JP4216715B2 - ペプチドコンジュゲート、金属錯体を含むそれらの誘導体及び磁気共鳴画像法(mri)のためのそれらの使用 - Google Patents
ペプチドコンジュゲート、金属錯体を含むそれらの誘導体及び磁気共鳴画像法(mri)のためのそれらの使用 Download PDFInfo
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- JP4216715B2 JP4216715B2 JP2003519106A JP2003519106A JP4216715B2 JP 4216715 B2 JP4216715 B2 JP 4216715B2 JP 2003519106 A JP2003519106 A JP 2003519106A JP 2003519106 A JP2003519106 A JP 2003519106A JP 4216715 B2 JP4216715 B2 JP 4216715B2
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- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/595—Gastrins; Cholecystokinins [CCK]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
Description
本発明は、CCK A型及び/もしくはB型コレシストキニン受容体並びに/又はSSTR1〜5型ソマトスタチン受容体を過剰発現している原発ヒト腫瘍及びそれらの転移を同定及び位置決定するための、核磁気共鳴画像法(MRI)において使用するための造影剤の新規クラスに関するものである。
Asp−Tyr−Met−Gly−Trp−Met−Asp−Phe−アミド
を有している。オクタペプチドはCCK8として既知である。
Bは、1個以上の一般式(II)又は(III)
AA0はL体又はD体の任意のアミノ酸であり;
AA1はAsp又はGluであり;
AA2はTyr又はSO3H−Tyrであり;
AA3はMet、Nle又はLeuであり;
AA6はMet、Nle又はLeuであり;
AA8はPhe又はその対応するアミノアルコールであり;
AA′1、AA′3 AA′6及びAA′8はL体又はD体の天然又は非天然いずれかの任意のアミノ酸であり;
AA′8はL体又はD体の天然又は非天然いずれかの任意のアミノ酸に由来するアミノアルコール誘導体であってもよく;
R2はヒドロキシ基、アミノ基又はC1〜C4アルコキシ基であり;
vは1〜5の整数であり;
wはゼロ又は1である〕の直鎖型、分岐型又は環式のペプチドを表し;
Pは、t個のA単位と共有結合することができ、1個以上のBの単位と共有結合により結合した直鎖型又は分岐型の重合体鎖を表し;
tは2〜100の範囲の整数であり;
Aは、Pと共有結合しており、かつアミノ基、ピリジノ基、カルボキシ基、ホスホン酸基、ホスフィン酸基、ヒドロキシル基及びカルボキサミド基より選択される配位部位6〜8個を含有している環式又は非環式のキレート化剤を表し、21〜29、42、44又は57〜71の範囲の原子番号を有する2〜3価金属をキレート化することができる〕の化合物に関する。
ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノホスホニウムヘキサフルオロホスフェート(PyBop)、1−ヒドロキシベンゾトリアゾール(HOBt)、全てのFmoc−アミノ酸誘導体(Fmoc=9−フルレニル(flurenyl)メチルオキシカルボニル)及びRinkアミドMBHA樹脂は、カルバイオケム(Calbiochem)−ノババイオケム(Novabiochem)(Laufelfingen, CH)より購入した。〔O−(7−アゾベンゾトリアゾール−イル)−1,1,3,3−テトラメチルウロニウム〕ヘキサフルオロホスフェート(HATU)は、アプライドバイオシステムズ(Applied Biosystem)より購入した。N,N−ビス〔2−〔ビス〔2−(1,1−ジメチルエトキシ)−2−オキソエチル〕アミノ〕エチル〕−L−グルタミン酸1−(1,1−ジメチルエチル)エステル(保護DTPA−GLU)は、以前に記載されたようにして調製した。他の全ての化学物質は、アルドリッチ(Aldrich)(Milwaukee, WI, USA)より入手し、特記しない限りさらに精製することなく使用した。
(DTPA−GLU)4(Lys)2Lys−Gly−CCK8のガドリニウム錯体の合成
