磁気共鳴機器で単位肝臓体積が発生する電磁信号を測定することができる。同様に、この数値を肝臓繊維化の程度を識別することに用い、肝臓繊維化のクラス分けの根拠とすることができる。 In FIG. 2, at the time of examination, it is not necessary to sample tissues or body fluids by liver biopsy or the like, and the radioactive drug Tc-99m-SOCTA-galactopeptide or Tc-99m-DTPA-galactopeptide is intravenously injected into the human body, and Tc-99m -SOCTA-galactopeptide or Tc-99m-DTPA-galactopeptide binds to hepatic cell receptor (tested as Hepatic lectin or hepatic GalNAc receptor) as a target, and Tc-99m Γ-rays and liver volume radiated from the body, the γ-ray dose emitted by the unit liver volume is calculated, and the medical image value of this unit volume is used to identify the degree of liver fibrosis. It can be a basis for classification. When a magnetic contrast agent such as Mn-DTPA-galactopeptide or Gd-DTPA-galactopeptide is intravenously injected into a human body, an electromagnetic signal that generates a unit liver volume can be measured with a nuclear magnetic resonance apparatus. Similarly, this value can be used to identify the degree of liver fibrosis and serve as a basis for classification of liver fibrosis.

図３は、Tc-99m-SOCTA-galactopeptideの調合フローを説明し、第１ステップは、ガラクトースペプチドを凍晶SOCTA中に加え、SOCTAはimidazole ester bondでガラクトースペプチドとアミノ結合し、第２ステップは、SOCTAがN2S2構造を有するので直接Tc-99mを結合でき、従って、Tc-99m-SOCTA-galactopeptideの調合を完成することができる。該凍晶SOCTAは潮解し難く、室温保存が1年以上に達することができる。 FIG. 3 illustrates the preparation flow of Tc-99m-SOCTA-galactopeptide. In the first step, galactose peptide is added to frozen crystal SOCTA, SOCTA is amino-bonded with galactose peptide by imidazole ester bond, and the second step is In addition, since SOCTA has an N 2 S 2 structure, Tc-99m can be bound directly, and thus the preparation of Tc-99m-SOCTA-galactopeptide can be completed. The frozen crystal SOCTA is not easily deliquescent and can be stored at room temperature for more than one year.

医学的な検討によると、肝臓繊維化は、コラーゲンが異常に増加し、コラーゲンが肝臓門脈から中央の静脈に向かって徐々に増加することによって、肝臓細胞に進入し血流量が減少し、肝臓細胞がこの箇所で貧血状態になる。予期できるのはコラーゲンの増加が酷くなると、貧血程度も酷くなることである。肝臓繊維化時、肝臓は局所貧血状況であり、従来技術「局所貧血肝臓細胞上のガラクトースペプチド受容体とその内に飲み込まれたガラクトースペプチド量はいずれも減少し、且つ減少する量と貧血程度は正比例関係を有する」に基づき、その肝臓繊維化時に細胞膜上のガラクトースペプチド受容体が減少することを推測できると同時に、飲み込む肝臓細胞のTc-99m-SOCTA-galactopeptideも少なく、図３のようなTc-99m-SOCTA-galactopeptideは図２の肝臓標的糖質の医学イメージ分子造影の概念と技術に適合しているので、肝臓繊維化の程度を識別することに用いることができる。   According to medical examination, liver fibrosis is caused by abnormal increase in collagen, and collagen gradually increases from the liver portal vein toward the central vein, thereby entering the liver cells and reducing blood flow. Cells become anemic at this point. What can be expected is that when the increase in collagen becomes severe, the degree of anemia becomes severe. At the time of liver fibrosis, the liver is in a local anemia situation, and the prior art `` galactose peptide receptor on local anemia liver cells and the amount of galactose peptide engulfed therein are both reduced, and the amount of decrease and the degree of anemia are Based on the fact that the galactose peptide receptor on the cell membrane decreases during fibrosis of the liver, there is also a small amount of Tc-99m-SOCTA-galactopeptide in the swallowed liver cells, and the Tc as shown in FIG. Since -99m-SOCTA-galactopeptide is compatible with the concept and technique of medical image molecular imaging of liver target carbohydrate in FIG. 2, it can be used to identify the degree of liver fibrosis.

