JP2005232190A - 生体内診断剤に適する化合物 - Google Patents
生体内診断剤に適する化合物 Download PDFInfo
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- JP2005232190A JP2005232190A JP2005128309A JP2005128309A JP2005232190A JP 2005232190 A JP2005232190 A JP 2005232190A JP 2005128309 A JP2005128309 A JP 2005128309A JP 2005128309 A JP2005128309 A JP 2005128309A JP 2005232190 A JP2005232190 A JP 2005232190A
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Abstract
【解決手段】 本発明は、NIR範囲において蛍光法及び透視法による診断の造影剤として特定の光物理的性質又は薬理化学的性質を有する水溶性色素及びそれらの生体分子付加物を使用する近赤外線(NIR線)による生体内診断用の新規な色素並びにこのような色素を含有する診断薬。
【選択図】 なし
Description
生物学的組織は、650〜1000nmの範囲の長波光に対して比較的高い透過性を示すので、診断者は、したがって完全に異なる組織画像形成方法を使用できる。近赤外範囲の光は数cmの組織を透過することができることから、透視画像形成に利用される。この手法により、現時点では、副鼻腔及び上顎洞の炎症だけでなく、組織の表在性帯域における蓄積液又は血液の検出が容易となる(Beduthan J.、Muller G.;Infrarotdiaphanoskopie、Med.Tech.1(1992)13〜17)。
近赤外線の照射に伴う主要な問題は、光が異常に広く散乱して、光物理的特性が異なるにもかかわらず明瞭な輪郭の物体のかなりぼやけた画像しか得られないことである。この問題は、表面からの距離が大きいほど大きくなり、透視法及び蛍光線検出法の両方において主要な限定要因と考えることができる。
ヒトにおける生体内診断に色素を用いる例としては、血液を光度法によりトレースして、分布領域、血流又は代謝及び排泄機能を測定し、眼の透明構造を可視化(眼科学)することが挙げられる。このような用途に用いられる好ましい色素は、インドシアニングリーン及びフルオレセインである(Googe、J.M.等、Intraoperative Fluorescein Angiography;Ophthalmology、100(1993)1167〜70)。
インドシアニングリーンは、アルブミンに100%結合し、肝臓で可動である。蛍光定量効率は、含水環境中では低い。そのLD50(0.84mmol/kg)は十分高く、強力なアナフィラキシー反応が生じることがある。インドシアニングリーンは、溶解したときに不安定であり、析出が生じることから生理食塩水媒体には適用できない。
このように、公知のNIR線を用いた生体内診断の現状の方法には、数多くの欠点があり、このために、医療診断に広く使用されるのが妨げられている。
可視光又はNIR線を直接使用するのは、入射光が大きく散乱するために、表在体帯域に限られている。
したがって、本発明の目的は、従来技術の欠点を克服する生体内診断法を提供することである。
Bk−(F−Wn)m (I)
(式中、kは0〜6の数を表し、nは0〜10の数を表し、mは1〜100の数を表し;
Bは特異的細胞集団に結合するか、受容体に選択的に結合するか、組織又は腫瘍に蓄積するか、一般的に血液中にとどまるか、あるいは非選択的に結合する巨大分子である、分子量が30000以下である生物学的検出単位であり;
Fは650〜1200nmの範囲に極大吸収を示す色素を表し;
Wは式Iで表される化合物のn−オクタノール−水分布係数がk=0に関して2.0以下であるときに水に対する溶解度を向上させる親水基を表す)で表される化合物及びそれらの生理学的に許容される塩を用いる生体内診断方法を提供することにより解決される。
式IIa
L1〜L7は同一又は異なり、各々独立してフラグメントCH又はCR
