JP6556805B2 - 前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 - Google Patents
前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 Download PDFInfo
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- JP6556805B2 JP6556805B2 JP2017210775A JP2017210775A JP6556805B2 JP 6556805 B2 JP6556805 B2 JP 6556805B2 JP 2017210775 A JP2017210775 A JP 2017210775A JP 2017210775 A JP2017210775 A JP 2017210775A JP 6556805 B2 JP6556805 B2 JP 6556805B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A61K51/04—Organic compounds
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Description
前立腺癌(PCa)は、米国および欧州諸国の住人において主要な癌である。西半球で少なくとも100〜200万人の男性が前立腺癌に苦しみ、該疾患は55歳〜85歳の6人に一人に見られると推定される。米国において毎年、前立腺癌と診断された30万を超す新たな症例が見られる。該疾患の死亡率は肺癌に次いで2番目である。コンピューター連動断層撮影(CT)、磁気共鳴(MR)画像化および超音波などの現在の解剖学的方法は、前立腺癌の臨床画像化の主流である。手術、放射線治療、薬物療法および最小侵襲性治療に対して世界規模で現在推定20億ドルが使われている。しかしながら、現在、再発性、転移性、アンドロゲン独立型の前立腺癌については効果的な治療法はない。
特許請求の範囲において特徴付けられる態様を提供することにより、前記の課題の解決は達成される。
〔1〕式(Ia)または(Ib):
〔2〕R'-リンカー-R構造を有する化合物であり、ここでR'=-DOTAであり、R=-Glu-尿素-Lys:
であり、
式中、R'-リンカー-Rは、
から選択される、〔1〕記載の化合物、
〔3〕以下:
から選択される、〔1〕または〔2〕記載の化合物、
〔4〕放射線標識化合物の調製のための〔1〕〜〔3〕いずれか記載の化合物の使用、
〔5〕放射線核種および〔1〕〜〔3〕いずれか記載の化合物を含む、金属複合体、
〔6〕放射線核種が、111In、90Y、68Ga、177Lu、99mTc、64Cu、153Gd、155Gd、157Gd、213Bi、225AcまたはFeである、〔5〕記載の金属複合体、
〔7〕〔1〕〜〔3〕いずれか記載の化合物、または〔5〕または〔6〕記載の金属複合体、またはその薬学的に許容され得る塩もしくはエステル、および薬学的に許容され得る担体を含む、医薬組成物、
〔8〕患者における画像化方法における使用のための、〔1〕〜〔3〕いずれか記載の化合物または〔5〕または〔6〕記載の金属複合体、
〔9〕前立腺癌および/またはその転移の診断方法における使用のための、〔1〕〜〔3〕いずれか記載の化合物または〔5〕または〔6〕記載の金属複合体、
〔10〕前立腺癌および/またはその転移の治療方法における使用のための、〔1〕〜〔3〕いずれか記載の化合物または〔5〕または〔6〕記載の金属複合体
に関する。
本発明は、前立腺癌の種々の病期の治療のための放射性医薬品、およびトレーサー、画像化剤としての核医学におけるその使用に関する。
実施例1:DOTAコンジュゲートインヒビターの合成
DOTAコンジュゲートPSMAインヒビターは、固相ペプチド合成を介して合成する(スキーム2参照)。第1の工程において、3mmolのビス(tert-ブチル)-L-グルタミン酸塩酸塩および3mLのN-エチルジイソプロピルアミン(DIPEA)の200mL 乾燥CH2Cl2中の混合物を、1mmolトリホスゲンの10mL 乾燥CH2Cl2の溶液に、5℃で3時間かけて添加して、グルタミル部分のイソシアネートをインサイチュで生成した。反応後、0.5mmolの樹脂固定(2-クロロ-トリチルレジン)ε-アリルオキシカルボニル保護リシンを添加して緩やかに撹拌しながら16時間反応させた。樹脂をろ過して除き、4mL CH2Cl2中50mgテトラキス-(トリフェニル)パラジウムおよび400μLモルホリンを使用して2時間かけてアリルオキシ保護基を除去した。
