JP5057994B2 - 光学イメージング - Google Patents
光学イメージング Download PDFInfo
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- JP5057994B2 JP5057994B2 JP2007550320A JP2007550320A JP5057994B2 JP 5057994 B2 JP5057994 B2 JP 5057994B2 JP 2007550320 A JP2007550320 A JP 2007550320A JP 2007550320 A JP2007550320 A JP 2007550320A JP 5057994 B2 JP5057994 B2 JP 5057994B2
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- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
Description
AMD 加齢黄斑変性症
CCD 電荷結合素子
CNV 脈絡膜血管新生
ICG インドシアニングリーン
NIR 近赤外
PDT 光力学的療法
RGD アルギニン−グリシン−アスパラギン酸
RPE 網膜色素上皮
SLO 走査レーザー検眼鏡検査
VEGF 血管内皮増殖因子
2つの型のAMD、即ち乾性及び湿性が存在する。乾性AMDは、萎縮性、非滲出性又はドルーゼノイド黄斑変性ともいわれる。乾性AMDでは、網膜廃棄物の蓄積の結果として、ドルーゼンといわれる黄白色の沈着物が網膜色素上皮(RPE)とブルーフ膜との間に蓄積する。ドルーゼン沈着物は白色光又は蛍光眼底イメージングで見ることができ、診断のために造影剤は不要である。ドルーゼン沈着物は、RPEで適正に取り扱われない、光受容体細胞からの廃棄産物からなる。RPE細胞は、通常は「門番」として作用し、ブルーフ膜を通して光受容体に栄養素を供給すると共に光受容体から廃棄産物を除去する。黄斑部の内部及び外部で生じるドルーゼン沈着物は、光受容体の正常な機能及び維持を妨げ、これらの細胞の進行変性を引き起こすと考えられる。しかし、ドルーゼン沈着物は視力喪失なしに多年にわたり網膜中に存在することもある。乾性AMDに原因する視力喪失は、長い年月の経過中に極めて徐々に起こる。
A−Z
(Xa)
式中、Aは下記の式(Xb)で定義され、Zは任意にはスペーサー基を介してAのX1、X6又はX7の1以上に結合した1以上の光学イメージング用レポーターを表す。かかる造影剤は、さらに2つの環化架橋を含む。
Ra−C(=O)−X1−X2−X3−G−D−X4−X5−X6−X7
(Xb)
式中、X3、G及びDは前記に定義した通りである。
下記に示すようなAsp−Cys−Arg−Gly−Asp−Cys−Phe−CysペプチドからなるペプチドベクターDは、アスパラギン酸(X1)をアミノ官能化シアニン染料に結合するか、或いはシアニン染料のNHSエステルをX7に位置するアミノ−PEGと反応させることで、シアニン染料(例えば、Cy7)のような光学イメージング用レポーターに結合できる。
造影剤Eは、RGD型ペプチド(Lys−Cys−Arg−Gly−Asp−Cys−Phe−Cys)を2つのシアニン染料基(Cy5.5)に結合したものからなる。
造影剤Fは、RGD型ペプチド(Lys−Asp−Cys−Arg−Gly−Asp−Cys−Phe−Cys−Gly)をCy5に結合したものからなる。
造影剤Jは、RGDペプチド(Lys−Asp−Cys−Arg−Gly−Asp−Cys−Phe−Cys−Gly)をフルオレセインに結合したものからなり、「離散型」構造をなしている。
造影剤Kは、RGDペプチド(Lys−Cys−Arg−Gly−Asp−Cys−Phe−Cys)を異なる部位でフルオレセインに結合したものからなり、「からみ合い型」構造をなしている。
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
Fmoc N−α−(9−フルオレニルメチルオキシカルボニル)
HATU 2−(1H−7−アザベンゾトリアゾール−1−イル)−1,1,3,3− テトラメチルウロニウム
HPLC 高速液体クロマトグラフィー
LC_MS 液体クロマトグラフィー質量分析法
NMM N−メチルモルホリン
tBu tert−ブチル
TFA トリフルオロ酢酸
THF テトラヒドロフラン
実施例1:Cys2−6:c[CH 2 CO−Lys(Cy5ビス−SO 3 )−Cys−Arg−Gly−Asp−Cys−Phe−Cys]−(PEG) n −NH 2 (n=1)(造影剤B)の合成
2a)17−(Fmoc−アミノ)−5−オキソ−6−アザ−3,9,12,15−テトラオキサヘプタデカン酸の合成
乾燥THF(100ml)中における乾燥テトラエチレングリコール(19.4g、0.100mol)及びメタンスルホニルクロリド(25.2g、0.220mol)の溶液をアルゴン下に保ち、氷/水浴中で0℃に冷却した。フラスコに、乾燥THF(25ml)中におけるトリエチルアミン(22.6g、0.220mol)の溶液を45分かけて滴下した。1時間後、冷却浴を取り除き、撹拌を4時間続けた。水(60ml)を添加した。混合物に炭酸水素ナトリウム(6g、pH8)及びアジ化ナトリウム(14.3g、0.220mol)をこの順序で添加した。THFを留去し、水溶液を24時間還流した(2つの層が生じた)。混合物を冷却し、エーテル(100ml)を添加した。水性相を塩化ナトリウムで飽和させた。両相を分離し、水性相をエーテル(4×50ml)で抽出した。合わせた有機相をブライン(2×50ml)で洗い、乾燥した(MgSO4)。濾過及び濃縮により、22.1g(91%)の黄色油を得た。それ以上の精製なしに生成物を次の段階で使用した。