(但し、Rはハロゲン原子、ヒドロキシ基、カルボキシ基、アセトキシ基、アミノ基、ニトロ基、シアノ基、スルホン酸基、又は炭素数6以下のアルキル残基、アルケニル残基、ヒドロキシアルキル残基、カルボキシアルキル残基、アルコキシ残基、アルコキシカルボニル残基、スルホアルキル残基、アルキルアミノ残基、ジアルキルアミノ残基若しくはハロゲンアルキル残基、又は炭素数9以下のアリール残基、アルキルアリール残基、ヒドロキシアリール残基、カルボキシアリール残基、スルホアリール残基、アリールアミノ残基、ジアリールアミノ残基、ニトロアリール残基若しくはハロゲンアリール残基であるか、
Rは−CO−フラグメントを介して結合した2つの異なる位置での一つの結合を表す)を表し、
R3 〜R12は同一又は異なり、各々独立して水素原子、前記残基B若しくはW、炭素数6以下のアルキル残基若しくはアルケニル残基、又は炭素数9以下のアリール残基若しくはアラルキル残基であり、前記アルキル残基、アルケニル残基、アリール残基又はアラルキル残基は任意に前記した追加の残基Wを担持しているか、
X及びYは同一又は異なり、各々独立してO、S、Se若しくはTe、又は−C(CH3)2−、−CH=CH−又は−CR13R14−フラグメント(式中、R13及びR14は独立して水素原子、前記残基B又はW、炭素数6以下のアルキル残基若しくはアルケニル残基又は炭素数9以下のアリール残基若しくはアラルキル残基であり、
前記アルキル残基、アルケニル残基、アリール残基又はアラルキル残基は任意の前記した追加の残基Wを担持している)である〕で表されるシアニン色素を表すか、
R3〜R12、x及びyは前記した通りである)で表されるスクアレイン色素か、
一般式III
−(CH2)a−O−Z又は(−CH2−CH2−O)a−Z (III)
Zは水素原子か、2〜n−1(但し、nは炭素原子数である)個のヒドロキシ基を含む炭素数3〜6のアルキル残基か、炭素数6〜10であり且つ2〜4個の追加のヒドロキシ基を担持しているアリール残基若しくはアラルキル残基か、炭素数1〜6であり且つ1〜3個の追加のカルボキシ基を担持しているアルキル残基か、炭素数6〜9であり且つ1〜3個の追加のカルボキシル基を担持しているアリール残基であるか、炭素数6〜15のアラルキル残基、ニトロアリール−残基若しくはニトロアラルキル残基か、1〜3個の追加のカルボキシ基を担持している炭素数2〜4のスルホアルキル残基を含んでなるか、
−(CH2)o−(CO)p−NR1−(CH2)s−(NH−CO)q−R2
(IIIc)
(式中、o及びsは独立して0、1、2、3、4、5又は6の数を表し、
p及びqは独立して0又は1を表し、
R1及びR2は独立して一般式IIIa及びIIIbの置換基を除いて前記した残基Zを表すか、独立して一般式IIId又はIIIe
前記した一般式IIIcで表される残基を表す本発明による方法に特に適当である。
使用される測定法は、当業者に公知のものである。また、専門家も、本発明で使用される一般式Iで表される色素の一定吸収又は蛍光波長での最適な記録及び評価条件を得るのに、どの装置パラメータを設定すべきかがわかるであろう。
上記の方法では、組織の深層で数mm3 しか容積のない小対象物又は非透明体液での局在化さえ可能である。必然的に伴う光散乱及び限定された解像度のため、このような対象の正確な形状及び大きさを測定することはまだ困難であるが、ある種の重要な診断上の問題を解決するにはこのことは必要とされない。
驚くべきことに、シアニン色素を投与後にCCDカメラを用いて撮影したマウス(スイスヌード)のX線透視画像は、同様に投与したポルフィリンと比較して、蛍光強度が1000倍であった。
本発明に使用される化合物は、種々の方法で組織に適用される。色素の静脈内投与が、特に好ましい。
Bが、ポリリシン、ポリエチレングリコール、メトキシポリエチレングリコール、ポリビニルアルコール、デキストラン、カルボキシデキストラン又はFに共有結合するカスケード様構造等の非選択的結合巨大分子である他の化合物は、本発明に準じて使用できる。
スルホアルキル基は、好ましくは2−スルホエチル基、3−スルホプロピル基及び4−スルホブチル基である。
本発明により使用される色素は、スペクトル範囲650〜1200nmの範囲で吸収を示す。これらの化合物の吸収係数は、色素1分子について約100000 l mol-1cm-1以上である。蛍光定量効率は、蛍光画像形成に使用される全ての色素について5%を超える。
X及びYは各々独立して−O−、−S−、−CH=CH−又は−C(CH2R32)(CH2R33)−フラグメントを表し、
R20〜R29、R32及びR33は独立して水素原子、ヒドロキシ基、カルボキシ残基、スルホン酸残基、炭素数10以下のカルボキシアルキル残基、アルコキシカルボニル残基若しくはアルコキシオキソアルキル残基、又は炭素数4以下のスルホアルキル残基を表すか、
