JP2018513102A - 磁気共鳴画像法用の造影剤 - Google Patents
磁気共鳴画像法用の造影剤 Download PDFInfo
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- JP2018513102A JP2018513102A JP2017524028A JP2017524028A JP2018513102A JP 2018513102 A JP2018513102 A JP 2018513102A JP 2017524028 A JP2017524028 A JP 2017524028A JP 2017524028 A JP2017524028 A JP 2017524028A JP 2018513102 A JP2018513102 A JP 2018513102A
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- ascorbate
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- acceptable salt
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Abstract
Description
本出願は、2015年9月30日に出願された米国仮特許出願第62/234,986号に対する利益を主張するものである。この仮特許出願の開示全体を、参照することができ、ここに引用することで本明細書の一部をなすものとする。
本発明は、磁気共鳴画像法用の造影剤として有用な組成物及びその使用方法に関する。
(スピン−スピン緩和速度、1/T2のアスコルベートによる強調)
以前の研究では、バルク水プロトンと低分子量溶質及び高分子の移動可能なプロトン(例えば、−NH2、−OH、−SH、−NH)との交換によって生じるT2強調に関するNMR/MRIコントラスト効果について報告されている。このプロトン交換による1/T2に関するコントラスト効果は、以下のように記載される:
によって算出できる。pKH3O+及びpKOH−=15.7であるが、触媒濃度に対するプロトン移動の非線形依存性のために、Kcは予測がより困難である。それにもかかわらず、中性pHでの効率的な交換触媒反応が、pKD−pKAとの間の少なくとも中程度の差及び生理的pHでの触媒活性酸性型又は塩基性型交換触媒の有意な濃度によって達成される。
(インビボの例)
〈正常な脳灌流及び物質代謝〉
図9で、インビボにおける、高用量非経口アスコルベート(2g/kg、右IJiv注射)後のアスコルベートT2コントラスト変化を示す。図9Aでは、正常C57ブラックマウスの中脳を通る従来の単一スライスアキシャルFSE T2WI画像を示している。右の2つの画像は、アスコルベートi.v.投与中及び投与後におけるコントラスト変化の「初回通過」抽出を示す。脳組織のT2信号を、アスコルベート投与の直後及び10分後に収集し、次にアスコルベート投与前に収集したT2脳信号から差し引く。アスコルベートが信号強度の減少をもたらすので、より高信号の投与前スキャンからの減算により、脳組織を通る通過灌流(血流)の正味の陽性「マップ」が得られる。10分において、灌流効果はほぼ消失し、組織取り込みに関連する早期の信号強度変化が観察され始めている。図9Bでは、高用量アスコルベートの組織取り込みによる信号変化を示している。信号強度のカラー−リュートマップは投与前スキャンから減算されず、したがって、正常C57マウスでは30〜60分に最大となる、予想された経時的T2信号減少を示している。
(インビボの例)
〈新皮質拡延性抑制と関連した限局性脳代謝亢進〉
図10で、新皮質拡延性抑制の齧歯類モデルにおけるアスコルベートT2強調を示す。拡延性抑制(SD)は、60年前にLoaoによって最初に記載されたCNS組織の実験的に再生可能な病態生理学的現象である。皮質の限局的な領域がイオン摂動の臨界閾値に達した後、細胞脱分極の大きい拡散波が始まり灰白質組織に広がる可能性があるが、その拡散波が誘導された灰白質域に限局されたままであり、白質経路を通らない。誘導メカニズム(例えば、適用された塩化カリウムの局所的高濃度)が同じ領域に対して連続的である場合、拡延性抑制のこれらの波は8〜10分に1回繰り返されて、2〜3時間持続する。SDに伴って脳代謝の顕著な変化が起こり、組織学的に検出可能なニューロン損傷がSD後には存在しないので、これらの物質代謝は、非虚血性の過剰興奮性脳組織、例えば、てんかん発作焦点の代謝フラックスを変化させる。
(インビボの例)
〈心臓灌流及び代謝イメージング〉