塩酸(200ml)中における1,11−ジアジド−3,6,9−トリオキサウンデカン(20.8g、0.085mol)の懸濁液を機械的に激しく撹拌しながら、エーテル(150ml)中におけるトリフェニルホスフィン(19.9g、0.073mol)の溶液を室温で3時間かけて添加した。反応混合物をさらに24時間撹拌した。両相を分離し、水性相をジクロロメタン(3×40ml)で抽出した。水性相を氷/水浴中で冷却し、pHをKOHの添加で約12に調整した。生成物をジクロロメタン(5×50ml)で抽出した。合わせた有機相を乾燥した(MgSO4)。濾過及び蒸発により、14.0g(88%)の黄色油を得た。MALDI−TOF質量分析法(マトリックス:α−シアノ−4−ヒドロキシケイ皮酸)による分析の結果、予想通り219にM+Hピークが得られた。1H(500MHz)及び13C(125MHz)NMR分光法を用いた追加の特性決定により、構造が確認された。
ジクロロメタン(100ml)中における11−アジド−3,6,9−トリオキサウンデカナミン(10.9g、50.0mmol)の溶液に、無水ジグリコール酸(6.38g、55.0mol)を添加した。反応混合物を1晩撹拌した。HPLC分析(カラム,Vydac 218TP54、溶媒,A=水/0.1%TFA及びB=アセトニトリル/0.1%TFA;勾配,20分間で4〜16%B;流量,1.0ml/分;214nm及び284nmでUV検出)は、出発原料が18.3分の保持時間を有する生成物に完全に転化したことを示した。溶液を濃縮することで定量的収量の黄色シロップを得た。LC_MS(ESイオン化)で生成物を分析したところ、予想通り335に[MH]+が得られた。1H(500MHz)及び13C(125MHz)NMR分光法の結果は構造に一致していた。それ以上の精製なしに生成物を次の段階で使用した。
H2(g)−Pd/C(10%)を用いて、水(100ml)中における17−アジド−5−オキソ−6−アザ−3,9,12,15−テトラオキサヘプタデカン酸(8.36g、25.0mmol)の溶液を還元した。反応は、LC−MS分析が出発原料の完全な転化を示すまで行った(カラム,Vydac 218TP54;溶媒,A=水/0.1%TFA及びB=アセトニトリル/0.1%TFA;勾配,20分間で4〜16%B;流量,1.0ml/分;214nm及び284nmでUV検出;ESイオン化は出発原料について335及び生成物について309にM+Hを与えた)。溶液を濾過し、次の段階ので直接使用した。
(25.0mmolのアミノ酸に相当する)上記17−アミノ−5−オキソ−6−アザ−3,9,12,15−テトラオキサヘプタデカン酸の水溶液に、重炭酸ナトリウム(5.04g、60.0mmol)及びジオキサン(40ml)を添加した。ジオキサン中におけるFmocクロリド(7.11g、0.275mol)の溶液を滴下した。反応混合物を1晩撹拌した。ジオキサンを蒸発させて除去し(rotavapor)、水性相を酢酸エチレンで抽出した。水性相を塩酸の添加で酸性化し、沈殿した物質をクロロホルムで抽出した。有機相を乾燥し(MgSO4)、濾過し、濃縮することで、11.3g(85%)の黄色シロップを得た。LC−MS分析(カラム,Vydac 218TP54;溶媒,A=水/0.1%TFA及びB=アセトニトリル/0.1%TFA;勾配,20分間で40〜60%B;流量,1.0ml/分;214nm及び284nmでUV検出;ESイオン化は5.8分の生成物ピークについて予想通り531にM+Hを与えた)で構造を確認した。分析結果は極めて低い副生物含有量を示し、それ以上の精製なしにこの物質を使用した。
実施例2の造影剤(造影剤H)を光学イメージング用造影剤として用いて、ラットにおける脈絡膜血管新生のイメージングを行った。
造影剤溶液を静脈内注射(200μg/kg)することで、レーザー処置後0日目から14日目まで造影剤を用いた分子血管造影検査を行った。
Harlan社から供給されるLong Evans(系統)ラットを投与前に最低1週間環境順化させた。本研究のためには、全部で27頭の雄及び0頭の雌を入手した。飼育のためには、Allentown固体底型ポリスルホンケージを個別に使用した。
CNV誘発後1時間目(レーザー処置後0日目)に、造影剤溶液(造影剤H又は陰性対照)を20μg/kgの投与量でラットに注射した。投与直後に画像を撮影した。
Claims (10)
- ヒト又は動物の身体の湿性加齢黄斑変性症(AMD)のイメージングのための造影剤であって、当該造影剤が、血管新生に関連するレセプターに親和性を有するベクターを光学イメージング用レポーターに結合したものであり、次の式(Xa)で定義される造影剤。
A−Z (Xa)
式(Xa)中、Aは下記の式(Xb)で定義されるものであって、2つの環化架橋を含んでおり、
ZはAのX 1 、X 6 又はX 7 の1以上に任意にはスペーサー基を介して結合したフルオレセイン又はシアニン染料から選択される1以上の光学イメージング用レポーターを表す。
R a −C(=O)−X 1 −X 2 −X 3 −G−D−X 4 −X 5 −X 6 −X 7 (Xb)