一般式VI
−(O)v−(CH2)o−CO−NR34−(CH2)s−(NH−CO)q−R35
(VI)
で表される残基であるが、但し、X及びYはO、S、−CH=CH−又は−C(CH3)2 −であり、残基R20〜R29の少なくとも一つは非選択的結合巨大分子か、一般式VI
(式中、o及びsは0又は独立して1〜6の整数を表し、
q及びvは独立して0又は1を表し、
R34は水素原子又はメチル残基を表し、
R35は炭素数3〜6であり且つ2〜n−1(nは炭素数)個のヒドロキシ基を含んでなるアルキル残基か、1〜3個の追加のカルボキシ基を担持する炭素数1〜6のアルキル残基か、炭素数6〜9のアリール残基か、炭素数7〜15のアリールアルキル残基か、式IIId又はIIIe
R20とR21、R21とR22、R22とR23、R24とR25、R25とR26、R26とR27は、点在する炭素原子と5員又は6員芳香族又は飽和アニーニング環を形成する〕で表されるシアニン色素及びそれらの生理学的に許容される塩が提供される。
一般式Vで表される本発明による化合物では、ヒドロキシ基又はカルボキシ基を含有するアルキル残基、アリール残基又はアラルキル残基は、上記した好ましい組成を有する。
5−〔2−〔(1,2−ジカルボキシエチル)アミノ〕−2−オキソエチル〕−2−〔7−〔5−〔2−(1,2−ジカルボキシエチル)アミノ〕−2−オキソエチル〕−1,3−ジヒドロ−3,3−ジメチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−1−(4−スルホブチル)−3H−インドリウム、分子内塩、カリウム水素塩、
2−〔7−〔1,3−ジヒドロ−3,3−ジメチル−5−〔2−〔(メトキシポリオキシエチレン)−アミノ〕−2−オキソエチル〕−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−5−〔2−〔(メトキシポリオキシエチレン)アミノ〕−2−オキソエチル〕−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩、
3−(3−カルボキシプロピル)−2−〔7−〔3−(3−カルボキシプロピル)−1,3−ジヒドロ−3−メチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3−メチル−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩、
2−〔7−〔1,3−ジヒドロ−5−〔2−〔(2,3−ジヒドロキシプロピル)アミノ〕−2−オキソエチル〕−3,3−ジメチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−5−〔2−〔(2,3−ジヒドロキシプロピル)アミノ〕−2−オキソエチル〕−3,3−ジメチル−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩。
好ましい化合物群は、タンパク質への親和性をほとんど示さず、その薬物動力学的挙動は、例えば、インシュリン又はサッカロースと同様である。
物質の許容度は、極めて良好である。LD50値が単一色素分子について体重1kg当り0.5mmolを超える物質が、特に好ましい。
本発明の化合物及び本発明で使用される化合物について説明した光物理的及び薬物動力学的性質も、ヒトにおける適用が承認された唯一のシアニン色素であるインドシアニングリーン(カルディオグリーン)とは異なる。
本発明の別の態様によれば、一般式I(但し、Bのk値が1以上、好ましくは1又は2である)で表される化合物が提供される。
したがって、化合物F−Wnは、生物学的検出単位上でアミン、ヒドロキシ、アルデヒド又はスルフヒドリル基に共有結合できる基を少なくとも一つ、好ましくは正確に一つ含有する。このような基は、文献から公知であり、例えば、DE-OS3912046にある程度詳細に記載されている。
さらに、アルコール系官能を有するカルボキシ基は、適当な活性試薬(例えば、DCC)を用いたエステル結合又はエーテル構造を形成してよく、アルデヒド官能はヒドラジンと結合してイミン構造を形成してもよい。
F−Wn化合物を、好ましくは、生物学的検出単位Bと、DMF中か、含水環境中か、DMF/水混合物中で、pH値7.4〜10で反応させる。色素と生体分子のモル割合(仕込み比)を、吸収分光測定を用いて測定する。結合しない成分は、クロマトグラフィー又は濾過により分離する。
