JP2012514007A - トシラート前駆体からの18f−放射性標識スチリルピリジンおよびその安定性医薬組成物の合成 - Google Patents
トシラート前駆体からの18f−放射性標識スチリルピリジンおよびその安定性医薬組成物の合成 Download PDFInfo
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- JP2012514007A JP2012514007A JP2011543721A JP2011543721A JP2012514007A JP 2012514007 A JP2012514007 A JP 2012514007A JP 2011543721 A JP2011543721 A JP 2011543721A JP 2011543721 A JP2011543721 A JP 2011543721A JP 2012514007 A JP2012514007 A JP 2012514007A
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Abstract
Description
本出願は、合衆国法典第35巻第119(e)条に基づき、2008年12月31日に出願された米国仮特許出願番号第61/141,885号の優先権を主張し、その開示内容はすべて、参照により本明細書に組み込まれる。
本発明は、一般には18F-放射性標識化された脳造影剤の合成法、さらに具体的には18F-放射性標識化されたスチリルピリジンおよびそのトシラート前駆体を合成する方法、および18F-放射性標識化された脳造影剤を含む安定した医薬組成物に関する。
本発明の実施形態は、有効量の18F-放射性標識化合物、約1.0%から約20%(v/v)のエチルアルコール、および少なくとも約0.1%(w/v)のアスコルビン酸またはその塩を有する脳の神経変性疾患の陽電子放出断層撮影法(PET)用の放射性医薬組成物を対象とする。様々な実施形態において、18F-放射性標識化合物は患者の脳内の病的標的に結合できる。病的標的は、自然にまたは病理学的に変化したタンパク質、ペプチド、またはオリゴヌクレオチド、β-アミロイド、α-シヌクレイン、または水疱性モノアミン輸送体2(VMAT2)の異常集中を含み得る。
説明されている特定の組成物または方法論は異なり得るため、本発明はこれらに限られない。さらに、本説明中で使用されている用語は特定のバージョンまたは実施形態を説明するものであり、本発明の範囲を限定することを意図していない。別途定義されていない限り、本明細書中で使用されているすべての技術用語および科学用語は本分野において当業者により一般的に理解されるものと同じ意味を持つ。不一致がある場合、定義を含め、本特許出願明細書が優先される。
本明細書中で開示される発明をより効率的に理解するために、以下の実施例が提供されている。これらの実施例は例証のみを目的とし、如何なる方法によっても本発明を限定するものとは解釈すべきではない。
実施例1.0. AV-105トシラート前駆体の18F-AV-45への合成
実施例1.1. tert-ブチル4-ビニルフェニルカルバミン酸塩
実施例1.2. tert-ブチルメチル(4-ビニルフェニル)カルバミン酸塩
実施例1.3. 2-(2-(2-(5-ヨードピリジン-2-イルオキシ)エトキシ)エトキシ)エタノール
実施例1.4. (E)-tert-ブチル4-(2-(6-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ピリジン-3-イル)ビニル)フェニル(メチル)カルバミン酸塩
実施例1.5. (E)-2-(2-(2-(5-(4-(tert-ブトキシカルボニル(メチル)アミノ)スチリル)ピリジン-2-イルオキシ)エトキシ)エトキシ)エチル4-メチルベンゼンスルホナート(AV-105)
実施例2.0. AV-105からの18F-AV-45の放射性合成
実施例3.0. 19F-AV-45を可溶化および18F-AV-45を安定化させるための製剤
表1. 合成終了(EOS)時の18F-AV-45注射の放射化学純度率分析
表2. 18F-AV-45注射における19F-AV-45の合成終了(EOS)時およびEOSから2時間後のUV純度分析*
表3. アスコルビン酸ナトリウム0.5%で製造および製剤された18F-AV-45注射の長期安定性
Claims (25)
- 脳の神経変性疾患の陽電子放出断層撮影(PET)のための放射性医薬組成物であって、
有効量の18F-放射性標識化合物、
約1.0%から約20%(v/v)までのエチルアルコール、および
少なくとも約0.1%(w/v)のアスコルビン酸またはその塩を含む放射性医薬組成物。 - 18F-放射性標識化合物が患者の脳内の病的標的に結合することができる請求項1記載の放射性医薬組成物。
- 病的標的が自然にまたは病理学的に変化したタンパク質、ペプチド、オリゴヌクレオチドの異常集中である請求項2記載の放射性医薬組成物。
- 病的標的がβ-アミロイドである請求項2記載の放射性医薬組成物。
- 病的標的がα-シヌクレインである請求項2記載の放射性医薬組成物。
- 病的標的が水疱性モノアミン輸送体2(VMAT2)である請求項2記載の放射性医薬組成物。
- 18F-放射性標識化合物がスチリルピリジン誘導体である請求項1記載の放射性医薬組成物。
- 18F-放射性標識化合物が((E)-4-(2-(6-(2-(2-(2-[18F]フルオロエトキシ)エトキシ)エトキシ)ピリジン-3-イル)ビニル)-N-メチルベンゼンアミン)(18F-AV-45)である請求項1の放射性医薬組成物。
