JPH01176000A - Radioactive medicine and polymer compound for preparing said medicine - Google Patents
Radioactive medicine and polymer compound for preparing said medicineInfo
- Publication number
- JPH01176000A JPH01176000A JP63078448A JP7844888A JPH01176000A JP H01176000 A JPH01176000 A JP H01176000A JP 63078448 A JP63078448 A JP 63078448A JP 7844888 A JP7844888 A JP 7844888A JP H01176000 A JPH01176000 A JP H01176000A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- polymer compound
- metal element
- radioactive
- dtpa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 80
- 230000002285 radioactive effect Effects 0.000 title claims abstract description 40
- 229920000642 polymer Polymers 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title abstract description 5
- 229910052751 metal Inorganic materials 0.000 claims abstract description 36
- 239000002184 metal Substances 0.000 claims abstract description 35
- 239000003446 ligand Substances 0.000 claims abstract description 30
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 22
- 108010002913 Asialoglycoproteins Proteins 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 239000012217 radiopharmaceutical Substances 0.000 claims description 15
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 15
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- 229960003330 pentetic acid Drugs 0.000 abstract description 21
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 abstract description 19
- 108010006523 asialoglycoprotein receptor Proteins 0.000 abstract description 19
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 abstract description 15
- -1 cyclic acid anhydride Chemical class 0.000 abstract description 13
- 239000013522 chelant Substances 0.000 abstract description 7
- 238000003756 stirring Methods 0.000 abstract description 7
- 239000007853 buffer solution Substances 0.000 abstract description 5
- 208000019423 liver disease Diseases 0.000 abstract description 3
- 108010044715 asialofetuin Proteins 0.000 abstract description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract 1
- 229910052738 indium Inorganic materials 0.000 abstract 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000002347 injection Methods 0.000 description 24
- 239000007924 injection Substances 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 238000001962 electrophoresis Methods 0.000 description 8
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- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 7
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- XAYJLNQRRDKMGS-YTQLPXDHSA-N (4r,5s,6s,7r)-4,5,6,7,8-pentahydroxy-3-sulfanylideneoctanenitrile Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=S)CC#N XAYJLNQRRDKMGS-YTQLPXDHSA-N 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
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- 238000001727 in vivo Methods 0.000 description 4
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 102000008100 Human Serum Albumin Human genes 0.000 description 3
- 108091006905 Human Serum Albumin Proteins 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- YEEGWNXDUZONAA-UHFFFAOYSA-K 5-hydroxy-2,8,9-trioxa-1-gallabicyclo[3.3.2]decane-3,7,10-trione Chemical compound [Ga+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YEEGWNXDUZONAA-UHFFFAOYSA-K 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- GYHNNYVSQQEPJS-OIOBTWANSA-N Gallium-67 Chemical compound [67Ga] GYHNNYVSQQEPJS-OIOBTWANSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 229940055742 indium-111 Drugs 0.000 description 2
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 2
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- 229910052713 technetium Inorganic materials 0.000 description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
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- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- PMHQXRGRBMOZDU-UHFFFAOYSA-N 1,1-diaminoethanethiol Chemical compound CC(N)(N)S PMHQXRGRBMOZDU-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- GFIWSSUBVYLTRF-UHFFFAOYSA-N 2-[2-(2-hydroxyethylamino)ethylamino]ethanol Chemical compound OCCNCCNCCO GFIWSSUBVYLTRF-UHFFFAOYSA-N 0.000 description 1
- CQMNNMLVXSWLCH-UHFFFAOYSA-B 2-hydroxypropane-1,2,3-tricarboxylate;tin(4+) Chemical compound [Sn+4].[Sn+4].[Sn+4].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O CQMNNMLVXSWLCH-UHFFFAOYSA-B 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- QXADHXQCAQTNGW-UHFFFAOYSA-M sodium;boric acid;hydroxide Chemical compound [OH-].[Na+].OB(O)O QXADHXQCAQTNGW-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- CVKJXWOUXWRRJT-UHFFFAOYSA-N technetium dioxide Chemical compound O=[Tc]=O CVKJXWOUXWRRJT-UHFFFAOYSA-N 0.000 description 1
- BKVIYDNLLOSFOA-OIOBTWANSA-N thallium-201 Chemical compound [201Tl] BKVIYDNLLOSFOA-OIOBTWANSA-N 0.000 description 1
- ZIPSUOPRDBUYPW-UHFFFAOYSA-J thorium(4+) tetrabenzoate Chemical compound C(C1=CC=CC=C1)(=O)[O-].[Th+4].C(C1=CC=CC=C1)(=O)[O-].C(C1=CC=CC=C1)(=O)[O-].C(C1=CC=CC=C1)(=O)[O-] ZIPSUOPRDBUYPW-UHFFFAOYSA-J 0.000 description 1
- FAKFSJNVVCGEEI-UHFFFAOYSA-J tin(4+);disulfate Chemical compound [Sn+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O FAKFSJNVVCGEEI-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YJGJRYWNNHUESM-UHFFFAOYSA-J triacetyloxystannyl acetate Chemical compound [Sn+4].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O YJGJRYWNNHUESM-UHFFFAOYSA-J 0.000 description 1
- YQMWDQQWGKVOSQ-UHFFFAOYSA-N trinitrooxystannyl nitrate Chemical compound [Sn+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O YQMWDQQWGKVOSQ-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- HCHKCACWOHOZIP-OIOBTWANSA-N zinc-62 Chemical compound [62Zn] HCHKCACWOHOZIP-OIOBTWANSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は放射性医薬品とその調製用高分子化合物に関す
る。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a radiopharmaceutical and a polymer compound for its preparation.
（従来技術）
アシアロ糖蛋白質受容体は、動物レクチンと呼ばれる分
子識別能を有する蛋白質の一種であり、動物細胞、特に
肝細胞に広く見出だされている。(Prior Art) The asialoglycoprotein receptor is a type of protein called animal lectin that has molecular recognition ability, and is widely found in animal cells, especially hepatocytes.
・人肝細胞から単離されているアシアロ糖蛋白質受容体
は分子量約４万の単一なポリペプチドから構成されてお
り、糖鎖非還元末端にガラクトース残基を持つ糖蛋白質
（アシアロ糖蛋白質）を識別する受容体である。・The asialoglycoprotein receptor isolated from human liver cells is composed of a single polypeptide with a molecular weight of approximately 40,000, and is a glycoprotein (asialoglycoprotein) with a galactose residue at the non-reducing end of the sugar chain. It is a receptor that identifies
アシアロ糖蛋白質受容体の生理学的な機能については不
明な点が多いが、肝細胞表面に存在する受容体は肝血流
中の糖蛋白質と結合して複合体を形成し、細胞内に取り
込まれた後、細胞内を輸送され、ライソゾームで解離す
ることから、糖蛋白質の代謝過程を担っていると信じら
れている。このため慢性肝炎、肝硬変、原発性肝ガン等
の肝疾患では、アシアロ糖蛋白質の血中濃度が上昇する
と言う現象が見られ、薬物投与によって作成した実験的
肝障害モデルでは肝臓のアシアロ糖蛋白質受容体の量が
低下する事実が認められている。Although much remains unknown about the physiological functions of asialoglycoprotein receptors, the receptors present on the surface of hepatocytes bind to glycoproteins in the hepatic bloodstream to form complexes that are taken up into cells. After that, it is transported within the cell and dissociated in lysosomes, so it is believed that it plays a role in the metabolic process of glycoproteins. Therefore, in liver diseases such as chronic hepatitis, cirrhosis, and primary liver cancer, a phenomenon in which the blood concentration of asialoglycoprotein increases is observed, and in experimental liver damage models created by drug administration, the asialoglycoprotein receptor in the liver is It is acknowledged that body mass decreases.
このことはアシアロ糖蛋白質様物質、すなわちアシアロ
糖蛋白質受容体指向性化合物を用いて、肝臓中のアシア
ロ糖蛋白質受容体の量及び質を評価することにより肝疾
患を診断することが可能であることを意味する。This means that it is possible to diagnose liver disease by evaluating the quantity and quality of asialoglycoprotein receptors in the liver using asialoglycoprotein-like substances, that is, asialoglycoprotein receptor-directed compounds. means.
（発明が解決しようとする問題点）
上記のような診断方法においては、放射性同位元素を用
いる核医学的手法が適しているが、従来標識に用いられ
てきた核種としては、ヨウ素元素の放射性同位体である
ｌ−１３１及びｌ−１２５放射性金属元素であるテクネ
チウム（Ｔｃ−９９ｍ）等が知られている。しかしなが
ら、ｒ−１３１や１−１２５は、物理学的半減期が長く
（８日及び６０日）、かつ生体内において酵素的に脱ヨ
ード化反応をうけ、目的臓器以外の組織に放射性被曝を
与えると共に、動態検査や定量的評価に誤差を与えるた
め、適当な核種とは言えない。(Problems to be solved by the invention) Nuclear medicine methods using radioisotopes are suitable for the above-mentioned diagnostic methods, but radioisotopes of iodine have been used as nuclides that have been conventionally used for labeling. Technetium (Tc-99m), a radioactive metal element, and the like are known. However, r-131 and 1-125 have long physical half-lives (8 and 60 days) and undergo enzymatic deiodination reactions in vivo, causing radioactive exposure to tissues other than the target organ. At the same time, it causes errors in dynamic tests and quantitative evaluations, so it cannot be said to be an appropriate nuclide.