これらの物質は、全く異なる性質を有していてもよい。また、これらの分子量は、数百〜100000以上でよい。物質は、中性でも、帯電してもよい。酸性色素並びにナトリウム、メチルグルタミン、リシン等の生理学的に許容される塩基の塩、又はリチウム、カルシウム、マグネシウム、カチオンの形態のガドリニウムを含有する塩の形態でもよい。
本発明の別の態様によれば、一般式Iで表される化合物の使用と類似した一般式Vで表されるシアニン色素のNIR線を用いた生体内診断のための使用が提供される。
本発明のさらに別の態様によれば、一般式V又はIで表される化合物を含有する診断試薬が提供される。
実施例
実施例1
5−〔2−〔(1,2−ジカルボキシエチル)アミノ〕−2−オキソエチル〕−2−〔7−〔5−〔2−(1,2−ジカルボキシエチル)アミノ〕−2−オキソエチル〕−1,3−ジヒドロ−3,3−ジメチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−1−(4−スルホブチル)−3H−インドリウム、分子内塩、カリウム水素塩の調製
分析:
理論値:C54.43、H5.54 、N5.40 、O24.68、S6.18 、K3.77
実測値:C54.04、H5.81 、N5.22 、 S6.13 、K3.85
2−〔7−〔5−〔2−〔(11−カルボキシ−2−オキソ−1,4,7,10−テトラアザ−4,7,10−トリ(カルボキシメチル)−1−ウンデシル)アミノ〕−2−オキソエチル〕−1,3−ジヒドロ−3,3−ジメチル−1−エチル−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−1−(4−スルホブチル)−3H−インドリウム、分子内塩の調製
分析:
理論値:C59.32、H6.60 、N9.88 、O20.96、S3.23
実測値:C54.15、H6.70 、N9.50 、 S3.19
2−〔7−〔1,3−ジヒドロ−3,3−ジメチル−5−〔2−〔(メトキシポリオキシエチレン)−アミノ〕−2−オキソエチル〕−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−5−〔2−〔(メトキシポリオキシエチレン)アミノ〕−2−オキソエチル〕−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩の調製
平均分子量:理論値10771、実測値10820
2−〔7−〔1,3−ジヒドロ−3,3−ジメチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−5−(メトキシポリオキシエチレン)アミノカルボニル−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩の調製
平均分子量:理論値 5701、実測値:5795
3−(3−カルボキシプロピル)−2−〔7−〔3−(3−カルボキシプロピル)−1,3−ジヒドロ−3−メチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3−メチル−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩の調製
理論値:C60.13、H6.28 、N3.42 、O19.54、S7.83 、Na2.81
実測値:C59.90、H6.34 、N3.39 、 S7.72 、Na2.78
2−〔〔3−〔〔3−(3−カルボキシプロピル)−1,3−ジヒドロ−3−メチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕メチル〕−2−ヒドロキシ−4−オキソ−2−シクロブテン−1−イリデン〕メチル〕−1,1−ジメチル−3−エチル−1H−ベンズ(e)インドリウム、分子内塩の調製
理論値:C68.60、H6.20 、N4.10 、O16.40、S4.70
実測値:C68.25、H6.35 、N4.04 、 S4.59
2−〔7−〔1,3−ジヒドロ−5−〔2−〔(2,3−ジヒドロキシプロピル)アミノ〕−2−オキソエチル〕−3,3−ジメチル−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−5−〔2−〔(2,3−ジヒドロキシプロピル)アミノ〕−2−オキソエチル〕−3,3−ジメチル−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩の調製