Gly−CCK8(配列:H−Gly−Asp−Tyr−Met−Gly−Trp−Met−Asp−Phe−NH2)合成は、Fmocプロトコルを使用して標準的な条件下で固相で実施した。RinkアミドMBHA樹脂(0.54mmol/g、54μmol規模、0.100g)を使用した。各回にPyBop及びHOBtにより活性化されたN保護アミノ酸4当量、並びにN,N−ジイソプロピルエチルアミン(DIPEA)8当量を含むDMFを添加し、60分間攪拌して、二重カップリングを実施した。ペプチドGly−CCK8合成が完了した時点で、混合物DMF/ピペリジン70/30 1.5mLを2回使用することにより、Fmoc脱保護用の容器へ樹脂を移した。PyBop及びHOBtにより活性化されたFmoc−Lys(Fmoc)−OH 4当量及びN,N−ジイソプロピルエチルアミン(DIPEA)8当量を含むDMFを添加した。Fmoc脱保護後、同様にしてFmoc−Lys(Fmoc)−OHの残基2個を2個のリシンアミノ官能へとカップリングし、完全に保護された(Fmoc−Lys(Fmoc))2Lys−Gly−CCK8−樹脂を得た。この生成物のうちの少量を、脱保護及び切断のため処理し、粗ペプチド(Lys)2Lys−Gly−CCK8を質量分析及びHPLCにより分析した。ペプチド同一性の確認後、完全に保護された(Fmoc−Lys(Fmoc))2Lys−Gly−CCK8−樹脂をFmoc脱保護し、DTPA−GLUカップリングした。DTPA−GLUカップリングは、PyBop及びHOBtにより活性化されたN,N−ビス〔2−〔ビス〔2−(1,1−ジメチルメトキシ)−2−オキソエチル〕アミノ〕エチル〕−L−グルタミン酸1−(1,1−ジメチルエチル)エステル(保護DTPA−GLU)2当量及びDIPEA 4当量を含むDMFを使用して実施し;攪拌時間は単一カップリングで8時間であった。脱保護及び分解のため、完全に保護されたコンジュゲートペプチド樹脂をトリイソプロピルシラン(2.0%)、エタンジチオール(2.5%)及び水(1.5%)を含有しているTFAで処理した。ジエチルエーテルを滴下にて添加することにより粗生成物を0℃で沈殿させた。粗混合物の精製を、RP−HPLCにより実施し、2個の主生成物を得た。
さらにNaOH溶液を添加して溶液pHを絶えず調節しながら、上記工程Aで得られた化合物の溶液にGdC13の1mM溶液を室温で添加した。そのMSは、示された構造と一致した。
(DTPA−GLU)3(Lys)2Lys−G1y−CCK8のガドリニウム錯体の合成
さらにNaOH溶液を添加して溶液pHを絶えず調節しながら、(実施例1の工程Aに示されたようにして調製された)(DTPA−GLU)3(Lys)2Lys−Gly−CCK8の溶液にGdC13の1mM溶液を室温で添加した。そのMSは、示された構造と一致した。
(DTPAGLU)4(Lys)2Lys−Gly−バプレオチドのガドリニウム錯体の合成
実施例1に記載されたのと同じ手法に従った。(バプレオチド配列:D−Phe−Cys−Phe−D−Trp−Lys−Val−Cys−Trp−NH2,Cys2−Cys7S−S架橋)。システイン架橋の環化は、ジメチルスルホキシド(DMSO)の0.5mM水性溶液中で実施した。粗混合物の精製をRP−HPLCにより実施し、主生成物として(DTPA−GLU)4(Lys)2Lys−Gly−バプレオチドを得た。(DTPA−GLU)4(Lys)2Lys−Gly−バプレオチド Rt=25.0分;MW=3336(計算値3335)。そのMSは、示された構造と一致した。
さらにNaOH溶液を添加して溶液pHを絶えず調節しながら、実施例3Aの化合物の溶液にGdC13の1mM溶液を室温で添加した。そのMSは、示された構造と一致した。その錯体の緩和度は15mM-1s-1であった。
(DO3A−Ar)4(Lys)2Lys−Gly−バプレオチドのガドリニウム錯体の合成
キレート化化合物及び対応するガドリニウム錯体を、実施例3に記載された方法に従い得た。そのMSは、示された構造と一致した。
(Lys(DTPA−GLU)−βAla)4Lys(DTPA−GLU)−Gly−CCK8のガドリニウム錯体の合成
Gly−CCK8(配列:H−Gly−Asp−Tyr−Met−Gly−Trp−Met−Asp−Phe−NH2)。その合成は、Fmocプロトコルを使用して標準的な条件下で固相で実施した。RinkアミドMBHA樹脂(0.54mmol/g、54μmol規模、0.100g)を使用した。各回に、PyBop及びHOBtにより活性化されたN保護アミノ酸4当量及びN,N−ジイソプロピルエチルアミン(DIPEA)8当量を含むDMFを添加し、60分間攪拌して、二重カップリングを実施した。ペプチドGlyCCK8合成が完了した時点で、Fmoc脱保護用の容器に樹脂を移し、PyBop及びHOBtにより活性化されたFmoc−Lys(Mtt)−OH 4当量及びN,N−ジイソプロピルエチルアミン(DIPEA)8当量を含むDMFを添加した。Mtt Lys側鎖保護基をTFA/トリイソプロピルシラン/CH2Cl2(1:5:94)混合物による処理により除去し;次いでHATUにより活性化されたN,N−ビス〔2−〔ビス〔2−(l,l−ジメチルエトキシ)−2−オキソエチル〕アミノ〕エチル〕−L−グルタミン酸1−(1,1−ジメチルエチル)エステル(保護DTPA−GLU)及びDIPEA 4当量を、DMF中でLys ε−アミノ基にカップリングした。