テクネチウム−９９ｍにはそのような欠点が認められな
いが、分子内にテクネチウムとキレート結合を形成しう
る配位子を持ち、結合部位を有するアシアロ糖蛋白質受
容体指向性化合物に限り有効である。例えば、ガラクト
ース結合血清アルブミン（以後ＮＧＡ（ネオガラクトア
ルブミン）と略す。）は分子内のシスティン、リジン、
グルタミン酸残基等を介してテクネチウムと結合するこ
とができる。しかしながら、その結合能や結合安定性は
必ずしも充分に満足出来るものではない。例えば代表的
な放射性金属であるテクネチウム−９９ｍを標識する場
合、標識化のため過テクネチウム塩と還元剤としての第
一スズ塩を組み合わせて使用するのが普通であるが、得
られた標識体のイン・ビトロ並びにイン・ビボにおける
安定性が充分でないため、不安定化に伴ってコロイド様
の二酸化テクネチウム（”ＩＩＩＴＣＯりを含む不純物
が生成する。この物質は肝臓の網内系に取り込まれるた
め、その存在はアシアロ糖蛋白質受容体の様相を評価し
えなくする。安定性を向上させるためには還元剤である
第一スズ塩の使用量を増加させればよいが、第一スズ塩
はテクネチウム標識が可能な弱酸性以上のｐＨ領域にお
いてコロイド化し、精確なイメージングを困難にする。Although technetium-99m does not have such a drawback, it is only effective for asialoglycoprotein receptor-directed compounds that have a binding site and a ligand that can form a chelate bond with technetium in the molecule. For example, galactose-bound serum albumin (hereinafter abbreviated as NGA (neogalactalbumin)) has cysteine, lysine,
It can bind to technetium via glutamic acid residues and the like. However, its binding ability and binding stability are not necessarily fully satisfactory. For example, when labeling technetium-99m, a typical radioactive metal, it is common to use a combination of pertechnetium salt and stannous salt as a reducing agent. Due to insufficient stability in vitro and in vivo, destabilization results in the formation of impurities including colloidal technetium dioxide (IIITCO). This substance is taken up by the reticuloendothelial system of the liver, Its presence makes it impossible to evaluate the aspect of the asialoglycoprotein receptor.In order to improve the stability, it is possible to increase the amount of stannous salt, which is a reducing agent, but stannous salt It forms a colloid in the slightly acidic or higher pH range where labeling is possible, making accurate imaging difficult.
これを防ぐには、ＮＧＡを充分量加えてこれに遊離の第
一スズ塩を結合させればよいが、この結果放射性比濃度
を上げることが困難となる。このことはＮＧＡのような
受容体指向性化合物の場合、その使用量に制限があるこ
とを考えると、好ましいものではない。This can be prevented by adding a sufficient amount of NGA to bind the free stannous salt, but this makes it difficult to increase the radioactive specific concentration. This is not desirable in the case of receptor-directed compounds such as NGA, considering that there is a limit to the amount of the receptor-directed compound used.
（問題点を解決するための手段）
本発明者等は種々研究を重ねた結果、アシアロ糖蛋白質
受容体指向性化合物に２官能性配位子化合物を結合させ
た高分子化合物が放射性金属元素のキャリヤーとして有
用であり、かかるキャリヤーに放射性金属元素を結合さ
せた放射性金属元素結合高分子化合物は前記欠点が克服
された放射性医薬品として有用であることを見出だした
。(Means for Solving the Problems) As a result of various studies, the present inventors have discovered that a polymer compound in which a bifunctional ligand compound is bonded to an asialoglycoprotein receptor-directed compound is capable of absorbing radioactive metal elements. It has been found that a radioactive metal element-bound polymer compound, which is useful as a carrier, and in which a radioactive metal element is bound to such a carrier, is useful as a radiopharmaceutical that overcomes the above-mentioned drawbacks.
上記放射性金属元素結合高分子化合物は、放射性金属元
素と強固なキレート結合を形成する２官能性配位子を有
しており、イン・ビトロ及びイン・ビボのいずれにおい
ても安定であるため、高圧放射性医薬品を提供すること
が可能である。The above-mentioned radioactive metal element-bonded polymer compound has a bifunctional ligand that forms a strong chelate bond with the radioactive metal element, and is stable both in vitro and in vivo. It is possible to provide radiopharmaceuticals.
本発明の要旨は、
２官能性配位子化合物（１）とアシアロ糖蛋白質受容体
指向性化合物（２）を化学結合させて成る高分子化合物
（Ａ）、
該高分子化合物（Ａ）に放射性金属元素（３）をキレー
ト結合させて成る放射性金属元素結合高分子化合物（Ｂ
）、
前記高分子化合物（Ａ）を含む放射性医薬品調製用組成
物（Ｃ）、及び
前記放射性金属元素結合高分子化合物（Ｂ）を含む放射
性医薬品（Ｄ）
に存する。The gist of the present invention is to provide a polymer compound (A) formed by chemically bonding a bifunctional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2); A radioactive metal element-bonded polymer compound (B) formed by chelating a metal element (3)
), a radiopharmaceutical preparation composition (C) containing the polymer compound (A), and a radiopharmaceutical (D) containing the radioactive metal element-bonded polymer compound (B).
上記高分子化合物（Ａ）及び放射性金属元素結合高分子
化合物（Ｂ）は文献未載の新規物質であり、アシアロ糖
蛋白質受容体を含む臓器の描出、アシアロ糖蛋白質受容
体の量及び質に変化を来す疾患の検出、アシアロ糖蛋白
質受容体の動態検査等の核医学的用途に適した放射性医
薬品を提供することができるものである。また、アシア
ロ糖蛋白質受容体は主として肝細胞に存在するものであ
るから、従来品とは異なった診断能力を有する肝イメー
ジング剤を提供することが出来る。The above-mentioned polymer compound (A) and radioactive metal element-bound polymer compound (B) are new substances that have not been described in any literature, and they can visualize organs containing asialoglycoprotein receptors and change the quantity and quality of asialoglycoprotein receptors. The present invention can provide a radiopharmaceutical suitable for nuclear medicine applications such as detection of diseases causing asialoglycoprotein receptors and dynamic examination of asialoglycoprotein receptors. Furthermore, since the asialoglycoprotein receptor is mainly present in hepatocytes, it is possible to provide a liver imaging agent that has diagnostic ability different from conventional products.
（作用）
上記２官能性配位子化合物（１）としては、放射性金属
元素（３）に対して強固なキレート結合を形成し得る２
官能性配位子を有し、かつ比較的緩和な条件下でアシア
ロ糖蛋白質受容体指向性化合物（２）と反応し得る官能
基（例えばアミノ基、カルボキシル基、ホルミル基、チ
オール括）を有するものが使用される。その具体例とし
ては、式％式％
で表されるジエチレントリアミン五酢酸サイクリック酸
無水物、式
で表されるエチレンジアミン四酢酸すクシンイミドエス
テル、式
％式％
（式中、Ｒ１及びＲ１はそれぞれ水素、Ｃ７〜Ｃ３アル
キルまたはフェニルを示す。）で表される３−アミノメ
チレン−２，４−ペンタンジオン−ビス（チオセミカル
バゾン）誘導体、式
％式％
（式中、Ｒ１及びＲ１はそれぞれ水素またはＣｌ−０３
アルキル、ｎはθ〜３の整数を示す。）で表される１−
（ｐ−アミノアルキル）フェニルプロパン−１゜２−ジ
オン−ビス（チオセミカルバゾン）誘導体、デフェロキ
サミン、式
％式％
（式中、ＲＩ””’ Ｒｓは水素または０１〜Ｃ３アル
キルを示す。）で表される２−プロピオンアルデヒド−
ビス（チオセミカルバゾン）誘導体などが挙げられる。(Function) The above-mentioned bifunctional ligand compound (1) is a compound capable of forming a strong chelate bond with the radioactive metal element (3).
It has a functional ligand and has a functional group (e.g., amino group, carboxyl group, formyl group, thiol group) that can react with the asialoglycoprotein receptor-directed compound (2) under relatively mild conditions. things are used. Specific examples thereof include diethylenetriaminepentaacetic acid cyclic acid anhydride represented by the formula %, ethylenediaminetetraacetic acid succinimide ester represented by the formula, and formula % (where R1 and R1 are each hydrogen , C7-C3 alkyl or phenyl), a 3-aminomethylene-2,4-pentanedione-bis(thiosemicarbazone) derivative represented by the formula % formula % (wherein R1 and R1 are each hydrogen or Cl-03
Alkyl and n represent an integer of θ to 3. ) 1−
(p-Aminoalkyl)phenylpropane-1゜2-dione-bis(thiosemicarbazone) derivative, deferoxamine, formula % (wherein, RI""' Rs represents hydrogen or 01-C3 alkyl) 2-propionaldehyde represented by
Examples include bis(thiosemicarbazone) derivatives.