典型的に、容量100μL中1.5nmolの合成した実施例1の化合物(0.1M HEPESバッファpH 7.5に溶解)を10μL 2.1M HEPES溶液および40μL[68Ga]Ga3+溶離液(40MBq)の混合物に添加した。標識溶液のpHを4.5に調整した。
200mLの乾燥CH2Cl2中3mmolのビス(tert-ブチル)L-グルタミン酸塩酸塩および1.5mLのN-エチルジイソプロピルアミン(DIPEA)の混合物を10mLの乾燥CH2Cl2中1mmolトリホスゲンの溶液に0℃で4時間かけて添加して、インサイチュでグルタミル部分のイソシアネートを生成した。反応混合物を25℃で1時間撹拌後、4mL DCM中0.5mmolの樹脂固定(2-クロロ-トリチルレジン)ε-アリルオキシカルボニル保護リジンを添加して、緩やかに撹拌しながら16時間反応させた。樹脂をろ過して除き、4mL CH2Cl2中30mgテトラキス(トリフェニル)パラジウム(0)および400μLモルホリンを使用してアリルオキシ保護基を3時間かけて除去した。以下、4-(Fmoc-アミノメチル)安息香酸(MB4の場合)またはFmoc-3-(2-ナフチル)-L-アラニンおよびトランス-4-(Fmoc-アミノメチル)シクロヘキサンカルボン酸(MB17の場合)それぞれの3回のカップリングを、最終容量4mL DMF中2mmolのFmoc保護酸、1.96mmolのHBTUおよび2mmolのN-エチルジイソプロピルアミンを使用して段階的に行った。3.95当量のHBTUおよびDIPEAでの2時間の活性化後、樹脂負荷に対して4当量のトリス(t-bu)-DOTA(Chematech)を、最終容量3mL DMF中で3時間反応させた。トリフルオロ酢酸、トリイソプロピルシランおよび水(95:2.5:2.5)からなる2mLの混合物中、生成物を樹脂から切断した。RP-HPLCを用いて精製を行い、精製した生成物を分析用RP-HPLCおよびMALDI-MSを用いて分析した。
177Lu標識
177Lu(約100MBq)を、Chelexを含む200μlの0.4M酢酸ナトリウムバッファ(pH=5)と混合した。10% DMSO水中10μlの1mM化合物溶液、2μlのアスコルビン酸飽和溶液および40μlの177Lu含有溶液を混合して、95℃に10分間加熱した。放射性HPLC(水中0〜100% ACN、5分以内、Monolithカラム)で標識を調べた。
PETスキャンのために、CHX-DTPAを68Gaで標識した。1mlの68Gaを、0.6M HClを用いて68Ge/68Ga発生物質から溶出させた。298μl NaOAcバッファおよび1μlのDMSO中10mMのCHX-DTPA溶液を添加して、5分間インキュベートした。その後、SOLAカートリッジを用いて生成物を精製した。0.9% NaCl溶液を用いて洗浄を行い、溶出にはエタノールを使用した。次いでエタノールを蒸発させ、残った生成物を100μlの0.9% NaCl溶液および10μlのリン酸バッファに溶解した。
フィルタープレートMultiScreenHTS-DVを、1ウェル当たり1% BSAを添加した100μl PBSと30分間室温でインキュベートした。PBS/BSA溶液を除去後、50μl Opti-MEM中の105 LNCaP細胞を各ウェルに適用した。300μl Opti-MEM中異なる濃度の化合物(各ウェルにおいて0、0.5、1、2.5、5、10、25、50、100、500、1000および5000nMの濃度を生じる)を、Opti-MEM中3μl 150nM 125I標識MIP-1466の溶液と混合した。50μlの得られた溶液を各ウェルに添加し、各濃度をピペッティングで4倍希釈した(in quadruples)。ここで各ウェルは、0.75nMの濃度の放射活性標識リガンドおよび上述の濃度の標識されていないリガンドである競合物を含んだ。次いでプレートを振盪器上、室温で45分間インキュベートした。
マウスへの注射前に、精製した68Ga-CHX-DTPAカップリングPSMAインヒビターを含む溶液をろ過滅菌した。100μlのこの溶液をシリンジに吸い上げ、BALB/cヌードマウスLNCaP異種移植片の尾部静脈に静脈内注射した。Siemens Inveon PETを使用してPETスキャンを140分間記録した(図15)。
一連の新規の化合物を比較するために、PSMA発現細胞株LNCaPを使用して競合結合親和性および特異的内在化を分析した。特異的細胞取り込みを測定するために、細胞を2-(ホスホノメチル)-ペンタン二酸(PMPA)でブロッキングした。酵素系NAALADaseアッセイにより阻害能力も調べた。