- 18F-AV-45がトシラート前駆体から生成される請求項8の放射性医薬組成物。
- 18F-放射性標識化合物がジヒドロテトラベナジン(DTBZ)の誘導体である請求項1記載の放射性医薬組成物。
- 18F-放射性標識化合物が(2R,3R,11bR)-9-(3-[18F]フルオロプロポキシ)-3-イソプロピル-10-メトキシ-11b-メチル-2,3,4,6,7,11b-ヘキサヒドロ-1H-ピリド[2,1-a]イソキノリン-2-オール(18F-AV-133)である請求項1記載の放射性医薬組成物。
- エチルアルコール濃度が約1.0%から約15.0%(v/v)までの範囲内である請求項1記載の放射性医薬組成物。
- アスコルビン酸またはその塩が約0.1%から約1.0%(w/v)までの範囲内である請求項1記載の放射性医薬組成物。
- 放射性医薬組成物のpHが約4.5から約8.0までの範囲内である請求項1記載の放射性医薬組成物。
- 放射性医薬組成物の純度が合成終了から少なくとも約4時間後の測定時に約90%以上である請求項1記載の放射性医薬組成物。
- 神経変性疾患の診断に使用するための請求項1記載の放射性医薬組成物。
- 神経変性疾患が、認知症、認知障害、アルツハイマー病、パーキンソン病、レビー小体型認知症、および血管性認知症の少なくとも一つである請求項16記載の放射性医薬組成物。
- 脳の陽電子放出断層撮影法(PET)のための放射性医薬組成物であって、
有効量の18F-放射性標識化合物、
少なくとも約1.0%(v/v)のエチルアルコール、および
少なくとも約0.1%(w/v)のアスコルビン酸塩を含み、ここで、18F-放射性標識化合物は合成終了時から合成終了から約12時間後までに約10%未満分解する放射性医薬組成物。 - 患者において神経変性疾患を診断するための方法であって、
患者の神経変性疾患に関連する標的に結合可能な放射性医薬組成物を投与する手順を含み、前記放射性医薬組成物は有効量の18F-放射性標識化合物、少なくとも約1.0%(v/v)のエチルアルコール、および少なくとも約0.1%(w/v)のアスコルビン酸ナトリウムを含み、
標的が位置することが予測されるところの領域を含む患者の脳の一部を造影する手順、および
標的を検出する手順を含むことを特徴とする方法。 - 造影手順が、陽電子放出断層撮影法(PET)、コンピュータ断層撮影と同時のPET(PET/CT)、磁気共鳴画像法と同時のPET(PET/MRI)、またはその組み合わせを使用して実行される請求項19の方法。
- β-アミロイド沈着物に結合可能な18F-放射性標識医薬組成物を生成する方法であって、
トシラート前駆体を合成する手順、
トシラート前駆体の求核18Fフッ素化をジメチルスルホキシド(DMSO)溶液中で行い、18F放射性医薬品を準備する手順、および
アスコルビン酸またはその塩を含む含水エチルアルコール中で18F放射性医薬品を製剤する手順を含み、
ここで、最終的に得られた18F-放射性標識医薬組成物において、エチルアルコールが約1.0%(v/v)の最低濃度で存在し、アスコルビン酸またはその塩の最低濃度が約0.1%(w/v)であることを特徴とする方法。 - トシラート前駆体(E)-2-(2-(2-(5-(4-(tert-ブトキシカルボニル(メチル)アミノ)スチリル)ピリジン-2-イルオキシ)エトキシ)エトキシ)エチル4-メチルベンゼンスルホン酸塩(AV-105)を生成する方法であって、
(i)モノBoc保護のビニルアニリン化合物を用意する手順、
(ii)そのビニルアニリン化合物をメチル、t-ブチルカルバミン酸誘導体に転換する手順、
(iii)2-ハロー5-ヨードピリジンをトリエチレングリコールと反応させる手順、
(iv)手順(ii)のメチル、t-ブチルカルバミン酸誘導体を手順(iii)の結果として得られる化合物と反応させ、(E)-tert-ブチル4-(2-(6-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ピリジン-3-イル)ビニル)フェニル(メチル)カルバミン酸塩を生成する手順、および
(v)(E)-tert-ブチル4-(2-(6-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ピリジン-3-イル)ビニル)フェニル(メチル)カルバミン酸塩を塩化トシルと反応させ、AV-105を形成する手順を含むことを特徴とする方法。 - 放射性医薬組成物を生成する方法であって、
請求項23のトシラート前駆体(E)-2-(2-(2-(5-(4-(tert-ブトキシカルボニル (メチル)アミノ)スチリル)ピリジン-2-イルオキシ)エトキシ)エトキシ)エチル4-メチルベンゼンスルホン酸塩(AV-105)をジメチルスルホキシド(DMSO)溶液または他の高沸点の非プロトン性溶媒中の18F-フッ素イオンと反応させ、((E)-4-(2-(6-(2-(2-(2-[18F]フルオロエトキシ)エトキシ)エトキシ)ピリジン-3-イル)ビニル)-N-メチルベンゼンアミン)(18F-AV-45)を生成する手順、
18F-AV-45を単離する手順、および
18F-AV-45を精製する手順を含むことを特徴とする方法。 - さらに、約1.0%から約15%(v/v)までのエチルアルコールおよび約0.1%から約1.0%(w/v)までのアスコルビン酸塩を含む溶液中で18F-AV-45を製剤する手順を含む、請求項23記載の方法。
- アスコルビン酸塩がアスコルビン酸ナトリウムであり、その濃度が約0.5%(w/v)である請求項24記載の方法。
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