実験結果について分析すると、貧血時、ヘモグロビンαchain（分子量15.1kD）とヘモグロビンβchain（分子量15.9kD）はいずれも減少する。15.1kD（ヘモグロビンαchain）と15.9kD（ヘモグロビンβchain）の２つの蛋白のピークを固定観察し、SELDI-TOF（質量分析表面によって高められるレーザーの脱着またはイオン化経過時間を用いて）技術によって正常人と、肝臓繊維化患者の血清蛋白質図の変化を分析し、結果として肝臓繊維化患者の15.1kDと15.9kDこの２つの蛋白ピークが確実に減少または消失することが実証される、図５、図６参照。   Analyzing the experimental results, hemoglobin α chain (molecular weight 15.1 kD) and hemoglobin β chain (molecular weight 15.9 kD) both decrease during anemia. Two protein peaks, 15.1 kD (hemoglobin α chain) and 15.9 kD (hemoglobin β chain) are fixedly observed, and SELDI-TOF (using laser desorption or ionization elapsed time enhanced by the mass spectrometry surface) technique is used to connect normal subjects. Analysis of changes in serum protein diagram of liver fibrosis patients, and as a result, it is demonstrated that these two protein peaks are surely reduced or eliminated in liver fibrosis patients 15.1 kD and 15.9 kD. reference.

図５からF0級の肝臓繊維化患者がその他のレベルの肝臓繊維化患者と15.1kDと15.9kDの２つの蛋白ピークが明らかに異なることが分かる。   It can be seen from FIG. 5 that the F1 grade liver fibrosis patients are clearly different from other levels of liver fibrosis patients in the two protein peaks of 15.1 kD and 15.9 kD.

図６は、40人の肝臓繊維化患者の15.1kDと15.9kDの２つの蛋白ピークの数値の統計分析であり、F0級の肝臓繊維化患者とその他のレベルの肝臓繊維化患者が15.1kDと15.9kDの２つの蛋白ピークが明らかに異なることが分かる。   Figure 6 is a statistical analysis of the numerical values of the two protein peaks at 15.1 kD and 15.9 kD in 40 liver fibrosis patients, with F1 grade liver fibrosis patients and other levels of liver fibrosis patients at 15.1 kD. It can be seen that the two protein peaks at 15.9 kD are clearly different.

正常人と肝臓繊維化患者の血清蛋白図の分析以外に、本発明は正常なマウスの肝臓と肝臓繊維化マウスの肝臓の組織蛋白図を分析した。マウスの肝臓は、冷凍した切片をガラス片に固定し、質量分析用のエネルギー量吸収物質を噴射し、同時に組織原位に組織蛋白を抽出し、エネルギー量吸収物質と混合させ、MALDI-TOF分析を行い、同様に15.1kD（ヘモグロビンαchain）と15.9kD（ヘモグロビンβchain）の変化を固定観察する。その結果、同様に繊維化マウスの肝臓の15.1kDと15.9kDの２つの蛋白ピークが大幅に減少することが実証される、図７、図８参照。   In addition to analysis of serum protein diagrams of normal individuals and liver fibrosis patients, the present invention analyzed tissue protein diagrams of normal mouse liver and liver of liver fibrosis mice. Mouse liver, frozen section fixed to glass piece, energy absorption material for mass spectrometry is injected, tissue protein is extracted at the same time, mixed with energy absorption material, MALDI-TOF analysis Similarly, the changes of 15.1 kD (hemoglobin α chain) and 15.9 kD (hemoglobin β chain) are fixedly observed. As a result, it is demonstrated that the two protein peaks of 15.1 kD and 15.9 kD in the liver of the fibrotic mouse are also greatly reduced, see FIGS. 7 and 8.