式(Xb)中、X 3 はアルギニン又はN−メチルアルギニンを表し、
Gはグリシンを表し、
Dはアスパラギン酸を表し、
R a は、X 2 、X 4 又はX 6 のいずれかとの架橋の一部をなす−(CH 2 ) n −又は−(CH 2 ) n −C 6 H 4 −基(式中、nは1〜10の正の整数を表す。)を表し、
X 1 は結合或いは1、2、3、4又は5個のアミノ酸残基を表していて、1以上のアミノ酸残基はスペーサー部分で任意に官能化されているか、或いは前記アミノ酸残基は官能性側鎖を有しており、
X 2 及びX 4 は独立に環化架橋を形成するアミノ酸残基を表し、
X 5 は疎水性アミノ酸を表し、
X 6 は環化架橋を形成するアミノ酸残基を表し、
X 7 はスペーサー又はバイオモディファイアー部分を表すか、或いは存在しない。 - 前記イメージングが、ヒト又は動物の身体に造影剤を投与し、ヒト又は動物の身体の眼又は眼の一部に光を照射し、前記造影剤が分布した眼又は眼の一部の画像を形成することを含む、請求項1記載の造影剤。
- 前記イメージングが、通常の検眼鏡検査、共焦点走査レーザー検眼鏡検査、インビボ共焦点顕微鏡検査、時間ドメイン及び周波数ドメインイメージング技術、並びに眼底カメラからなる群から選択されるイメージング技術による画像を形成することを含む、請求項1又は請求項2記載の造影剤。
- 前記イメージングが、ヒト又は動物の身体の眼又は眼の一部における血管新生レベルを評価することを含む、請求項1乃至請求項3のいずれか1項記載の造影剤。
- 潜在AMDの検出のための、請求項1乃至請求項4のいずれか1項記載の造影剤。
- 前記ベクターが、VEGFレセプター、胎盤増殖因子レセプター及び繊維芽細胞増殖因子レセプター、血小板由来内皮細胞増殖因子、アンジオポエチン、並びにインテグリンからなる群から選択されるレセプターのいずれかに親和性を有する、請求項1乃至請求項5のいずれか1項記載の造影剤。
- 前記ベクターがインテグリンに対して親和性を有する、請求項1乃至請求項8のいずれか1項記載の造影剤。
- 前記ベクターが、アンジオスタチン、エンドスタチン、バソスタチン、血小板第4因子及び抗トロンビンIIIの開裂生成物、RGDトリペプチド配列の小分子非ペプチド模倣体、並びにアミノ酸配列X3−G−D(式中、X3はアルギニン又はN−メチルアルギニンを表し、Gはグリシンを表し、Dはアスパラギン酸を表す。)を含むペプチドからなる群から選択される、請求項1乃至請求項7のいずれか1項記載の造影剤。
- AMDを処置するための薬物によるヒト又は動物の身体の湿性AMDの治療効果を監視するための、請求項1乃至請求項9のいずれか1項記載の造影剤。
- 血管新生に関連するレセプターに親和性を有するベクターを光学イメージング用レポーターに結合してなる造影剤を予め投与しておいたヒト又は動物の身体の眼の湿性AMDの画像を光学イメージングによって形成するための造影剤であって、当該造影剤が、次の式(Xa)で定義される造影剤。
A−Z (Xa)
式(Xa)中、Aは下記の式(Xb)で定義されるものであって、2つの環化架橋を含んでおり、
ZはAのX 1 、X 6 又はX 7 の1以上に任意にはスペーサー基を介して結合したフルオレセイン又はシアニン染料から選択される1以上の光学イメージング用レポーターを表す。
R a −C(=O)−X 1 −X 2 −X 3 −G−D−X 4 −X 5 −X 6 −X 7 (Xb)
式(Xb)中、X 3 はアルギニン又はN−メチルアルギニンを表し、
Gはグリシンを表し、
Dはアスパラギン酸を表し、
R a は、X 2 、X 4 又はX 6 のいずれかとの架橋の一部をなす−(CH 2 ) n −又は−(CH 2 ) n −C 6 H 4 −基(式中、nは1〜10の正の整数を表す。)を表し、
X 1 は結合或いは1、2、3、4又は5個のアミノ酸残基を表していて、1以上のアミノ酸残基はスペーサー部分で任意に官能化されているか、或いは前記アミノ酸残基は官能性側鎖を有しており、
X 2 及びX 4 は独立に環化架橋を形成するアミノ酸残基を表し、
X 5 は疎水性アミノ酸を表し、
X 6 は環化架橋を形成するアミノ酸残基を表し、
X 7 はスペーサー又はバイオモディファイアー部分を表すか、或いは存在しない。
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WO2008133693A1 (en) * | 2007-05-01 | 2008-11-06 | Richard Spaide | Autofluorescence photography using a fundus camera |
KR20150017387A (ko) * | 2007-05-16 | 2015-02-16 | 지이 헬스케어 에이에스 | 영상화를 위한 표지된 hgf 결합성 펩티드 |
KR20100017102A (ko) * | 2007-05-16 | 2010-02-16 | 지이 헬스케어 에이에스 | 광학 조영제 |
DE102007038730A1 (de) | 2007-08-16 | 2009-02-19 | Carl Zeiss Meditec Ag | Nachweis des menschlichen Vascular Endothelial Growth Factor |
