JP2020528059A - 悪性腫瘍を同定および診断するためならびに治療的抗腫瘍介入をモニターするための、99mTcチルマノセプトおよび関連する分子構造の使用 - Google Patents
悪性腫瘍を同定および診断するためならびに治療的抗腫瘍介入をモニターするための、99mTcチルマノセプトおよび関連する分子構造の使用 Download PDFInfo
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Abstract
Description
本明細書において使用される、有機化合物を含む化合物の命名法は、一般名、IUPAC、IUBMB、または命名法のためのCAS推薦を使用して与えられる。1つまたはそれ以上の立体化学的特徴が存在する場合には、立体化学のためのCahn−Ingold−Prelogルールが、立体化学的順位、E/Z表記等を表すために使用される。当業者は、名称が与えられれば、命名協定を使用した化合物の構造の系統的分類によるか、またはCHEMDRAW(商標)(Perkin Elmer Corporation、米国)のような市販のソフトウェアによるかのいずれかで、化合物の構造を容易に確認することができる。
本発明の実施形態は、1種またはそれ以上の活性な薬学的成分を送達するために取り付けられたCD206を標的とする部分(例えばマンノース)を含むことができるポリマー(例えば炭水化物)骨格を含む担体構造を使用することができる。そのような構造の例は、マンノシルアミノデキストラン(MAD)を含み、それは、骨格のグルコース残基にマンノース分子をコンジュゲートさせた、および骨格の他のグルコース残基に活性薬学的成分をコンジュゲートさせたデキストラン骨格を含むことができる。チルマノセプトはMADの特定の例である。DTPAがコンジュゲートしていないチルマノセプトであるチルマノセプトの誘導体はMADのさらなる例である(m−チルマノセプトと称されることもある)。
− ガドリニウム(Gd3+)のような磁性共鳴撮像(MRI)、常磁性および超常磁性酸化鉄のような超常磁性材料のために適当な造影剤;
− ヨード化された分子、イッテルビウムおよびジスプロシウムのようなコンピュータによる断層(CT)撮像のために適当な造影剤;
− 99mTc、210Bi、212Bi、213Bi、214Bi、131Ba、140Ba、11C、14C、51Cr、67Ga、68Ga、153Gd、88Y、90Y、91Y、123I、124I、125I、131I、111In、115mIn、18F、13N、105Rh、153Sm、67Cu、64Cu、166Ho、177Lu、223Ra、62Rb、186Reおよび188Re、32P、33P、46Sc、47Sc、72Se、75Se、35S、89Sr、182Ta、123mTe、127Te、129Te、132Te、65Znおよび89Zr、95Zr;または他のキレート可能な同位体(単数または複数)のようなシンチグラフの撮像(またはシンチグラフィー)のために適当な放射性同位体;
− 99mTc、111In、および123Iのような単一光子放射コンピュータ断層撮影(SPECT)のために適当なガンマ−放射剤。
− 光学撮像のために適当な染料および蛍光剤
− 18F、13N、64Cu、223Rbのような陽電子放出断層撮影(PET)のために適当な薬剤
を含むが、これらに限定されない。
−NH−(CH2)r−NH−、ここで、rは2〜5である、
−O−(CH2)r−NH−、ここで、rは2〜5である、
−NH−CH2−C(O)−、
−O−CH2−CH2−O−CH2−CH2−O−、
−NH−NH−C(O)−CH2−、
−NH−C(CH3)2C(O)−、
−S−(CH2)r−C(O)−、ここでrは1〜5である、
−S−(CH2)r−NH−、ここでrは2〜5である、
−S−(CH2)r−O−、ここでrは1〜5である、
−S−(CH2)−CH(NH2)−C(O)−、
−S−(CH2)−CH(COOH)−NH−、
−O−CH2−CH(OH)−CH2−S−CH(CO2H)−NH−、
−O−CH2−CH(OH)−CH2−S−CH(NH2)−C(O)−、
−O−CH2−CH(OH)−CH2−S−CH2−CH2−NH−、
−S−CH2−C(O)−NH−CH2−CH2−NH−、および
−NH−O−C(O)−CH2−CH2−O−P(O2H)−
を含む。
各Xは、独立にH、L1−A、またはL2−Rであり;各L1およびL2は、独立にリンカーであり;
各Aは、独立に検出標識またはHを含み;
各Rは、独立にCD206を標的とする部分またはHを含み;および
nは1以上の整数である)。
本発明の化合物は、開示されたスキームで示された反応を使用することにより、それに加えて文献で知られている、実験の部で例示された、または当業者には明らかな他の標準的操作で製造することができる。以下の例は、本発明がより完全に理解されるために提供され、例示にすぎず、限定するものと解釈されるべきではない。明確にするために、複数の置換基が本明細書で開示された定義の下に可能とされる場合に、比較的少ない置換基を有する例が示されている。
あるいは、本発明による化合物は、スキーム2に従って合成することができる。MADの遊離の第一級アミン基は、無水状態で過剰のラクトンと反応させることができる。未反応のラクトンが、減圧下で除去されて変態されたMAD6を得ることができる。対応するヒドラジン誘導体7は、シアノ水素化ホウ素ナトリウムまたはトリアセトキシ水素化ホウ素ナトリウムを還元剤として使用して、還元的アミノ化反応により製造することができる。