なお、そのもの自体はアシアロ糖蛋白質受容体指向性化
合物（２）と結合することができる官能基を有していな
くとも、容易にアミノ基、カルボキシル基、アルデヒド
基、チオール基等の官能基を導入し得る基または構造を
有してい°る場合は、放射性金属元素を捕捉する性質を
有する限り、２官能性配位子化合物（１）として使用す
ることかできる。例えばジメルカプトアセチルエチレン
ジアミン（Ｆ ｒｉｔｚｂｅｒｇ等： Ｊ、Ｎｕｃｌ、
Ｍｅｄ、、 ２３．９１７（１９８２））及びビスアミ
ノエタンチオール（ｐ ｒｉｔｚｂｅｒｇ等： Ｊ、Ｎ
ｕｃｌ、Ｍｅｄ、、 ２５．９１６（１９８４））に代
表されるＮ ｔ Ｓ ｔリガンド、サイクラン（Ｋｅｉ
ｒｉｎｇ等：Ｊ。Furthermore, even if the compound itself does not have a functional group capable of binding with the asialoglycoprotein receptor-directed compound (2), functional groups such as amino groups, carboxyl groups, aldehyde groups, and thiol groups can be easily introduced. If the compound has a group or structure capable of capturing a radioactive metal element, it can be used as the bifunctional ligand compound (1) as long as it has the property of capturing a radioactive metal element. For example, dimercaptoacetylethylenediamine (Fritzberg et al.: J, Nucl.
Med., 23.917 (1982)) and bisaminoethanethiol (Pritzberg et al.: J,N
Ucl, Med., 25.916 (1984));
ring et al.: J.
Ｎｕｃｌ、Ｍｅｄ、、 ２３．９１７（１９８２））に
代表されるＮ４リガンド、Ｎ、Ｎ’−ビス（２−ヒドロ
キシエチル）エチレンジアミン（Ｗａｇｎｅｒ Ｊｒ、
等： Ｐ ｒｏｃｅｅｄｉｎｇｓｏｆｔｈｅ Ｉ ｎｔ
ｅｒｎａｔｉｏｎａｌ Ｓｙｍｐｏｓｉｕ＋ｎ ｏｎ
Ｔｅｃｈｎｅ−ｔｉｕｍ ｉｎ Ｃｈｅｍｉｓｔｒｙ
ａｎｄ Ｎｕｃｌｅａｒ Ｍｅｄｉｃｉｎｅ。Nucl, Med., 23.917 (1982)), N,N'-bis(2-hydroxyethyl)ethylenediamine (Wagner Jr.,
etc.:ProceedingsoftheInt
ernational symposiu+n on
Technology in Chemistry
and Nuclear Medicine.
Ｐａｄｏｖａ、 Ｉ ｔａｌｙ、 １６１頁（１９８
２））に代表されるＮ２０．リガンドなどが挙げられる
。Padova, Italy, page 161 (198
2)) N20. Examples include ligands.
また、２官能性配位子化合物（１）は、複数個の反応性
基を有する高分子化合物（１ａ）に対しその少なくとも
１個の反応性基が残るように先に例、示したような２官
能性配位子化合物を化学結合させて得られたもの（以下
「高分子化２官能性配位子化合物」と言う。）であって
もよい。In addition, the bifunctional ligand compound (1) can be used in a manner such that at least one reactive group remains with respect to the polymer compound (1a) having a plurality of reactive groups, as shown in the example above. It may be one obtained by chemically bonding bifunctional ligand compounds (hereinafter referred to as "polymerized bifunctional ligand compound").
複数個の反応性基を有する高分子化合物（１ａ）として
は、ペント−サン、ヘキソ−サン、ポリグリコサミン、
ポリウロン酸、グリコサミノグリカン、グリコサミノグ
リカン、ヘテロヘキソーサミンなどのポリサッカライド
誘導体、より具体的にはアミロース、アミロペクチン、
デキストラン、セルロース、イヌリン、ペクチン酸、プ
ルラン誘導体などが使用される。その他、ポリアクロレ
イン誘導体、ポリサッカライド誘導体、ポリアミン誘導
体（特にポリリジンポリイミン誘導体）なども同様に使
用することができる。なお、これらは単体であってもよ
く、混合物や脱水縮合物であってもよい。Examples of the polymer compound (1a) having a plurality of reactive groups include pentosan, hexosane, polyglycosamine,
Polysaccharide derivatives such as polyuronic acids, glycosaminoglycans, heterohexosamines, more specifically amylose, amylopectin,
Dextran, cellulose, inulin, pectic acid, pullulan derivatives, etc. are used. In addition, polyacrolein derivatives, polysaccharide derivatives, polyamine derivatives (especially polylysine polyimine derivatives), etc. can be used similarly. In addition, these may be a single substance, a mixture, or a dehydrated condensate.
高分子化合物（Ａ）を製造するには、２官能性配位子化
合物（１）とアシアロ糖蛋白質受容体指向性化合物（２
）とを自体常套の手段で反応させて直接結合させるか、
もしくは適当な架橋剤を介して結合させ、透析法、塩析
法、ゲルろ適法、イオン交換クロマトグラフ法、電気泳
動法など自体常套の手段により精製すればよい。アシア
ロ糖蛋白質受容体指向性化合物（２）１分子当たりに結
合させる２官能性配位子化合物（１）の分子数は、アシ
アロ糖蛋白質受容体指向性化合物（２）が生理活性を失
わない限りにおいて制限はないが、通常、３０分子また
はそれ以下が望ましい。２官能性配位子化合物（１）と
して高分子化２官能性配位子化合物を使用する場合には
、通常、１０分子またはそれ以下であってもよい。To produce the polymer compound (A), a bifunctional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2
) by reacting with them by conventional means, or directly bonding them.
Alternatively, they may be bound via a suitable crosslinking agent and purified by conventional means such as dialysis, salting out, gel filtration, ion exchange chromatography, and electrophoresis. The number of molecules of the bifunctional ligand compound (1) to be bound per molecule of the asialoglycoprotein receptor-directed compound (2) should be determined as long as the asialoglycoprotein receptor-directed compound (2) does not lose its physiological activity. There is no limit to the number of molecules, but 30 molecules or less is usually desirable. When a polymerized bifunctional ligand compound is used as the bifunctional ligand compound (1), the number of molecules may generally be 10 molecules or less.
ここで言うアシアロ糖蛋白質受容体指向性化合物（２）
とは、生体内のアシアロ糖蛋白質受容体に対して結合親
和性を有する化合物を意味し、具体例としてはアシアロ
糖蛋白質（例えばＮＧＡアシアロオロソムコイド、アシ
アロフェツイン、アジアロセルロプラスミン、アシアロ
ハプトグロビン）、ガラクトース結合ポリリジン、ガラ
クトース結合ポリグロコサミンなどが挙げられる。Asialoglycoprotein receptor-directed compound (2) referred to here
means a compound that has binding affinity to asialoglycoprotein receptors in vivo, and specific examples include asialoglycoproteins (e.g., NGA asialoorosomucoid, asialofetuin, asialoceruloplasmin, asialohaptoglobin). , galactose-binding polylysine, galactose-binding polyglocosamine, and the like.
次に２官能性配位子化合物（１）としてジエチレントリ
アミン五酢酸サイクリック酸無水物（以下「ＤＴＰＡ酸
無水物」と略す。）を使用する場合を例に挙げ、これと
ＮＧＡ（２）との結合体（すなわち高分子化合物（Ａ）
）を製造する場合の好ましい手法を説明する。すなわち
、人血清アルブミン（以下ｒＨ９ＡＪと略す。）（市販
の注射用人血清アルブミン製剤を使用）にリン酸緩衝液
及びＤＴＰＡ酸無水物を加え、室温で数分間撹拌する。Next, we will give an example of the case where diethylenetriaminepentaacetic acid cyclic acid anhydride (hereinafter abbreviated as "DTPA acid anhydride") is used as the bifunctional ligand compound (1), and the combination of this and NGA (2). Conjugate (i.e. polymer compound (A)
) will be described below. That is, a phosphate buffer and DTPA acid anhydride are added to human serum albumin (hereinafter abbreviated as rH9AJ) (using a commercially available injectable human serum albumin preparation) and stirred for several minutes at room temperature.
これにホウ酸緩衝液を加え、ｐＨを調整してＤＴＰＡ−
Ｈ９Ａ溶液を得る。Add boric acid buffer to this, adjust the pH, and make DTPA-
Obtain H9A solution.