分析:
理論値:C56.70、H6.45 、N5.88 、O20.14、S6.73 、K4.10
実測値:C56.39、H6.88 、N5.67 、 S6.58 、K3.93
2−〔7−〔1,3−ジヒドロ−3,3−ジメチル−5−(メトキシカルボニル)−1−(4−スルホブチル)−2H−インドール−2−イリデン〕−1,3,5−ヘプタトリエニル〕−3,3−ジメチル−5−(メトキシカルボニル)−1−(4−スルホブチル)−3H−インドリウム、ナトリウム塩を、麻酔した腫瘍を有するマウス(スイスヌード、右後脚腫瘍LS174T)に、体重1kg当り3.8μmolを静脈内投与した。
Claims (2)
- 下記一般式I:
Bk−(F−Wn)m (I)
[式中、kは0〜6の数を表し;
nは0〜10の数を表し;
mは1〜100の数を表し;
Bは、特定の細胞集団に結合するか、受容体に選択的に結合するか、組織もしくは腫瘍に蓄積するか、又は全身的に血液中にとどまる分子量が30000以下の生物学的検出ユニット、あるいは非選択的に結合する巨大分子であり;
Fは650〜1200nmの範囲に極大吸収を示す色素であって、下記一般式IIa:
式中、
rは0、1又は2の数を表すが、但し、r=2の場合、一双のフラグメントL6及びL7は同一でも異なっていてもよく、
L1〜L7は同一又は異なり、各々独立してフラグメントCH又はCRであり、
ここで、Rはハロゲン原子、ヒドロキシ基、カルボキシ基、アセトキシ基、アミノ基、ニトロ基、シアノ基、スルホン酸基、又は炭素数6以下のアルキル基、アルケニル基、ヒドロキシアルキル基、カルボキシアルキル基、アルコキシ基、アルコキシカルボニル基、スルホアルキル基、アルキルアミノ基、ジアルキルアミノ基若しくはハロゲンアルキル基、又は炭素数9以下のアリール基、アルキルアリール残、ヒドロキシアリール基、カルボキシアリール基、スルホアリール基、アリールアミノ基、ジアリールアミノ基、ニトロアリール基若しくはハロゲンアリール基であるか、或いは
Rは別の基Rに結合して散在する基L1〜L7とともに4員環〜6員環を形成する結合を表すか、或いは
Rは−CO−フラグメントを介して結合した2つの異なる位置での一つの結合を表す)を表し;
R3 〜R12は同一又は異なり、各々独立して水素原子、前記の基B若しくは後記のW、炭素数6以下のアルキル基若しくはアルケニル基、又は炭素数9以下のアリール基若しくはアラルキル基であり、前記アルキル基、アルケニル基、アリール基又はアラルキル基は任意に後記の追加の基Wを担持しており、或いは飽和、不飽和又は芳香族でもよく且つ任意に前記の追加の基Rを担持していてもよい5員〜6員環が、点在するC原子に相応の配慮をした上で各対の隣接残基R3〜R10にアニーリングしており;
X及びYは同一又は異なり、各々独立してO、S、Se若しくはTe、又は−C(CH3)2−、−CH=CH−又は−CR13R14−フラグメントであり、
ここで、R13及びR14は独立して水素原子、前記の基B又は後記のW、炭素数6以下のアルキル基若しくはアルケニル基又は炭素数9以下のアリール基若しくはアラルキル基であり、前記アルキル基、アルケニル基、アリール基又はアラルキル基は任意の後記の追加の残基Wを担持していともよく、ここで、
Wは、一般式Iにおいて、カルボキシル基もしくはスルホン酸基又は12個までの炭素原子を含むカルボキシアルキル、アルコキシカルボニルもしくはアルコキシオキソアルキル基であり、そして、WはR4とR8、及び/又はR6とR10、及び/又はR11とR12の位置を占めることを特徴とする〕
で表される化合物を含んで成る、NIR照射に基礎を置く生体内診断薬。 - 請求項1に記載のシアニン色素を含んで成る生体内診断薬。
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US8293782B2 (en) | 2009-01-30 | 2012-10-23 | Canon Kabushiki Kaisha | Compound, probe containing the novel compound, and fluorescence-imaging contrast agent containing the novel compound or the probe |
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