図７から、正常なマウスの肝臓と繊維化マウスの肝臓の分子量15197.2蛋白の発現が明らかに異なり、繊維化マウス肝臓が明らかに減少していることが分かる。   From FIG. 7, it can be seen that the expression of the molecular weight 15197.2 protein in the liver of normal mice and the liver of fibrotic mice is clearly different, and the fibrotic mouse liver is clearly decreased.

図８から、正常なマウスの肝臓と繊維化マウスの肝臓の分子量15858.3蛋白の発現が明らかに異なり、繊維化マウス肝臓の方が、明らかに減少が大きいことが分かる。   From FIG. 8, it can be seen that the expression of molecular weight 15858.3 protein in the liver of normal mouse and that of fibrotic mouse are clearly different, and that the decrease in fibrotic mouse liver is clearly larger.

ヘモグロビンの減少は、肝臓繊維化が、確かに貧血現象が存在していることを説明している。肝臓標的糖質分子イメージ技術はイメージ空間分布および量化データを提供し、ガラクトースペプチドをイメージ医学用の金属に接触させ、静脈注射すれば、肝臓繊維化の程度を精確に識別でき、肝臓繊維化クラス分け診断と治療後の効果追跡の検査方法とすることができる。   The decrease in hemoglobin explains that liver fibrosis does indeed exist for anemia. Liver-targeted carbohydrate molecular imaging technology provides image spatial distribution and quantification data, and when the galactose peptide is contacted with an imaging medical metal and injected intravenously, the degree of liver fibrosis can be accurately identified and liver fibrosis class It can be set as the inspection method of divided diagnosis and effect tracking after treatment.

肝臓繊維化を早期発見し、適切に投薬し、肝臓繊維化が完全に復原するまで好転させることができ、肝臓標的糖質医学イメージ分子造影は、イメージ空間分布と定量データを提供でき、肝臓繊維化レベルの精確な識別のための検査方法を提供できる。   Liver fibrosis can be detected early, properly dosed and reversed until hepatic fibrosis is fully restored, liver-targeted glycomedical imaging molecular imaging can provide image spatial distribution and quantitative data, liver fibrosis It is possible to provide an inspection method for accurate identification of the activation level.

造影剤方面において、本発明の実施例は、Tc-99m-SOCTA-galactopeptideを定量且つ肝臓繊維化の程度を識別する肝臓標的糖質イメージ分子造影剤として採用する。Galactopeptideと肝臓細胞は強力な結合力を備え、SOCTAの保存安定性は明らかにDTPAより優れている。従来使用する双官能基結合剤の多くは、DTPA anhydride (DTPA:diethylene-triamine-penta-acetic acid)を用い、この双官能基結合剤は弱アルカリ水溶液中でアミノ基と反応が速く、2時間内に反応が完成するが、空気に触れると不安定になり、潮解しやすく、保存が困難である。それに対してSOCTAの安定性は好ましく、凍晶のSOCTAは室温に1年放置しても依然としてアミノ基との結合に用いることができ、それとアミノ基の結合反応が比較的時間がかかるが、通常16時間であり、潮解し難く、空気に触れても安定であり、１つの薬場の原料の1つとし、長期保存でき、有利である。   In the direction of the contrast agent, the examples of the present invention employ Tc-99m-SOCTA-galactopeptide as a liver target carbohydrate image molecular contrast agent that quantitatively identifies the degree of liver fibrosis. Galactopeptide and liver cells have a strong binding force, and the storage stability of SOCTA is clearly superior to DTPA. Many of the conventionally used bifunctional binders use DTPA anhydride (DTPA: diethylene-triamine-penta-acetic acid), which reacts with amino groups quickly in weak alkaline aqueous solution for 2 hours. The reaction is completed inside, but when exposed to air, it becomes unstable, easily deliquescent, and difficult to preserve. On the other hand, the stability of SOCTA is preferred, and frozen crystal SOCTA can still be used for binding with amino groups even after standing at room temperature for 1 year, and the binding reaction of amino groups with it takes a relatively long time. It is 16 hours, hard to deliquesce, stable even when exposed to the air, and can be stored for a long time as one of the raw materials of one drugstore.