別にシアノメチルチオガラクトースにナトリウムメトキ
サイドのメタノール溶液を加え、室温で数１０時間反応
させた後、メタノールを蒸発させて２−イミノメトキシ
−１−チオガラクトースを得る。これに上記ＤＴＰＡ−
Ｈ９Ａ溶液を加え、室温に２４時間放置する。酢酸を加
えて反応を停止し、ｐ）ｌを調整してＤＴＰＡ−ＮＧＡ
溶液を得る。Separately, a methanol solution of sodium methoxide is added to cyanomethylthiogalactose, and the mixture is reacted at room temperature for several tens of hours, and then the methanol is evaporated to obtain 2-iminomethoxy-1-thiogalactose. Add to this the above DTPA-
Add H9A solution and leave at room temperature for 24 hours. Add acetic acid to stop the reaction, adjust p)l and prepare DTPA-NGA.
Obtain a solution.
このようにして製造されたＤＴＰＡ−ＮＧＡ（ジエチレ
ントリアミン五酢酸結合ネオガラクトアルブミン）は次
の化学構造を有するものと考えられる：
（ガラクトース）ｎ −（Ｉ Ｓ Ａ） −（Ｄ Ｔ
Ｐ Ａ）ｍ（ただし、ｍとｎはそれぞれ１〜５０の整数
であり、ｍ＋ｎは２〜５０の整数である。）高分子化合
物（Ａ）は放射性医薬品調製用キャリヤーとして有用な
ものである。すなわち、高分子化合物（Ａ）には、放射
性金属元素（３）と強固なキレート結合をする２官能性
配位子化合物（１）が導入されており、これにより放射
性金属元素（３）を捕捉することができる。従って、こ
れまで放射性金属元素（３）で標識しえなかったアシア
ロ糖蛋白質受容体指向性化合物（２）も安定に標識でき
るようになった。The thus produced DTPA-NGA (diethylenetriaminepentaacetic acid-conjugated neogalactalbumin) is thought to have the following chemical structure: (galactose) n -(ISA) -(DT
P A) m (where m and n are each integers from 1 to 50, and m+n is an integer from 2 to 50.) The polymer compound (A) is useful as a carrier for the preparation of radiopharmaceuticals. That is, the bifunctional ligand compound (1) that forms a strong chelate bond with the radioactive metal element (3) is introduced into the polymer compound (A), thereby capturing the radioactive metal element (3). can do. Therefore, it has become possible to stably label the asialoglycoprotein receptor-directed compound (2), which could not previously be labeled with the radioactive metal element (3).
なお、２官能性配位子化合物（１）として前記高分子化
２官能性配位子化合物を使用した場合、これには複数個
の２官能性配位子が存在するから、これにより複数個の
放射性金属元素（３）を捕捉することができ、安定で比
放射能が非常に高い放射性医薬品を得ることができる。In addition, when the above-mentioned polymerized bifunctional ligand compound is used as the bifunctional ligand compound (1), since a plurality of bifunctional ligands are present in this, this causes a plurality of difunctional ligands. The radioactive metal element (3) can be captured, and a stable radiopharmaceutical with extremely high specific radioactivity can be obtained.
放射性医薬品調製用キャリヤーとしての高分子化合物（
Ａ）は溶液の形で保存されてもよいが、通常は凍結乾燥
法、低温減圧蒸留法などにより粉末状態に変換して保存
され、用に臨み無菌水、生理食塩水、壊耐液などに溶解
される。粉末状態または溶解後の高分子化合物（Ａ）に
は、必要に応じ医薬的に許容し得る溶解補助剤（例えば
有機溶媒）、ｐ）（調節剤（例えば酸、塩基、緩衝剤）
、安定剤（例えばアスコルビン酸）、保存剤（例えば安
息香酸壬トリウム）、等張網（例えば塩化ナトリウム）
などや放射性金属元素（３）の原子価状態を調整するた
めの還元剤や酸化剤が配合されてもよい。Polymeric compounds as carriers for the preparation of radiopharmaceuticals (
Although A) may be stored in the form of a solution, it is usually converted into a powder state by freeze-drying, low-temperature vacuum distillation, etc., and then stored in sterile water, physiological saline, sterile liquid, etc. before use. be dissolved. The polymer compound (A) in powder form or after dissolution may contain pharmaceutically acceptable solubilizing agents (e.g., organic solvents), p) (regulators (e.g., acids, bases, buffers)) as necessary.
, stabilizers (e.g. ascorbic acid), preservatives (e.g. thorium benzoate), isotonic agents (e.g. sodium chloride).
A reducing agent or an oxidizing agent may be added to adjust the valence state of the radioactive metal element (3).
上記した放射性金属元素（３）としては、放射能を有す
る金属元素であって、核医学的手法に適した物理的特性
、化学的特性を有し、しかも２官能性配位子化合物（１
）の配位子構造により容易に捕捉され得るものが使用さ
れる。その具体例としては、ガリウム−６７、ガリウム
−６８、タリウム−２０１、インジウム−１１１，テク
ネチウム−９９ｍ１亜鉛−６２、銅−６２等が挙げられ
る。The radioactive metal element (3) mentioned above is a radioactive metal element that has physical and chemical properties suitable for nuclear medicine techniques, and is also a difunctional ligand compound (1).
) is used that can be easily captured by the ligand structure. Specific examples include gallium-67, gallium-68, thallium-201, indium-111, technetium-99ml, zinc-62, copper-62, and the like.
これらは通常、塩、特に水溶性塩の形で使用され、水性
媒体中において、高分子化合物（Ａ）と接触せしめてそ
の標識化を行う。ただし、放射性金属元素（３）が安定
なキレート錯体を形成し得る原子価状態にある場合には
（例えばガリウム−６７、インジウム−１１１）、反応
系に他の試剤を存在せしめる必要はないが、安定なキレ
ート錯体を形成するために原子価状態を変化させる必要
がある場合には（例えばテクネチウム−９９ｍ）、反応
系に還元剤または酸化剤を存在せしめる必要がある。These are usually used in the form of salts, particularly water-soluble salts, and are labeled by contacting them with the polymer compound (A) in an aqueous medium. However, if the radioactive metal element (3) is in a valence state that allows it to form a stable chelate complex (e.g. gallium-67, indium-111), there is no need for other reagents to be present in the reaction system; When it is necessary to change the valence state to form a stable chelate complex (eg, technetium-99m), a reducing or oxidizing agent must be present in the reaction system.
還元剤の例としては２価の第一スズ塩（例えばハロゲン
化スズ、硫酸スズ、硝酸スズ、酢酸スズ、クエン酸スズ
）が挙げられる。酸化剤の具体例としては、過酸化水素
などがある。Examples of reducing agents include divalent stannous salts (eg, tin halides, tin sulfate, tin nitrate, tin acetate, tin citrate). Specific examples of oxidizing agents include hydrogen peroxide.
例えば放射性金属元素（３）としてテクネチウム−９９
ｍを使用する場合、高分子化合物（Ａ）を水性媒体中還
元剤としての第一スズの存在下、過テクネチウム酸イオ
ンの形でテクネチウム−９９ｍで処理することによって
テクネチウム−９９ｍ標識高分子化合物（Ｂ）を調整す
ることができる。上記調製に際し、各試剤の混合順序に
ついて格別の制限はないが、通常、水性媒体中で最初に
第一スズ塩と過テクネチウム酸イオンを混合することは
避けた方が望ましい。For example, technetium-99 as a radioactive metal element (3)
When using m, the technetium-99m-labeled polymeric compound ( B) can be adjusted. In the above preparation, there are no particular restrictions on the order in which the reagents are mixed, but it is generally preferable to avoid mixing the stannous salt and pertechnetate ion in the aqueous medium first.
このようにして得られた放射性金属元素結合高分子化合
物（Ｂ）が放射性医薬品として有用であるためには、核
医学的適用目的に充分な放射能量と放射性濃度を有する
ことが必要である。例えば、放射性金属元素（３）とし
てテクネチウム−９９ｍを使用した場合、投与時に約０
．５〜５ 、０ ｔｔｔＱ当たり、０．１〜５０’ｘＣ
ｉの放射能濃度を有することが望ましい。また、このよ
うな放射性金属元素結合高分子化合物（Ｂ）は調製後直
ちに投与されてもよいが、好ましくは調製後適当時間保
存に耐えうる程度の安定性を有することが望ましい。な
おまた、放射能金属元素結合高分子化合物（Ｂ）には、
必要に応じｐＨ調節剤（例えば酸、アルカリ、緩衝剤）
、安定剤（例えばアスコルビン酸）、等張化剤（例えば
塩化ナトリウム）などが配合されてもよい。In order for the thus obtained radioactive metal element-bonded polymer compound (B) to be useful as a radiopharmaceutical, it must have sufficient radioactivity and radioactivity concentration for nuclear medicine applications. For example, when technetium-99m is used as the radioactive metal element (3), approximately 0
．． 5~5, 0.1~50'xC per 0 tttQ
It is desirable to have a radioactivity concentration of i. Further, although such a radioactive metal element-bonded polymer compound (B) may be administered immediately after preparation, it is desirable that it has sufficient stability to withstand storage for an appropriate period of time after preparation. Furthermore, the radioactive metal element-bonded polymer compound (B) includes:
pH adjuster (e.g. acid, alkali, buffer) if necessary
, a stabilizer (for example, ascorbic acid), an isotonic agent (for example, sodium chloride), etc. may be added.