結合試験およびインビボ実験のために、LNCaP細胞(ヒト前立腺癌の転移性病変、ATCC CRL-1740)を、10%ウシ胎仔血清およびGlutamax(PAA, Austria)を補充したRPMI培地で培養した。細胞培養の間、細胞は湿潤空気、5%CO2で平衡化したインキュベーター中37℃で増殖させた。トリプシン-エチレンジアミン四酢酸(トリプシンEDTA;0.25%トリプシン、0.02% EDTA、全てPAA, Austria)を用いて細胞を回収し、PBSで洗浄した。
競合細胞結合アッセイおよび内在化実験を前述(Eder et al. 2012)の通りに行った。簡潔に、それぞれの細胞(1ウェル当たり105)を放射性リガンド(68Ga標識[Glu-尿素-Lys(Ahx)]2-HBED-CC(Schafer et al., 2012)と、12の異なる濃度の検体(0〜5000nM、100μL/ウェル)の存在下でインキュベートした。インキュベーション後、マルチスクリーン真空マニホールド(Millipore, Billerica, MA)を使用して洗浄を行った。γ線測定器(Packard Cobra II, GMI, Minnesota, USA)を用いて細胞結合放射能を測定した。50%阻害濃度(IC50)は、非線形回帰アルゴリズム(GraphPad Software)を使用してデータを適合させて計算した。実験は3回行った。
組み換えヒトPSMA(rhPSMA, R&D systems, Wiesbaden, Germany)をアッセイバッファ(50mM HEPES、0.1M NaCl、pH 7.5)で0.4μg/mLまで希釈した。基質Ac-Asp-Glu(Sigma, Taufkirchen, Germany、40μM終濃度)を、natGa標識験体と、最終容量125μLのアッセイバッファ中0.05nM〜1000nMの範囲の濃度で混合した。混合物を125μLのrhPSMA溶液(0.4μg/mL)と合わせて、37℃で1時間インキュベートした。95℃で5分間加熱して反応を停止した。250μLの15mMのオルト-フタルジアルデヒド(Sigma, Taufkirchen, Germany)溶液を全てのバイアルに添加して、周囲温度で10分間インキュベートした。最終的に、200μLの反応液をF16 Black Maxisorpプレート(Nunc, Langenselbold, Germany)上に充填して、330nmおよび450nmそれぞれの励起および放射の波長で、マイクロプレートリーダー(DTX-880, Beckman Coulter, Krefeld, Germany)を使用して読み取りを行った。GraphPad(GraphPad Software, California, USA)の1部位全体(one site-total)結合回帰アルゴリズムによりデータを分析した。
7〜8週齢の雄BALB/c nu/nuマウス(Charles River Laboratories)の右側の体幹に5×106個のLNCaP細胞(50%マトリゲル中;Becton Dickinson, Heidelberg, Germany)を皮下接種した。約1cm3の大きさまで腫瘍を成長させた。放射線標識化合物を尾静脈に注射した(1マウス当たり約1MBq;0.06nmol)。注射の1時間後、動物を屠殺した。目的の臓器を切除して、吸い取らせて(blotted)乾燥させて計量した。γ線測定器を使用して放射能を測定し、% ID/gとして計算した。
microPET試験について、0.15mlの容量の10〜25MBqの放射線標識化合物(約0.5nmol)を、側方尾静脈から、LNCaP腫瘍異種移植片を有するマウスに注射した。麻酔した動物(2%セボフルラン、Abbott, Wiesbaden, Germany)をInveon小動物PETスキャナー(Siemens, Knoxville, Tenn, USA)にうつむけの姿勢で配置し、動的microPETスキャンおよび20分静的スキャンを行った;図1、3、5〜14参照。
Ga-68で標識した放射性トレーサーMB17を用いてPET/CT画像化を行った(図17参照)。
治療のために、PSMAリガンドMB17をLu-177で放射線標識した。177LuCl3はPerkin Elmer (4GBq, NEZ307D, 0.04M HCl)から入手した。80nモルのMB17を5μLの20%アスコルビン酸を補充した400μLの酢酸ナトリウムバッファ(0.4M、pH 5)に溶解した。溶液を177LuCl3に移し、95℃で10分間インキュベートした。最後に2mLの0.9% NaClを添加した。品質管理のためにITLCおよび放射線HPLCを行った。
Claims (20)
- 下記式:
の化合物。 - 前記化合物が凍結乾燥された請求項1に記載の化合物。