図４は、SOCTAの化学構造であり、SOCTAは末端のimidazole ester bondでガラクトースペプチドとアミノ結合し、SOCTAがN2S2構造を有するのでTc-99mを結合し、肝臓標的糖質医学イメージ分子造影剤となることができる。 Fig. 4 shows the chemical structure of SOCTA. SOCTA is amino-bonded with a galactose peptide at the terminal imidazole ester bond, and TCC-99m is bonded to the liver target carbohydrate medical imaging molecule because SOCTA has an N 2 S 2 structure. Can be a contrast agent.

なお、本発明では好ましい実施例を前述の通り開示したが、これらは決して本発明を限定するものではなく、当該技術を熟知する者なら誰でも、本発明の精神と領域を脱しない均等の範囲内で各種の変動や潤色を加えることができることは勿論である。前記の実施例の説明中、Tc-99m-SOCTA-galactopeptideにより説明しているが、本発明はこれに制限するものではなく、潮解し難く、N2S2構造を有し、末端がester bondであれば、いずれもガラクトースペプチドとアミノ基結合でき、Tc-99mを結合し、肝臓標的糖質医学イメージ分子造影剤となることができる。DTPA anhydrideは、潮解し易いが、Mn-DTPA-galactopeptideとTc-99m-DTPA-galactopeptideの調合が可能であるため、本発明を実施でき、肝臓繊維化クラス分けの肝臓標的糖質医学イメージ分子造影剤とすることができる。 In the present invention, preferred embodiments have been disclosed as described above, but these are not intended to limit the present invention in any way, and any person who is familiar with the technology does not depart from the spirit and scope of the present invention. Of course, various fluctuations and hydration colors can be added. In the description of the above examples, Tc-99m-SOCTA-galactopeptide is used for explanation, but the present invention is not limited to this, it is difficult to deliquesce, it has an N 2 S 2 structure, and the end is an ester bond. Any of these can bind amino groups to galactose peptides, bind Tc-99m, and become a liver-targeted carbohydrate medical imaging molecular contrast agent. DTPA anhydride is easy to deliquesce, but since the preparation of Mn-DTPA-galactopeptide and Tc-99m-DTPA-galactopeptide is possible, the present invention can be carried out, and liver target carbohydrate medical imaging molecular imaging of liver fibrosis classification It can be used as an agent.

本発明の肝臓繊維化レベルを臨床精確識別することに適用可能な方法のフロー説明図である。It is a flow explanatory diagram of a method applicable to clinically accurate identification of the liver fibrosis level of the present invention. 図２は、本発明の肝臓標的糖質医学イメージ分子造影概念の説明図である。FIG. 2 is an explanatory view of the liver target carbohydrate medical image molecular imaging concept of the present invention. 本発明のTc-99m-SOCTA-galactopeptide調合フロー図である。It is a Tc-99m-SOCTA-galactopeptide preparation flow chart of the present invention. 本発明のSOCTAの構造説明図である。It is structure explanatory drawing of SOCTA of this invention. 本発明のSELDI-TOF分析による血清蛋白質の化学式の説明図である。It is explanatory drawing of the chemical formula of the serum protein by the SELDI-TOF analysis of this invention. 本発明のSELDI-TOF分析による血清蛋白質の化学式の化学式の統計分析図である。It is a statistical analysis figure of the chemical formula of the chemical formula of serum protein by SELDI-TOF analysis of the present invention. 本発明の組織蛋白質図であり、15.1kDの蛋白発現量を示す図である。It is a tissue protein figure of this invention, and is a figure which shows the protein expression level of 15.1 kD. 本発明の組織蛋白質図であり、15.9kDの蛋白発現量を示す図である。It is a tissue protein figure of this invention, and is a figure which shows the protein expression level of 15.9kD. 現在臨床肝臓繊維化組織病理切片クラス分けの結果図である。It is a result figure of clinical liver fibrosis histopathology section classification now.