（実施例） 以下に実施例を示し、本発明を更に具体的に説明する。(Example) EXAMPLES The present invention will be explained in more detail with reference to Examples below.
実施例１
ＮＧＡ−ＤＴＰＡ結合体を含む組成物の製造：ＨＳＡ注
射液（２０％）５０ｊ＋Ｃをとり、０ 、１ ｘＱリン
酸緩衝液（ｐＨ８，０）１１７ｘＣを加え、マグネチッ
クスターラーで撹拌しながらＤＴＰＡ酸無水物５２１２
１９を加える。４℃で約５分間反応させ、０．０５ＩＩ
１１２の試料を採取した後、ＩＮ水酸化ナトリウム１０
ｍ＋２と０．６Ｍホウ酸緩衝液（ｐＨ８、５）２３＊Ｑ
を加え、ｐＨを調整する。試料０．０５ｉ（！について
は、これに０．１Ｍクエン酸緩衝液０ 、１ ｘＱを加
えて混合し、この液０．１１をとり、予め１ｍＭ塩化イ
ンジウム０．３ＭＱ、２ｍＣ１／ｘ（ｌ塩化インジウム
（ｌ ｌ ｌ Ｉｎ ）液０．４＋（，０，１Ｍクエン
酸緩衝液０ 、６ ｘＱの入ったバイアルに加え、３０
分間室温で放置する。更に１ｍＭジエチレントリアミン
五酢酸（Ｄ Ｔ Ｐ Ａ）溶液０ 、３ ｙｘ（ｌを加
えた後、下記条件の電気泳動法によりＨ９Ａ−ＤＴＰＡ
−”’Ｉｎと遊離の１１１Ｉｎ−ＤＴＰＡを分離し、そ
れぞれの放射能を計測する。Example 1 Manufacture of a composition containing NGA-DTPA conjugate: Take HSA injection solution (20%) 50j+C, add 0,1xQ phosphate buffer (pH 8,0) 117xC, and stir with a magnetic stirrer. DTPA acid anhydride 5212
Add 19. React at 4°C for about 5 minutes, and 0.05II
After taking 112 samples, IN sodium hydroxide 10
m+2 and 0.6M borate buffer (pH 8, 5) 23*Q
and adjust the pH. For sample 0.05i (!), add 0.1M citrate buffer 0, 1xQ and mix, take 0.11 of this solution and preliminarily add 1mM indium chloride 0.3MQ, 2mC1/x (l chloride Indium (l l l In ) solution 0.4+(,0.1M citrate buffer 0,6 xQ) was added to the vial containing 30
Leave at room temperature for a minute. After further adding 0,3 yx (l) of 1mM diethylenetriaminepentaacetic acid (DTPA), H9A-DTPA was purified by electrophoresis under the following conditions.
-'''In and free 111In-DTPA are separated and their respective radioactivity is measured.
支 持 体： セルロ゛−スアセテート膜泳動緩衝液：
０．０６Ｍバルビタール緩衝液（ｐＨ８，６）
泳動条件： １ｍＡ／Ｃｘ ３０分間ここで得られ
た結果を次式で計算し、ＨＳＡＩ分子当たりのＤＴＰＡ
の結合率（Ｐ）を算出した。Support: Cellulose acetate membrane Running buffer:
0.06M barbital buffer (pH 8,6) Electrophoresis conditions: 1 mA/Cx 30 minutes The results obtained here were calculated using the following formula, and the DTPA per HSAI molecule was calculated using the following formula.
The binding rate (P) was calculated.
ここでＷはバイアルに加えたＨＳＡの＊９ｆｆｉ、Ａは
ＨＳＡ−ＤＴＰＡ−”’Ｉｎの割合（％）を示す。Here, W indicates *9ffi of HSA added to the vial, and A indicates the proportion (%) of HSA-DTPA-'''In.
上記反応条件で得られる結合率は約５であった。The binding rate obtained under the above reaction conditions was about 5.
これとは別にシアノメチル−チオガラクトースｉｏ９を
ナシ型フラスコにとり、乾燥メタノール２５０ｉＱを加
え、５０℃で溶解する。これにナトリウムメトキサイド
２７０ｍ９を加え、室温で４８時間反応させた後、メタ
ノールを減圧蒸発させ、これに先にｐＨ８整したｌ５Ａ
−ＤＴＰＡを加え、４℃で一夜反応させてＮＧＡ−ＤＴ
ＰＡを得る。Separately, cyanomethyl-thiogalactose io9 was placed in a pear-shaped flask, 250 iQ of dry methanol was added, and the mixture was dissolved at 50°C. After adding 270 m9 of sodium methoxide and reacting at room temperature for 48 hours, methanol was evaporated under reduced pressure and added to l5A, which had been adjusted to pH 8 in advance.
- Add DTPA and react overnight at 4°C to create NGA-DT
Get a PA.
このＮＧＡ−ＤＴＰＡは次の条件の高速液体クロマトグ
ラフィー法により精製する。This NGA-DTPA is purified by high performance liquid chromatography under the following conditions.
カ ラ ム： 東洋ソーダ製ＴＳＫ−３０００ＳＷカラ
ム（０，７５Ｘ ６０ｃｍ’）
溶 出 液： ０．ＩＭＭ化ナトリウム溶液溶出速度
： ０．７５酎／分
上記操作のうち、結合率の測定以外はすべて無菌的に行
うほか、使用する器具類はすべて１８０℃４時間の加熱
処理によるパイロジエンバーンするか、もしくは注射用
蒸留水で洗浄した後、オートクレーブで滅菌して用いた
。また緩衝液は注射用蒸留水を用いて調製し、メンブラ
ンフィルタ−を用いたろ過滅菌法により滅菌して用いた
。カラムは次亜塩素酸ナトリウム溶液で洗浄した後、０
１１Ｍ塩化ナトリウム溶液で平衡化した。ここで得た精
製ＮＧＡ−ＤＴＰＡは０．１Ｍクエン酸緩衝液（ｐＨ６
，０）で希釈し、ｌπ９／Ｒ（ｌの濃度とした後、メン
ブランフィルタ−でろ過しながら１ｘｉｉづつ無菌バイ
アルに分注し、目的とする組成物を得た。Column: Toyo Soda TSK-3000SW column (0.75X 60cm') Eluent: 0. IMMized sodium solution elution rate: 0.75/min All of the above operations except for the measurement of the binding rate are performed aseptically, and all instruments used are pyrogen-burned by heat treatment at 180°C for 4 hours. Alternatively, the sample was washed with distilled water for injection and then sterilized in an autoclave before use. A buffer solution was prepared using distilled water for injection, and was sterilized by filtration sterilization using a membrane filter. After washing the column with sodium hypochlorite solution,
Equilibrated with 11M sodium chloride solution. The purified NGA-DTPA obtained here was dissolved in 0.1M citrate buffer (pH 6).
.
実施例２
ＮＧＡ−ＤＴＰＡ−”’Ｉｎ注射液の製造及び性質：
実施例１で得た組成物を含むバイアルに市販の塩化イン
ジウム（＋＋＋Ｉｎ）注射液（２ｍｃ ｉ／ｘｉ２）
１ 。Example 2 Preparation and properties of NGA-DTPA-'''In injection: Commercially available indium chloride (+++In) injection (2mc i/xi2) in a vial containing the composition obtained in Example 1
1.
０１を加え、目的とする注射液を得た。以上の操作は無
菌的に行う。01 was added to obtain the desired injection solution. The above operations are performed aseptically.
ここで得られた注射液２５μｇをとり、下記条件の高速
液体クロマトグラフィー法で分析したところ、２量体の
存在率は１％、未反応のＤＴＰＡは検出限界以下であっ
た。また、主成分の保持時間は約２５分であり、別に得
た検量線から計算するとその平均分子量は約７５，００
０であった。When 25 μg of the injection solution obtained here was analyzed by high performance liquid chromatography under the following conditions, the presence rate of the dimer was 1%, and the amount of unreacted DTPA was below the detection limit. In addition, the retention time of the main component is about 25 minutes, and the average molecular weight is about 75,000 when calculated from a separately obtained calibration curve.
It was 0.