- 請求項1記載の化合物および薬学的に許容され得る担体を含む医薬組成物であって、請求項1記載の化合物および薬学的に許容され得る担体が凍結乾燥されている医薬組成物。
- 前記薬学的に許容され得る担体がマンニトール、ラクトース、グルコース、およびアルブミンから選択される請求項3に記載の医薬組成物。
- 請求項1に記載の化合物の立体異性体。
- 下記式:
(式中、R’は、下記式の−キレート剤:
を表し、
前記−キレート剤は、放射性核種と複合体化されている。)の化合物。 - 前記放射性核種が、89Zr、44Sc、111In、90Y、68Ga、177Lu、99mTc、64Cu、67Cu、153Gd、155Gd、157Gd、213Bi、および225Acからなる群から選択される、請求項6に記載の化合物。
- 前記放射性核種が、64Cu、67Cu、68Ga、177Lu、および225Acからなる群から選択される、請求項6または7に記載の化合物。
- 前記放射性核種が、68Gaである、請求項6または7に記載の化合物。
- 前記放射性核種が、177Luである、請求項6または7に記載の化合物。
- 前記放射性核種が、225Acである、請求項6または7に記載の化合物。
- 前記放射性核種が、64Cuおよび67Cuからなる群から選択される、請求項6または7に記載の化合物。
- (1)下記式:
(式中、R’は、下記式の−キレート剤:
を表し、
前記−キレート剤は、放射性核種と複合体化されている。)の化合物、および、
(2)薬学的に許容され得る担体、
を含む医薬組成物。 - 前記放射性核種が、89Zr、44Sc、111In、90Y、68Ga、177Lu、99mTc、64Cu、67Cu、153Gd、155Gd、157Gd、213Bi、および225Acからなる群から選択され、前記組成物はさらに賦形剤を含み、前記賦形剤は前記薬学的に許容され得る担体とは異なる、請求項13に記載の組成物。
- 前記放射性核種が、64Cu、67Cu、68Ga、177Lu、および225Acからなる群から選択される、請求項14に記載の組成物。
- 前記放射性核種が、68Gaである、請求項14または15に記載の組成物。
- 前記放射性核種が、177Luである、請求項14または15に記載の組成物。
- 前記放射性核種が、225Acである、請求項14または15に記載の組成物。
- 前記放射性核種が、64Cuおよび67Cuからなる群から選択される、請求項14または15に記載の組成物。
- 前記組成物が緩衝化された溶液である、請求項14または15に記載の組成物。
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JP2019218351A (ja) * | 2013-10-18 | 2019-12-26 | ドイチェス クレブスフォルシュンクスツェントルム | 前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 |
JP2021059557A (ja) * | 2013-10-18 | 2021-04-15 | ドイチェス クレブスフォルシュンクスツェントルム | 前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 |
JP7036774B2 (ja) | 2013-10-18 | 2022-03-15 | ドイチェス クレブスフォルシュンクスツェントルム | 前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 |
JP7194161B2 (ja) | 2013-10-18 | 2022-12-21 | ドイチェス クレブスフォルシュンクスツェントルム | 前立腺特異的膜抗原(psma)の標識インヒビター、前立腺癌の治療のための画像化剤および薬剤としてのその使用 |
US11931430B2 (en) | 2013-10-18 | 2024-03-19 | Novartis Ag | Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer |
US11951190B2 (en) | 2013-10-18 | 2024-04-09 | Novartis Ag | Use of labeled inhibitors of prostate specific membrane antigen (PSMA), as agents for the treatment of prostate cancer |
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