Fmoc保護基を除去し、PyBop及びHOBtにより活性化されたFmocβAla−OH 4当量及びN,N−ジイソプロピルエチルアミン(DIPEA)8当量を含むDMFを添加した。Fmoc−Lys(Mtt)−OHから出発して同じ手法をそれぞれ4回繰り返し、完全に保護された生成物(Lys(DTPA−GLU)−βAla)4−Lys(DTPA−GLU)−Gly−CCK8を得た〔又は9回繰り返し、完全に保護された生成物(Lys(DTPA−GLU)−βAla)9−Lys(DTPA−GLU)−Gly−CCK8を得た。実施例6参照〕。脱保護及び分解のため、完全に保護されたコンジュゲートペプチド樹脂をトリイソプロピルシラン(2.0%)、エタンジチオール(2.5%)及び水(1.5%)を含有しているTFAで処理した。ジエチルエーテルを滴下にて添加することにより、0℃で粗生成物を沈澱させた。粗混合物の精製を、記述された方法を使用してRP−HPLCにより実施した。化合物(Lys(DTPA−GLU)−βAla)4−Lys(DTPA−GLU)−Gly−CCK8が、良好な収率(HPLCで精製された化合物に関しては40%)及び高い純度(HPLCにより95%)で得られた。(Lys(DTPA−GLU)−βAla)4−Lys(DTPA−GLU)−Gly−CCK8 Rt=23.5分。そのMSは、示された構造と一致した。
実施例1に記載された方法に従い、ガドリニウム錯体の調製物を得た。そのMSは、示された構造と一致した。
(Lys(DTPA−GLU)−βAla)9Lys(DTPA−GLU)−Gly−CCK8のガドリニウム錯体の合成
(Lys(DTPA−GLU)−βAla)4Lys(DTPA−GLU)−Gly−バプレオチドのガドリニウム錯体の合成
(Lys(DTPA−GLU)−βAla)9Lys(DTPA−GLU)−Gly−バプレオチドのガドリニウム錯体の合成
(Dap(DTPA−GLU)−βAla)4−Dap(DTPA−GLU)−Gly−CCK8のガドリニウム錯体の合成
Fmocプロトコルを使用して、そして代わりに本実施例のA)で調製された化合物及びFmoc−βAlaを使用して、実施例5に記載された戦略に従い、化合物を調製した。そのMSは、示された構造と一致した。
実施例1に詳細に与えられた手法に従い、錯体を調製した。そのMSは、示された構造と一致した。
(Dap(DTPA−GLU)−βAla)9−Dap(DTPA−GLU)−Gly−CCK8のガドリニウム錯体の合成
(Dap(DTPA−GLU)−βAla)4−Dap(DTPA−GLU)−バプレオチドのガドリニウム錯体の合成
(Dap(DTPA−GLU)−βAla)9−Dap(DTPA−GLU)−バプレオチドのガドリニウム錯体の合成
Claims (8)
- 21〜29、42、44又は57〜71の範囲の原子番号を有する金属元素の2〜3価イオン、常磁性金属との錯体、及び生理学的に適合性の塩基又は酸とのそれらの塩の形態の、請求項1記載の化合物。
- Fe(2+)、Fe(3+)、Cu(2+)、Cr(2+)、Cr(3+)、Eu(3+)、Gd(3+)、Tb(3+)、Dy(3+)、Ho(3+)、Er(3+)、Yb(3+)、Mn(2+)、Mn(3+)の2〜3価イオンとの錯体、及び生理学的に適合性の塩基又は酸とのそれらの塩の形態の、請求項2記載の化合物。
- Eu(3+)、Gd(3+)、Dy(3+)、Mn(2+)、Mn(3+)の2〜3価イオンと共に得られた錯体、及び生理学的に適合性の塩基又は酸とのそれらの塩の形態の、請求項3記載の化合物。
- 適切な担体と混和された請求項2の化合物を含有している医薬組成物及び診断用組成物。
- 器官及び/又は組織の画像化及びそれらの画像の記録のためのMRI検査において使用される診断用製剤の調製のための、請求項2の化合物及びそれらの塩の使用。
- 腫瘍又は原発腫瘍病理又は転移が存在している細胞、組織又は器官のin vitro及び/又はin vivoの画像化及びそれらの画像の記録のための、請求項7記載の使用。
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IT2001MI001708A ITMI20011708A1 (it) | 2001-08-03 | 2001-08-03 | Coniugati di peptidi, loro derivati con complessi metallici e utilizzo per i'indagine diagnostica tramite imaging per risonanza magnetica(m |
PCT/EP2002/008382 WO2003014157A2 (en) | 2001-08-03 | 2002-07-26 | Peptides conjugates, their derivatives with metal complexes and use thereof for magnetic resonance imaging (mri) |