カ ラ ム： 東洋ソーダ製ＴＳＫ−３０００ＳＷ（０
，７５ｘ ６０ｃｔ）
溶 出 液 ０．１Ｍ塩塩化ナトリウム溶液溶出度 ０
．７５ｘ（１／分
また、標識体３８０μ９をＳＤ系雌ラットの尾静脈より
投与し、投与後の経時的な体内分布挙動を観察した。結
果を第１図に示す。また、対照としてｌ！３１標識ＮＧ
Ａの結果を第２図に示す。その比較から明らかなように
、”Ｉ−ＮＧＡは肝臓のアシアロ糖蛋白質受容体を介し
て取り込まれた後、肝臓内で脱ヨード化反応をうけ、こ
こで生成した遊離のヨードは胃に集積したり、速やかに
尿中に排せつされるが、ＮＧＡ−ＤＴＰＡ−”’Ｉｎは
肝臓より主として腸管内に排せつされ、アシアロ糖蛋白
質受容体を介しての代謝の様相を示している。Column: Toyo Soda TSK-3000SW (0
,75x 60ct) Eluent 0.1M sodium chloride solution Elution degree 0
．． 75x (1/min) Labeled product 380 μ9 was also administered through the tail vein of SD female rats, and the distribution behavior in the body over time after administration was observed. The results are shown in Fig. 1. In addition, as a control, l!31 No sign
The results of A are shown in Figure 2. As is clear from the comparison, after I-NGA is taken up via the asialoglycoprotein receptor in the liver, it undergoes a deiodination reaction in the liver, and the free iodine produced here accumulates in the stomach. However, NGA-DTPA-'''In is mainly excreted into the intestinal tract rather than the liver, indicating that it is metabolized via asialoglycoprotein receptors.
実施例３
ＮＧＡ−ＤＴＰＡ−（Ｓｎ）結合体を含む組成物の製造
：
実施例１で得たＮＧＡ−ＤＴＰＡを生理食塩水で希釈し
、１５ｘｖ／ｘＱとする。次に塩化第一スズとアスコル
ビン酸をそれぞれ０．４ｍＭ５１．５ｍＭになるように
加え、塩酸液でｐＨを３〜５に調整する。ｐＨを調整し
たＮＧＡ−ＤＴＰＡ−（Ｓｎ）液はメンブランフィルタ
−でろ過しながら無菌バイアルに１ｘＱづつ分注し、目
的とする組成物を得た。Example 3 Manufacture of composition containing NGA-DTPA-(Sn) conjugate: NGA-DTPA obtained in Example 1 is diluted with physiological saline to make 15xv/xQ. Next, stannous chloride and ascorbic acid are added at a concentration of 0.4mM and 51.5mM, respectively, and the pH is adjusted to 3 to 5 with hydrochloric acid solution. The pH-adjusted NGA-DTPA-(Sn) solution was dispensed into sterile vials in 1×Q portions while being filtered with a membrane filter to obtain the desired composition.
以上の操作はすべて無菌的に行った。All of the above operations were performed aseptically.
実施例４
ＮＧＡ−ＤＴＰＡ−（Ｓｎ）−”ｍＴｃ注射液の製造及
び性質：
実施例３で得た組成物を含むバイアルに標識時５０ｍＣ
１／ｘ１２の過テクネチウム酸ナトリウム注射液１ｚ（
ｌを加え、ＮＧＡ−ＤＴＰＡ−（Ｓｎ）−”ｍＴＣ注射
液を得た。以上の操作は無菌的に行う。Example 4 Preparation and properties of NGA-DTPA-(Sn)-”mTc injection: Vials containing the composition obtained in Example 3 were exposed to 50 mC at the time of labeling.
1/x12 sodium pertechnetate injection 1z (
1 was added to obtain NGA-DTPA-(Sn)-''mTC injection solution. The above operations are performed aseptically.
ここで得られた標識体について、実施例２で示した雌ラ
ットにおける体内分布の挙動を調べた。Regarding the labeled product obtained here, the behavior of distribution in the body in female rats as shown in Example 2 was investigated.
結果を第３図に示す。この結果から明らかなように、Ｎ
ＧＡ−ＤＴＰＡ−（Ｓｎ）−”ｉＴｃは速やかに肝臓に
取り込まれた後、主に腸管より排せつされ、体内での安
定な挙動が示された。また、標識後１時間、４時間及び
２４時間後における標識率を測定するために実施例１で
示した電気泳動法により分析を行った。結果を第１表に
示す。この結果からＮＧＡ−ＤＴＰＡ−（Ｓｎ）−”ｍ
ＴｃはＤＴＰＡを介さないで直接標識したＮＧＡ−ＤＴ
ＰＡ（Ｓｎ）−”ｉＴｃに比べ、明らかに安定で標識率
のよい放射性医薬品であることがわかる。The results are shown in Figure 3. As is clear from this result, N
GA-DTPA-(Sn)-"iTc was rapidly taken up into the liver and then excreted mainly from the intestinal tract, indicating stable behavior in the body. In order to measure the subsequent labeling rate, analysis was performed using the electrophoresis method shown in Example 1. The results are shown in Table 1. From these results, NGA-DTPA-(Sn)-"m
Tc is NGA-DT directly labeled without DTPA
It can be seen that this is a radiopharmaceutical that is clearly more stable and has a better labeling rate than PA(Sn)-"iTc.
第１表
実施例５
Ｐｏｌｙ−Ｌｙｓ（ＤＴＰＡ、Ｇａ１）結合体を含む組
成物の製造ニー
平均分子量８，０００のポリリジン臭酸塩（Ｐｏｌｙ−
１、ｙｓ）７７Ｒ９をとり、２酎の０．２Ｍホウ酸緩衝
液（ｐＨ８，５）に溶解した。この溶液にマグネックス
ターラーで撹拌しながらジエチレントリアミン五酢酸サ
イクリック酸無水物（ＣＡＤＴＰＡ）２５ｍ９を加える
。室温で５分間撹拌して反応させた後、２Ｎ水酸化ナト
リウム溶液適量を加え、さらに０２Ｍホウ酸緩衝液（ｐ
Ｈ８，５）１屑ｇを加えてｐ）ｌを調整した。・サンプ
ル液０ 、１ ＊Ｑをとり、これに０゜１Ｍクエン酸緩
衝液０．２酎と２ｎ＋Ｃｉ／ｘｆ２塩化インジウム（１
１１１ｎ）液０ 、１ ｒｔｔＱを加え、３０分間放置
し、標識化する。この標識体につき電気泳動法によりＰ
ｏ１ｙ−Ｌｙｓ−ＤＴＰＡ−Ｉｎと未反応のＤＴＰＡ−
Ｉｎを分離定量し、Ｐｏ１ｙ−Ｌｙｓ１分子に結合して
いるＤＴＰＡの分子数を計算したところ、約３分子であ
った。Table 1 Example 5 Preparation of a composition containing a Poly-Lys (DTPA, Ga1) conjugate
1, ys) 77R9 was taken and dissolved in 0.2M borate buffer (pH 8.5). Add 25 m9 of diethylenetriaminepentaacetic acid cyclic anhydride (CADTPA) to this solution while stirring with a Magnex stirrer. After reacting by stirring for 5 minutes at room temperature, an appropriate amount of 2N sodium hydroxide solution was added, and further 02M borate buffer (p
H8,5) 1 g of scraps was added to adjust p)l.・Take sample solution 0,1
111n) Add solutions 0 and 1 rttQ and leave for 30 minutes for labeling. This labeled substance was analyzed by electrophoresis to
o1y-Lys-DTPA-In and unreacted DTPA-
When In was separated and quantified and the number of DTPA molecules bonded to one Po1y-Lys molecule was calculated, it was approximately 3 molecules.
これとは別に２９のシアノメチル−チオガラクトースを
５０ｍ１２ナシ型フラスコに入れ、さらにメタノール５
０ｘ１２とナトリウムメトキサイド５４１９を加え、室
温で４８時間反応させる。反応後メタノールを減圧蒸発
させ、これに先に準備したｌ）Ｈ調整Ｐｏ１ｙ −Ｌｙ
ｓ −Ｄ Ｔ Ｐ Ａを全量加え、３５〜４０℃で１．
５時間反応させてＰ ｏｌｙ −Ｌ ｙｓ（Ｄ ＴＰＡ
、Ｇａ１）を得る。Separately, add 29 ml of cyanomethyl-thiogalactose to a 50 m 12 pear-shaped flask, and add 5 ml of methanol.
Add 0x12 and sodium methoxide 5419 and react at room temperature for 48 hours. After the reaction, methanol was evaporated under reduced pressure, and the previously prepared l) H-adjusted Po1y-Ly
Add the entire amount of s-DTPA and heat at 35-40°C.
After reacting for 5 hours, Poly-Lys(DTPA
, Ga1) are obtained.
このＰｏ１ｙ−Ｌｙｓ（ＤＴＰＡ、Ｇａ１）を次の条件
のゲルろ過クロマトグラフィー法により精製した。This Po1y-Lys (DTPA, Ga1) was purified by gel filtration chromatography under the following conditions.
ゲ ル ：セルロファインＧＣ−２５次（カラム ２．
２ｃｘｘ ５０ｃｍ）
溶出液 ： ０．１Ｍクエン酸緩衝液（ｐＨ５，７）上
記操作はすべて無菌的に行うほか、使用する器具類はす
べて１８０℃、４時間の加熱処理によるパイロジエンバ
ーンするか、もしくは注射用蒸留水で洗浄した後、オー
トクレーブで滅菌して用いた。また、緩衝液は注射用蒸
留水を用いて調製し、メンブランフィルタ−を用いてろ
過滅菌法により滅菌して用いた。カラムは次亜塩素酸ナ
トリラム溶液で洗浄した後、０．１Ｍ塩化ナトリウム溶
液で平衡化した。Gel: Cellulofine GC-25th order (column 2.