符号の説明Explanation of symbols

１ 肝臓繊維化レベルの識別方法
１０〜１１ ステップ 1 liver fibrosis level identification method 10-11 steps

Claims (8)

肝臓標的糖質医学イメージ分子造影法において、
（ａ）ガラクトースペプチドを含む医学イメージ造影剤を静脈注射し、
（ｂ）特定時間内に医学イメージ器具で単位肝臓体積が発生する医学イメージ信号を測定する
ことからなる肝臓繊維化レベルを臨床的に識別する方法。 In liver targeted carbohydrate medicine image molecular imaging,
(A) intravenously injecting a medical imaging contrast agent comprising a galactose peptide;
(B) A method of clinically identifying a liver fibrosis level comprising measuring a medical image signal in which a unit liver volume is generated with a medical image instrument within a specified time. 前記医学イメージ造影剤がTc-99m-SOCTA-galactopeptideまたはTc-99m-DTPA-galactopeptideであり、単光子放射コンピュータ断層測定機器で単位肝臓体積が放出するγ放射量を測定する請求項１記載の肝臓繊維化レベルを臨床的に識別する方法。 The liver according to claim 1, wherein the medical image contrast agent is Tc-99m-SOCTA-galactopeptide or Tc-99m-DTPA-galactopeptide, and the amount of γ radiation released by the unit liver volume is measured with a single photon emission computed tomography instrument. A method for clinically identifying fibrosis levels. 前記医学イメージ造影剤が磁性造影剤であり、核磁気共鳴機器で単位肝臓体積が発生する電磁信号を測定する請求項１記載の肝臓繊維化レベルを臨床的に識別する方法。 2. The method of clinically identifying a liver fibrosis level according to claim 1, wherein the medical image contrast agent is a magnetic contrast agent and an electromagnetic signal generated by a unit liver volume is measured by a nuclear magnetic resonance apparatus. 前記特定時間の長さが、6時間以内である請求項１記載の肝臓繊維化レベルを臨床的に識別する方法。 The method for clinically identifying a liver fibrosis level according to claim 1, wherein the length of the specific time is 6 hours or less. 双官能基結合剤によってガラクトースペプチドを結合した後、医学イメージ用金属と結合させて医学イメージ造影剤とし、該造影剤が必要な双官能基結合剤が室温保存で潮解し難く、保存期間が1年以上に達する肝臓繊維化レベルの評価に適用する肝臓標的糖質医学イメージ分子造影剤。 After binding the galactose peptide with a bifunctional group binder, it is combined with a medical image metal to form a medical image contrast agent. The bifunctional group binder that requires the contrast agent is difficult to deliquesce at room temperature storage, and the storage period is 1 A liver-targeted carbohydrate medical imaging molecular contrast agent applied to the evaluation of liver fibrosis levels reaching more than a year. 前記双官能基結合剤がN2S2構造を有、Tc-99mを結合し、その末端にester bondを有し、ガラクトースペプチドとアミノ結合した請求項５記載の肝臓繊維化レベルの評価に適用する肝臓標的糖質医学イメージ分子造影剤。 The bifunctional group binding agent has an N 2 S 2 structure, binds Tc-99m, has an ester bond at its end, and is amino-bonded to a galactose peptide. To the liver target carbohydrate medicine image molecular contrast agent. 前記双官能基結合剤がSOCTA（succinimidyl-3,6-diaza-5-oxo-3- [2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)-thio]octanoate）である請求項５記載の肝臓繊維化レベルの評価に適用する肝臓標的糖質医学イメージ分子造影剤。 The bifunctional group binder is SOCTA (succinimidyl-3,6-diaza-5-oxo-3- [2-((triphenylmethyl) thio) ethyl] -8-[(triphenylmethyl) -thio] octanoate) A liver-targeted carbohydrate medical imaging molecular contrast agent applied to the evaluation of liver fibrosis level according to 5. 前記造影剤のガラクトースペプチドが三鎖型のペプチドである請求項５記載の肝臓繊維化レベルの評価に適用する肝臓標的糖質医学イメージ分子造影剤。 The liver-targeted carbohydrate medical imaging molecular contrast agent applied to the evaluation of liver fibrosis level according to claim 5, wherein the contrast agent galactose peptide is a three-chain peptide.
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