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EP (1) | EP1412383B9 (ja) |
JP (1) | JP4216715B2 (ja) |
AT (1) | ATE345355T1 (ja) |
AU (1) | AU2002328981A1 (ja) |
DE (1) | DE60216111T2 (ja) |
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ITPD20030174A1 (it) * | 2003-07-31 | 2003-10-29 | Univ Padova | Coniugati polimerici per diagnostica e terapia |
WO2006002873A2 (en) | 2004-07-02 | 2006-01-12 | Bracco Imaging Spa | 1 , 4 -bis (carboxymethyl) -6- ' bis ( carboxymethyl) amino ! -6 -methyl- perhydro-1 , 4 diazepine (aazta) derivatives as ligands in high relaxivity contrast agents for use in magnetic resonance imaging (mri ) |
EP1898958A2 (en) * | 2005-05-31 | 2008-03-19 | INBIOS S.r.l. | Supramolecular aggregates containing chelating agents and bioactive peptides as effective and selective delivery tools for drugs and contrast agents in mri or nuclear medicine |
JP5377965B2 (ja) | 2005-09-09 | 2013-12-25 | ジョージア ステート ユニバーシティ リサーチ ファウンデーション、インコーポレイテッド | 標的化された造影剤および造影剤を標的化するための方法 |
CA2621763C (en) * | 2005-09-09 | 2021-04-06 | Georgia State University Research Foundation, Inc. | Targeted contrast agents and methods for targeting contrast agents |
US20090110640A1 (en) * | 2006-03-29 | 2009-04-30 | Oskar Axelsson | Contrast agents for magnetic resonance imaging and spectroscopy consisting of a cyclic oligoamid core of 3 to 4 identicial monomer units with 3 to 4 paramagnetic chelate side chains |
WO2008019123A2 (en) | 2006-08-04 | 2008-02-14 | Georgia State University Research Foundation, Inc. | Enzyme sensors, methods for preparing and using such sensors, and methods of detecting protease activity |
US8288530B2 (en) | 2006-11-06 | 2012-10-16 | The United States Of America, As Represented By The Department Of Health And Human Services | Method of preparing macromolecular contrast agents and uses thereof |
US8420327B2 (en) | 2006-12-14 | 2013-04-16 | Georgia State University Research Foundation | Analyte sensors, methods for preparing and using such sensors, and methods of detecting analyte activity |
WO2009146099A2 (en) | 2008-04-02 | 2009-12-03 | Georgia State University Research Foundation, Inc. | Contrast agents, methods for preparing contrast agents, and methods of imaging |