診断および/または治療部分のMAD誘導体4または7へのコンジュゲーションは、スキーム3で示されたようであることができる。MAD誘導体4または7は、無水酸性条件または水性酸性条件下におけるヒドラゾン連結の形成により、診断または治療部分にコンジュゲートすることができる。本明細書に記載される組成物の実施形態の例を図8に示す。
1. デキストランで構成される骨格、
2. デキストラン骨格のグルコース部分に取り付けられた分子連結鎖(複数)、
3. 分子連結鎖(複数)の部分に取り付けられたマンノース糖類、
4. マンノース部分により占められていない分子連結鎖(複数)に取り付けられた、1つまたはそれ以上の診断および/または治療部分、
5. マンノースに加えて他の糖部分が、マンノース部分または診断および/もしくは治療部分のいずれにも占められていない分子連結鎖(複数)に、場合により付加されることもある。
Claims (54)
- 1つまたはそれ以上の原発性腫瘍を検出するために使用される組成物であって、マンノシル化されたデキストラン化合物を含む前記組成物。
- 1つまたはそれ以上の転移性腫瘍を検出するために使用される組成物であって、マンノシル化されたデキストラン化合物を含む前記組成物。
- 検出は、マンノシル化されたデキストラン構造の、腫瘍関連マクロファージ(TAM)、骨髄系由来サプレッサー細胞(MDSC)およびCD206を発現している他の腫瘍関連免疫細胞への局在化を通して達成される、請求項1〜2のいずれか1項に記載の組成物。
- 転移は肝転移であることがある、請求項2に記載の組成物。
- 腫瘍を撮像するために使用される組成物であって、マンノシル化されたデキストラン構造である前記組成物。
- 腫瘍を撮像するために使用される組成物であって、デキストラン骨格を有しないマンノシル化された組成物である前記組成物。
- 撮像は、乳癌と関連しない腫瘍のためである、請求項1〜6のいずれか1項に記載の組成物。
- 1つまたはそれ以上の腫瘍を撮像するための:99mTcチルマノセプトを含む組成物であって、1つまたはそれ以上の腫瘍を撮像するために使用される前記組成物。
- グルコース部分で構成されるマンノシル化されたデキストラン分子構造を含む組成物であって:
デキストランで構成される骨格、デキストラン骨格のグルコース部分に取り付けられた少なくとも1つの連結鎖、少なくとも1つの連結鎖の部分に取り付けられた少なくとも1つのマンノース糖;
および少なくとも1つの連結鎖に取り付けられた1つまたはそれ以上の診断部分
を含む前記組成物。 - 少なくとも1つの連結鎖は、いかなるマンノース部分によっても占められていない、請求項9に記載の組成物。
- 少なくとも1つの他の糖部分は、少なくとも1つの連結鎖に付加されることができて、少なくとも1つの他の糖は、マンノース部分、診断または治療部分のいずれによっても占められていない、請求項9に記載の組成物。
- 治療剤をさらに含む、請求項9〜11のいずれか1項に記載の組成物。
- 腫瘍を撮像する方法であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の診断部分が取り付けられたデキストラン骨格を含む化合物を、対象に投与すること;
およびX線に基づくコンピュータ技術(CT)を用いる、単一光子放射のコンピュータ技術(SPECT)または陽電子放射断層撮影(PET)を使用して、前記対象を撮像すること
を含み;
像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む、前記腫瘍を撮像する方法。 - 腫瘍を撮像する方法であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の診断部分が取り付けられたデキストラン骨格を含む化合物を対象に投与すること;
およびX線に基づくコンピュータ技術(CT)を用いない、単一光子放射のコンピュータ技術(SPECT)または陽電子放射断層撮影(PET)を使用して、前記対象を撮像すること
を含み;
像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む
前記腫瘍を撮像する方法。 - 対象の撮像は、平面的ガンマ撮像を使用して行うことができて、像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む、請求項13〜14のいずれか1項に記載の方法。
- 乳癌の結果ではない腫瘍を撮像するための、請求項13〜14のいずれか1項に記載の方法。
- 化合物は治療剤をさらに含む、請求項13〜14のいずれか1項に記載の方法。
- 腫瘍を撮像する方法であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の治療部分が取り付けられたデキストラン骨格を含む化合物を対象に投与すること;
およびX線に基づくコンピュータ技術(CT)を用いる、単一光子放射のコンピュータ技術(SPECT)または陽電子放射断層撮影(PET)を使用して、前記対象を撮像すること
を含み、
像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む、前記腫瘍を撮像する方法。 - 腫瘍を撮像する方法であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の治療部分が取り付けられたデキストラン骨格を含む化合物を対象に投与すること;