図11は、非経口アスコルベートを用いた灌流及びバイアビリティの心臓イメージングを示す図である。図11Aでは、7Tにおけるラット心臓イメージングの2つの主要イメージング面、コロナル及びアキシャルを示している。呼吸同調を伴うレトロスペクティブゲーティングを用いて、7Tにおいて画像を集めた。収集シーケンスは中程度にT2強調されており、コントラスト効果を強調するために更に最適化することができる。図11Bでは、アスコルベートi.v.注射の最初のボーラスによる、左心室の全体にわたるT2信号強度の一過性減少を示している。初回通過流又は「灌流イメージング」のための最初のボーラスの後、可変フリップ角を使用した定量的T2マップは、心臓組織の緩徐なT2コントラスト変化を示し、アスコルベートの取り込みを反映している。代謝的に活性な生細胞のみが、アスコルベートを取り込むであろう。
(インビボの例)
〈モルモットにおける、アスコルベートの3つの異なる製剤の静脈内投与後のT2コントラスト変化〉
我々は、軽度麻酔したモルモットの全脳におけるT2コントラスト変化を7Tで調べた。モルモットは、ヒトと同様にアスコルベートを内因的に合成できないので、このモデルのMRI効果は患者のMRI変化をより予測できる。アスコルベートは、60分にわたって総用量2g/kgにコントロールされた注入によって、大腿静脈又は頸静脈から非経口投与した。MRIは、90分間行った。
Claims (26)
- 臓器若しくは臓器領域などの対象の身体若しくは身体領域の磁気共鳴画像法(MRI)画像を強調する方法を実施するためのアスコルベート又は医薬として許容されるその塩の使用、又は臓器若しくは臓器領域などの対象の身体若しくは身体領域の磁気共鳴画像法(MRI)画像を強調する方法を実施するための薬剤を調製するためのアスコルベート又は医薬として許容されるその塩の使用であって、前記方法が、アスコルベート又は医薬として許容されるその塩を、MRI画像を強調する量で前記対象に非経口投与するステップと、次いで、前記対象のMRIにより前記身体又は身体領域の画像を生成するステップとを含み、それによって前記アスコルベート又は医薬として許容されるその塩がMRI画像を強調する、使用。
- 前記身体領域が、頭部、頸部、胸部、腹部、骨盤、肢(複数可)、筋肉、脂肪又は骨である、請求項1に記載の使用。
- 前記臓器が、副腎、下垂体、胸腺、黄体、網膜、脳、脾臓、肺、精巣、リンパ節、肝臓、甲状腺、小腸粘膜、白血球、膵臓、腎臓又は唾液腺組織を含む、請求項1に記載の使用。
- 前記身体領域が脳である、請求項1に記載の使用。
- 前記身体領域が心臓である、請求項1に記載の使用。
- 前記アスコルベート又は医薬として許容されるその塩が、対象の体重1キログラム当たり0.02、0.1、0.2又は0.5グラムから対象の体重1キログラム当たり5、10、20、30又は40グラムまでの量で投与される、請求項1から5のいずれか1項に記載の使用。
- 前記投与ステップが、静脈内投与、例えば、静脈内注射によって行われる、先行する請求項のいずれか1項に記載の使用。
- 前記投与ステップが、腹腔内投与、例えば、腹腔内注射によって行われる、請求項1から7のいずれか1項に記載の使用。
- 前記画像がT2強調画像を含む、先行する請求項のいずれか1項に記載の使用。
- 前記画像が、代謝画像(例えば、腫瘍代謝画像又は脳代謝画像)を含む、先行する請求項のいずれか1項に記載の使用。
- 前記画像が灌流画像(例えば、心血管灌流画像)を含む、先行する請求項のいずれか1項に記載の使用。
- 前記生成ステップが、アスコルベート又は医薬として許容されるその塩の非経口投与中又は非経口投与後5、10、30、40、60、90若しくは120分以内に行われる、先行する請求項のいずれか1項に記載の使用。
- 前記アスコルベート又は医薬として許容されるその塩が、アスコルビン酸ナトリウム、アスコルビン酸メグルミン又はそれらの混合物(例えば、10:90、20:80、30:70又は40:60から90:10、80:20、70:30又は60:40までのモル又はミリモル(mM)比(アスコルビン酸メグルミン:アスコルビン酸ナトリウム)のアスコルビン酸メグルミン及びアスコルビン酸ナトリウム)である、先行する請求項のいずれか1項に記載の使用。
- 臓器又は臓器領域などの対象の身体又は身体領域の磁気共鳴画像法(MRI)画像を強調する方法であって、
アスコルベート又は医薬として許容されるその塩を、MRI画像を強調する量で前記対象に非経口投与するステップと、
次いで、前記対象のMRIにより前記身体又は身体領域の画像を生成するステップと
を含み、