EP2279190A1 (en) * | 2008-04-18 | 2011-02-02 | Ge Healthcare As | Compounds comprising paramagnetic chelates arranged around a central core and their use in magneto resonance imaging and spectroscopy |
ES2354320B2 (es) * | 2008-06-24 | 2011-10-11 | Universidade De Santiago De Compostela | Ciclopéptidos marcados magnéticamente con complejos de lantánidos. |
WO2015017815A1 (en) | 2013-08-01 | 2015-02-05 | Rochester Institute Of Technology | Modular imaging agents containing amino acids and peptides |
US10265014B2 (en) * | 2013-09-06 | 2019-04-23 | Somnology, Inc. | System and method for sleep disorder diagnosis and treatment |
US10265013B2 (en) * | 2013-09-06 | 2019-04-23 | Somnology, Inc. | System and method for sleep disorder diagnosis and treatment |
EP3101012A1 (en) | 2015-06-04 | 2016-12-07 | Bayer Pharma Aktiengesellschaft | New gadolinium chelate compounds for use in magnetic resonance imaging |
EP3389478B1 (en) | 2015-12-15 | 2021-03-31 | Mayo Foundation for Medical Education and Research | Systems and methods for linear-time clustering for bounded, repeatable, rare events in physiological signals |
JP7034160B2 (ja) | 2016-11-28 | 2022-03-11 | バイエル・ファルマ・アクティエンゲゼルシャフト | 磁気共鳴画像法に使用するための高緩和度ガドリニウムキレート化合物 |
US11944690B2 (en) | 2018-11-23 | 2024-04-02 | Bayer Aktiengesellschaft | Formulation of contrast media and process of preparation thereof |
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GB9215780D0 (en) * | 1992-07-24 | 1992-09-09 | Univ London Pharmacy | Peptide compounds |
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US6342598B1 (en) * | 1998-11-26 | 2002-01-29 | Bracco International B.V. | Amphipatic polycarboxylic chelates and complexes with paramagnetic metals as MRI contrast agents |
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AU2002328981A1 (en) | 2003-02-24 |
US20050008573A1 (en) | 2005-01-13 |
WO2003014157A2 (en) | 2003-02-20 |
ATE345355T1 (de) | 2006-12-15 |
EP1412383B9 (en) | 2007-10-03 |
DE60216111T2 (de) | 2007-04-05 |
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JP2005510461A (ja) | 2005-04-21 |
ITMI20011708A1 (it) | 2003-02-03 |
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