およびX線に基づくコンピュータ技術(CT)を用いない、単一光子放射のコンピュータ技術(SPECT)または陽電子放射断層撮影(PET)を使用して、前記対象を撮像すること
を含み、
像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む、前記腫瘍を撮像する方法。 - 対象の撮像は、平面的ガンマ撮像を使用して行われることができて、像は、対象における1つまたはそれ以上の腫瘍における前記化合物の取り込みの視覚的表示を含む、請求項18〜19のいずれか1項に記載の方法。
- 乳癌の結果でない腫瘍を撮像するための、請求項18〜20のいずれか1項に記載の方法。
- 腫瘍を撮像または検出するための組成物であって、腫瘍が、任意の解剖学的箇所で検出されるかまたは撮像されることができる前記組成物。
- 検出されおよび/または撮像される腫瘍は内臓の腫瘍である、請求項22に記載の組成物。
- 検出されおよび/または撮像される腫瘍は転移性腫瘍である、請求項22に記載の組成物。
- 内臓の腫瘍は、肺、結直腸、腎臓、卵巣、前立腺、精巣、膵の癌、リンパ腫等からなる群から選択される癌の結果である、請求項22に記載の組成物。
- 内臓の腫瘍は原発性腫瘍である、請求項22に記載の組成物。
- 転移性腫瘍は、肺、結直腸、腎臓、卵巣、前立腺、精巣、膵の癌、リンパ腫等からなる群から選択される癌の結果である、請求項24に記載の組成物。
- 転移性腫瘍は、原発性癌と同じ組織タイプにある、請求項24または27に記載の組成物。
- 転移性腫瘍は原発性癌と異なる組織にある、請求項24または27に記載の組成物。
- 1つまたはそれ以上の腫瘍を検出するために組成物を使用する方法であって、請求項22〜29のいずれか一項に記載の組成物を使用する、前記方法。
- 1つまたはそれ以上の転移した腫瘍を検出するための:99mTcチルマノセプトを含む組成物であって、1つまたはそれ以上の転移した腫瘍を検出するために使用される前記組成物。
- 組成物であって、腫瘍のサイズを、その質量およびサイズを推定することを含めて定量化するために使用される前記組成物。
- 組成物であって、腫瘍関連マクロファージを撮像するための前記組成物。
- 組成物であって:
腫瘍関連マクロファージ(TAM)を撮像するための診断部分を含む前記組成物。 - 腫瘍外縁部を決定するために使用されることはない、請求項22に記載の組成物。
- 工程は、腫瘍外縁部を決定することを含まない、請求項30に記載の方法。
- 手術中に使用されることはない、請求項22に記載の組成物。
- 撮像または検出は手術中ではない、請求項30に記載の方法。
- 樹状細胞を標的とすることに使用されない、請求項22に記載の組成物。
- 組成物であって:
腫瘍関連マクロファージを標的とするために使用されるマンノシル化された炭水化物構造を含む前記組成物。 - 請求項40に記載の組成物を使用する方法であって、樹状細胞を標的とすることを含まない、前記方法。
- 組成物であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の診断部分を有するデキストラン骨格を含む前記組成物。 - 組成物であって、1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の治療部分を有するデキストラン骨格を含む前記組成物。
- 腫瘍で活性化されたマクロファージを標的とするために使用される、請求項42または43に記載の組成物。
- 方法であって:
1つまたはそれ以上のCD206を標的とする部分および1つまたはそれ以上の診断部分を有する炭水化物骨格を含む組成物を、対象に投与する工程;
SPECT/CTを使用して、対象を撮像する工程;
および腫瘍関連マクロファージの存在を決定する工程
を含む前記方法。 - 腫瘍関連マクロファージの数を定量化する工程をさらに含む、請求項45に記載の方法。
- 腫瘍の存在を同定する工程をさらに含む、請求項45〜46のいずれか1項に記載の方法。
- 前から存在する腫瘍の転移を同定する工程をさらに含む、請求項45〜47のいずれか1項に記載の方法。
- 治療剤を腫瘍に投与するために、治療剤を含む本明細書に記載される組成物を投与する工程をさらに含む、請求項45〜48のいずれか1項に記載の方法。
- 治療剤を転移した腫瘍に投与するために、治療剤を含む本明細書に記載される組成物を投与する工程をさらに含む、請求項45〜49のいずれか1項に記載の方法。
- 投与が静脈内である、請求項45〜50のいずれか1項に記載の方法。
- 組成物は、99mTc、210Bi、212Bi、213Bi、214Bi、131Ba、140Ba、11C、14C、51Cr、67Ga、68Ga、153Gd、88Y、90Y、91Y、123I、124I、125I、131I、111In、115mIn、18F、13N、105Rh、153Sm、67Cu、64Cu、166Ho、177Lu、223Ra、62Rb、186Reおよび188Re、32P、33P、46Sc、47Sc、72Se、75Se、35S、89Sr、182Ta、123mTe、127Te、129Te、132Te、65Znおよび89Zr、および95Zrからなる群から選択される診断部分を含む、請求項22に記載の組成物。
- 診断部分は68Gaである、請求項52に記載の組成物。
- 診断部分は99mTcである、請求項52に記載の組成物。
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