それによって前記アスコルベート又は医薬として許容されるその塩が前記MRI画像を強調する、方法。 - 前記身体領域が、頭部、頸部、胸部、腹部、骨盤、肢(複数可)、筋肉、脂肪又は骨である、請求項14に記載の方法。
- 前記臓器が、副腎、下垂体、胸腺、黄体、網膜、脳、脾臓、肺、精巣、リンパ節、肝臓、甲状腺、小腸粘膜、白血球、膵臓、腎臓又は唾液腺組織を含む、請求項14に記載の方法。
- 前記身体領域が脳である、請求項14に記載の方法。
- 前記身体領域が心臓である、請求項14に記載の方法。
- 前記アスコルベート又は医薬として許容されるその塩が、対象の体重1キログラム当たり0.02、0.1、0.2又は0.5グラムから対象の体重1キログラム当たり5、10、20、30又は40グラムまでの量で投与される、請求項14から18のいずれか1項に記載の方法。
- 前記投与ステップが、静脈内投与、例えば、静脈内注射によって行われる、先行する請求項のいずれか1項に記載の方法。
- 前記投与ステップが、腹腔内投与、例えば、腹腔内注射によって行われる、請求項14から19のいずれか1項に記載の方法。
- 前記画像がT2強調画像を含む、先行する請求項のいずれか1項に記載の方法。
- 前記画像が、代謝画像(例えば、腫瘍代謝画像又は脳代謝画像)を含む、先行する請求項のいずれか1項に記載の方法。
- 前記画像が灌流画像(例えば、心血管灌流画像)を含む、先行する請求項のいずれか1項に記載の方法。
- 前記生成ステップが、アスコルベート又は医薬として許容されるその塩の非経口投与中又は非経口投与後5、10、30、40、60、90若しくは120分以内に行われる、先行する請求項のいずれか1項に記載の方法。
- 前記アスコルベート又は医薬として許容されるその塩が、アスコルビン酸ナトリウム、アスコルビン酸メグルミン又はそれらの混合物(例えば、10:90、20:80、30:70又は40:60から90:10、80:20、70:30又は60:40までのモル又はミリモル(mM)比(アスコルビン酸メグルミン:アスコルビン酸ナトリウム)のアスコルビン酸メグルミン及びアスコルビン酸ナトリウム)である、先行する請求項のいずれか1項に記載の方法。
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PCT/US2016/054478 WO2017059091A1 (en) | 2015-09-30 | 2016-09-29 | Contrast agents for magnetic resonance imaging |
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CN107087397B (zh) | 2020-12-18 |
CN107087397A (zh) | 2017-08-22 |
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CN106999613B (zh) | 2020-11-17 |
EP3183008A1 (en) | 2017-06-28 |
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US20210353780A1 (en) | 2021-11-18 |
JP6491747B2 (ja) | 2019-03-27 |
JP2018507165A (ja) | 2018-03-15 |
JP6415715B2 (ja) | 2018-10-31 |
US20180071410A1 (en) | 2018-03-15 |
CA2997791A1 (en) | 2017-04-06 |
CN106999613A (zh) | 2017-08-01 |
WO2017059092A1 (en) | 2017-04-06 |
US20190216954A1 (en) | 2019-07-18 |
US10286089B2 (en) | 2019-05-14 |
WO2017059091A1 (en) | 2017-04-06 |
US10111970B2 (en) | 2018-10-30 |
US20170189559A1 (en) | 2017-07-06 |
US11083803B2 (en) | 2021-08-10 |
US20170189561A1 (en) | 2017-07-06 |
EP3183009A1 (en) | 2017-06-28 |
US10695447B2 (en) | 2020-06-30 |
KR20180058726A (ko) | 2018-06-01 |
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