2cxx 50cm) Eluate: 0.1M citrate buffer (pH 5,7) All of the above operations are performed aseptically, and all instruments used are either pyrogen-burned by heat treatment at 180°C for 4 hours, or After washing with distilled water for injection, it was sterilized in an autoclave and used. Further, a buffer solution was prepared using distilled water for injection, and sterilized by filtration sterilization using a membrane filter before use. The column was washed with sodium hypochlorite solution and then equilibrated with 0.1M sodium chloride solution.
ここで得た精製Ｐｏ１ｙ−Ｌｙｓ（ＤＴＰＡ、Ｇａ１）
を濃度が１１１９／ＲＱになるように０．１Ｍクエン酸
緩衝ｉ’１ｌｔ（ｐＨ５，７）で希釈し、メンブランフ
ィルタ−でろ過しながらｌＲＯづつ無菌バイアルに分注
し、目的とする組成物を得た。Purified Po1y-Lys (DTPA, Ga1) obtained here
Dilute with 0.1M citrate buffer i'1lt (pH 5,7) to a concentration of 1119/RQ, and dispense 1RO into sterile vials while filtering with a membrane filter to obtain the desired composition. Obtained.
Ｘ１鯉１
Ｐｏｌｙ−Ｌｙｓ（ＤＴＰＡ、Ｇａ１）−”’Ｉ ｎ注
射液の製造及び性質ニー
実施例５で得た組成物を含むバイアルに市販の塩化イン
ジウム（＋＋＋１ｎ）注射液（２ｍＣｉ） １．０ｘＱ
を加え、目的とする注射液を得た。以上の操作は無菌的
に行う。X1 Carp 1 Poly-Lys (DTPA, Ga1)-”'I n Injection preparation and properties Commercially available indium chloride (+++1n) injection (2 mCi) in a vial containing the composition obtained in Example 5 1.0xQ
was added to obtain the desired injection solution. The above operations are performed aseptically.
ここで得られた標識体（３８０μ９）についてＳＤ系雌
ラットにおける体内分布挙動を調べた（尾静脈より投与
）。第２表に示す結果から明らかなように、Ｐｏ１ｙ−
Ｌｙｓ（ＤＴＰＡ、Ｇａ１）−”ｌＩｎは投与早期に肝
臓のアシアロ糖蛋白質受容体を介して肝臓に取り込まれ
た後、徐々に排せつされる。The biodistribution behavior of the labeled product (380μ9) obtained here in SD female rats was investigated (administered through the tail vein). As is clear from the results shown in Table 2, Po1y−
Lys(DTPA, Ga1)-"lIn is taken into the liver via the hepatic asialoglycoprotein receptor early after administration, and then gradually excreted.
従って、本島はアシアロ糖蛋白質受容体の評価に有望な
薬剤であることが理解できる。Therefore, it can be understood that Honjima is a promising drug for evaluating asialoglycoprotein receptors.
第２表 Ｐｏ１ｙ−ＬｙｓＣＤＴＰＡ、Ｇａ１）−”’
Ｉｎ注射液のラットにおける体内分布挙動
実施例７
Ｎ Ｇ Ａ −Ａｏ＋ｙｌｏｓｅ（Ｄ Ｆ Ｏ）結合体
を含む組成物の製造：−
デフェロキサミン（以下ＤＦＯと略す。）１５１９を０
．０３Ｍリン酸緩衝液（ｐＨ７、０） １ ｘＱに溶か
し、これにトリエチルアミン３．２μＱを加え、室温で
約５分間撹拌する。これに、水に溶解したジアルデヒド
アミロース（２５ｘｖ／ ｘＱ） １ ｚＱを加え、室
温で３０分間撹拌した。この溶液をＡ液とする。Table 2 Po1y-LysCDTPA, Ga1)-”'
Example 7 of biodistribution behavior of In injection solution in rats Production of composition containing NGA-Ao+ylose (DFO) conjugate: - Deferoxamine (hereinafter abbreviated as DFO) 1519 was added to 0
．． Dissolve in 1 x Q of 03M phosphate buffer (pH 7, 0), add 3.2 μQ of triethylamine, and stir at room temperature for about 5 minutes. To this was added dialdehyde amylose (25xv/xQ) 1 zQ dissolved in water, and the mixture was stirred at room temperature for 30 minutes. This solution will be referred to as Solution A.
別にシアノメチル−チオガラクトース１９をナシ型フラ
スコにとり、乾燥メタノール２５ａ＋＋２を加え、５０
℃で溶解する。これにナトリウムメトキサイド２７ｊＩ
９を加え、室温で４８時間反応させた後、メタノールを
減圧蒸発させる。次に人血清アルブミン１ｇを含む０．
２Ｍホウ酸緩衝液２０１１１２を加え、４°Ｃで一夜反
応させてＮＧＡ溶液を得る。この溶液をＢ液とする。Ｂ
液２．ＩＱにＡ液２ｘＱを加え、室温で約６時間撹拌し
て反応させた後、水酸化ホウ酸ナトリウム１ 、５ ｍ
ｇを加え、約１時間室温で撹拌しながら還元した。反応
液は１Ｍ塩化ナトリウム溶液に対して透析し、更に０．
０３Ｍリン酸緩衝液（ｐＨ７、０）を溶出液としてセフ
ァクリルＳ−２００（カラム直径２ 、２ ｃｍ、長さ
５０ｃｍ）を用いたカラムクロマトグラフィー法により
ＮＧＡ−ＡＩＩ＋ｙｌｏｓｅ（Ｄ Ｆ Ｏ）を精製する
。Separately, put cyanomethyl-thiogalactose 19 in a pear-shaped flask, add dry methanol 25a++2,
Dissolve at °C. Add sodium methoxide 27jI to this
After adding 9 and reacting at room temperature for 48 hours, methanol was evaporated under reduced pressure. Next, 0.00ml containing 1g of human serum albumin.
Add 2M borate buffer 201112 and react overnight at 4°C to obtain a NGA solution. This solution will be referred to as Solution B. B
Liquid 2. Add 2xQ of solution A to IQ, stir at room temperature for about 6 hours to react, and then add 1.5 m of sodium borate hydroxide.
g was added thereto, and the mixture was reduced while stirring at room temperature for about 1 hour. The reaction solution was dialyzed against 1M sodium chloride solution and further diluted with 0.
NGA-AII+ylose (DFO) is purified by column chromatography using Sephacryl S-200 (column diameter 2.2 cm, length 50 cm) using 03M phosphate buffer (pH 7.0) as an eluent.
上記操作はすべて無菌的に行うほか、使用する器具類は
すべて１８０℃、４時間の加熱処理によるパイロジエン
バーンするか、もしくは注射用蒸留水で洗浄した後、オ
ートクレーブで滅菌して用いた。また、緩衝液は注射用
蒸留水を用いて調製し、メンブランフィルタ−を用いて
ろ過滅菌法により滅菌したものを使用した。カラムは次
亜塩素酸ナトリウム溶液で洗浄した後、０．１Ｍ塩化ナ
トリウム溶液で平衡化した。All of the above-mentioned operations were performed aseptically, and all the instruments used were either pyrogen-burned by heat treatment at 180° C. for 4 hours, or washed with distilled water for injection and then sterilized in an autoclave. The buffer solution was prepared using distilled water for injection and sterilized by filtration sterilization using a membrane filter. The column was washed with sodium hypochlorite solution and then equilibrated with 0.1M sodium chloride solution.
ここで得た精製ＮＧＡ−Ａｍｙｌｏｓｅ（ＤＰＯ）は、
０．０３Ｍリン酸緩衝液で希釈して１ｙｇ／ｍＱとし、
メンブランフィルタ−でろ過しながらｔｘＱづつ無菌バ
イアルに分注し、目的とする組成物を得た。The purified NGA-Amylose (DPO) obtained here is
Diluted with 0.03M phosphate buffer to 1yg/mQ,
While filtering through a membrane filter, txQ was dispensed into sterile vials to obtain the desired composition.
上記結合体のＤＦＯ及びＡｍｙｌｏｓｅ量は電気泳動法
により分析した。すなわち、前記還元反応終了後の反応
液の一部にクエン酸ガリウム（＠ ７ Ｇ ａ ）注射
液１ｍｃｉを加えて標識し、これを試料とした。The amounts of DFO and Amylose in the above conjugate were analyzed by electrophoresis. That is, 1 mci of gallium citrate (@ 7 Ga) injection solution was added to a portion of the reaction solution after the completion of the reduction reaction to label it, and this was used as a sample.