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WO2010053101A1 (ja) * | 2008-11-06 | 2010-05-14 | 国立大学法人東北大学 | 眼内移行性の高い点眼剤および蛍光イメージング剤ならびにそれらの製造方法 |
EP2459053A2 (en) * | 2009-07-28 | 2012-06-06 | F. Hoffmann-La Roche AG | Non-invasive in vivo optical imaging method |
CN105111773B (zh) * | 2015-08-19 | 2017-06-27 | 大连理工大学 | 一类氨基菁类荧光染料及其制备方法和应用 |
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US6180084B1 (en) * | 1998-08-25 | 2001-01-30 | The Burnham Institute | NGR receptor and methods of identifying tumor homing molecules that home to angiogenic vasculature using same |
US6852318B1 (en) * | 1998-05-08 | 2005-02-08 | The Regents Of The University Of California | Methods for detecting and inhibiting angiogenesis |
US20030045681A1 (en) * | 1998-05-11 | 2003-03-06 | Anthony J. Zelano | Specific binding molecules for scintigraphy, conjugates containing them and therapeutic method for treatment of angiogenesis |
US6943153B1 (en) * | 1999-03-15 | 2005-09-13 | The Regents Of The University Of California | Use of recombinant gene delivery vectors for treating or preventing diseases of the eye |
US6534040B2 (en) | 1999-12-23 | 2003-03-18 | Health Research, Inc. | Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
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NO20004795D0 (no) | 2000-09-26 | 2000-09-26 | Nycomed Imaging As | Peptidbaserte forbindelser |
AU2002211649A1 (en) * | 2000-10-11 | 2002-04-22 | Targesome, Inc. | Targeted therapeutic agents |
JP2004535407A (ja) * | 2001-05-30 | 2004-11-25 | ターゲサム・インコーポレーテッド | 標的化多価高分子 |
NZ530156A (en) * | 2001-07-10 | 2007-04-27 | Ge Healthcare As | Peptide-based compounds for targeting integrin receptors for use as diagnostic imaging agents |
EP1420831A1 (en) * | 2001-07-27 | 2004-05-26 | Targesome, Inc. | Lipid constructs as therapeutic and imaging agents |
EP1539739B1 (en) * | 2002-08-16 | 2010-11-24 | Janssen Pharmaceutica NV | Piperidinyl compounds that selectively bind integrins |
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EP1606256B1 (en) * | 2003-03-12 | 2011-05-04 | Celgene Corporation | N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses |
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US8236283B2 (en) | 2012-08-07 |
CN101272808A (zh) | 2008-09-24 |
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JP2008526352A (ja) | 2008-07-24 |
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