電気泳動法により分析されたＮ Ｇ Ａ −Ａ ｍｙｌ
ｏｓｅ（ＤＦ Ｏ）−”Ｇａ、Ａｍｙｌｏｓｅ（Ｄ Ｆ
Ｏ）−”Ｇａ、Ｄ Ｆ ０１１？Ｇａの値から本例で
得られた結合体中におけるＮＧＡＩ分子当たりのＤＦ’
Ｏの分子数は１１゜５個、Ａｍｙｌｏｓｅの分子数は０
．７個と算出された。NGA-A myyl analyzed by electrophoresis
ose(DF O)-”Ga, Amylose(DF
O)-"Ga, D F 011? DF' per NGAI molecule in the conjugate obtained in this example from the value of Ga
The number of molecules of O is 11°5, and the number of molecules of Amylose is 0.
．． It was calculated to be 7 pieces.
実施例８
ＮＧＡ−Ａｍｙｌｏｓｅ（ＤＦＯ）−８７Ｇａ注射液の
製造及び性質ニー
実施例７で得た組成物を含むバイアルにクエン酸ガリウ
ム（＠ ７ Ｇ ａ）注射液２ｍＣ１を加え、ＮＧ’Ａ
”Ａｍｙｌｏｓｅ（ＤＦＯ） −８７Ｇａ注射液を得た
。以上の操作は無菌的に行う。ここで得られた標識体に
ついて電気泳動法で標識率を算出したところ、標識体以
外の放射能ピークは認められず、高純度の放射性医薬品
であることか示された。Example 8 Preparation and properties of NGA-Amylose (DFO)-87Ga injection 2 mC of gallium citrate (@7 Ga) injection was added to the vial containing the composition obtained in Example 7, and NG'A
"Amylose (DFO) -87Ga injection solution was obtained. The above operations were performed aseptically. When the labeling rate of the labeled substance obtained here was calculated by electrophoresis, no radioactive peaks other than the labeled substance were observed. It was shown that it was a highly pure radiopharmaceutical.
（発明の効果）
本発明において、アシアロ糖蛋白質受容体指向性化合物
には、放射性金属元素と容易かつ強固にキレート結合を
形成し得る２官能性配位子が導入されているから、これ
を放射性金属元素と接触させた場合、該放射性金属元素
が強固に結合した放射性医薬品を容易に得ることができ
る。(Effects of the Invention) In the present invention, the asialoglycoprotein receptor-directed compound is introduced with a bifunctional ligand that can easily and firmly form a chelate bond with a radioactive metal element. When brought into contact with a metal element, a radiopharmaceutical to which the radioactive metal element is firmly bound can be easily obtained.
第１図、第２図及び第３図はそれぞれ’ ｌ ｌ Ｉｎ
−ＤＴＰＡ−ＮＧＡ、 １！３ｒ −ＮＧＡ及び”ｍＴ
ｃ−ＤＴＰＡ−ＮＧＡの雌ラットにおける体内分布挙動
を示すグラフである。
図面中、ＬＩＶは肝臓、ＦＥｃ糞、ＬＩＴは大腸、ＵＲ
Ｎは尿、Ｓｌ子は小腸、ＢＬＤは血液、ＳＴＭは胃を示
す。
特許出願人 日本メジフィジックス株式会社代理人 弁
理士 青 山 葆 はが１名第１図
注入後１７）ｖＦＩＪＩ （Ｆｇｔ）
第２図
注入後の時間（時）Figures 1, 2 and 3 are respectively ' l l In
-DTPA-NGA, 1!3r -NGA and “mT
1 is a graph showing the biodistribution behavior of c-DTPA-NGA in female rats. In the drawing, LIV is liver, FEc feces, LIT is large intestine, UR
N indicates urine, Sl indicates small intestine, BLD indicates blood, and STM indicates stomach. Patent applicant Nippon Mediphysics Co., Ltd. Agent Patent attorney Haga Aoyama 1 person Figure 1 After injection 17) vFIJI (Fgt) Figure 2 Time after injection (hours)
Claims (1)
容体指向性化合物（２）を化学結合させて成る高分子化
合物（Ａ）。 ２、２官能性配位子化合物（１）とアシアロ糖蛋白質受
容体指向性化合物（２）を化学結合させて成る高分子化
合物（Ａ）に放射性金属元素（３）をキレート結合させ
て成る放射性金属元素結合高分子化合物（Ｂ）。 ３、２官能性配位子化合物（１）とアシアロ糖蛋白質受
容体指向性化合物（２）を化学結合させて成る高分子化
合物（Ａ）を含む放射性医薬品調製用組成物（Ｃ）。 ４、２官能性配位子化合物（１）とアシアロ糖蛋白質受
容体指向性化合物（２）を化学結合させて成る高分子化
合物（Ａ）に放射性金属元素（３）をキレート結合させ
て成る放射性金属元素結合高分子化合物（Ｂ）を含む放
射性医薬品（Ｄ）。[Scope of Claims] A polymer compound (A) formed by chemically bonding a mono-, di-functional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2). 2. Radioactive compound made by chelating a radioactive metal element (3) to a polymer compound (A) made by chemically bonding a difunctional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2). Metal element-bonded polymer compound (B). 3. A radiopharmaceutical preparation composition (C) comprising a polymer compound (A) formed by chemically bonding a bifunctional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2). 4. Radioactive compound made by chelating a radioactive metal element (3) to a polymer compound (A) made by chemically bonding a bifunctional ligand compound (1) and an asialoglycoprotein receptor-directed compound (2) A radiopharmaceutical (D) containing a metal element-bonded polymer compound (B).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US139558 | 1987-12-30 | ||
| US07/139,558 US5032678A (en) | 1986-12-30 | 1987-12-30 | Radio labeled high molecular compound comprising unit of asialoglycoprotein acceptor-directing compound and unit of chelate forming compound chemically bonded thereto |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01176000A true JPH01176000A (en) | 1989-07-12 |
Family
ID=22487259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63078448A Pending JPH01176000A (en) | 1987-12-30 | 1988-03-30 | Radioactive medicine and polymer compound for preparing said medicine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01176000A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2646608A1 (en) * | 1989-05-04 | 1990-11-09 | Wisconsin Alumni Res Found | COMPLEXES FOR LOCATING AND TREATING TUMORS, AND TEST KIT INCLUDING ONE OF SUCH COMPLEXES |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4010251A (en) * | 1974-12-16 | 1977-03-01 | Green Allan M | Scanning agent composition and use in imaging liver and for biliary function |
| US4098780A (en) * | 1975-06-04 | 1978-07-04 | Paul Goran Sigvard Lindroos | Method of treating liquids containing blood substances |
| JPS5634634A (en) * | 1979-08-29 | 1981-04-06 | Nippon Mejifuijitsukusu Kk | Stable radiological diagnostic agent labeled with technetium-99m |
| US4401647A (en) * | 1980-03-03 | 1983-08-30 | The Regents Of The University Of Ca | Radiolabeled neoglycopeptides |
| JPS5946227A (en) * | 1982-06-07 | 1984-03-15 | ミシガン ステイト ユニバーシティー | Manufacture and use of metal chelate conjugated monoclonal antibody |
| JPS63170400A (en) * | 1986-12-30 | 1988-07-14 | Nippon Mejifuijitsukusu Kk | Radioactive medicine and high polymer compound for preparation thereof |
| JPS63170389A (en) * | 1986-12-30 | 1988-07-14 | Nippon Mejifuijitsukusu Kk | Radioactive medicine and high-molecular compound for preparation thereof |
-
1988
- 1988-03-30 JP JP63078448A patent/JPH01176000A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4010251A (en) * | 1974-12-16 | 1977-03-01 | Green Allan M | Scanning agent composition and use in imaging liver and for biliary function |
| US4098780A (en) * | 1975-06-04 | 1978-07-04 | Paul Goran Sigvard Lindroos | Method of treating liquids containing blood substances |
| JPS5634634A (en) * | 1979-08-29 | 1981-04-06 | Nippon Mejifuijitsukusu Kk | Stable radiological diagnostic agent labeled with technetium-99m |
| US4401647A (en) * | 1980-03-03 | 1983-08-30 | The Regents Of The University Of Ca | Radiolabeled neoglycopeptides |
| JPS5946227A (en) * | 1982-06-07 | 1984-03-15 | ミシガン ステイト ユニバーシティー | Manufacture and use of metal chelate conjugated monoclonal antibody |
| JPS63170400A (en) * | 1986-12-30 | 1988-07-14 | Nippon Mejifuijitsukusu Kk | Radioactive medicine and high polymer compound for preparation thereof |
| JPS63170389A (en) * | 1986-12-30 | 1988-07-14 | Nippon Mejifuijitsukusu Kk | Radioactive medicine and high-molecular compound for preparation thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2646608A1 (en) * | 1989-05-04 | 1990-11-09 | Wisconsin Alumni Res Found | COMPLEXES FOR LOCATING AND TREATING TUMORS, AND TEST KIT INCLUDING ONE OF SUCH COMPLEXES |
| EP0471790A1 (en) * | 1989-05-04 | 1992-02-26 | Wisconsin Alumni Research Foundation | Method for localization and treatment of tumors and complexes therefor |
| EP0471790A4 (en) * | 1989-05-04 | 1992-07-08 | Wisconsin Alumni Research Foundation | Method for localization and treatment of tumors and complexes therefor |
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