JP2021515005A - 標識オキシトシンならびに製造および使用の方法 - Google Patents
標識オキシトシンならびに製造および使用の方法 Download PDFInfo
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- JP2021515005A JP2021515005A JP2020545532A JP2020545532A JP2021515005A JP 2021515005 A JP2021515005 A JP 2021515005A JP 2020545532 A JP2020545532 A JP 2020545532A JP 2020545532 A JP2020545532 A JP 2020545532A JP 2021515005 A JP2021515005 A JP 2021515005A
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- oxytocin
- oxytocin peptide
- labeled
- peptide
- compound
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
-
- 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
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/084—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being oxytocin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
Abstract
Description
本出願は、その内容が全体として参照により本明細書に援用される、2018年3月1日に出願された米国仮出願第62/637,187号に基づく優先権利益を主張する。
ASCIIテキストファイルでの配列表の提出
技術分野
本出願は、13N−オキシトシン、13N−オキシトシンを含む組成物、13N−オキシトシンの使用方法、および13N−オキシトシンの製造方法を提供する。
オキシトシンが特定の適応症について治療上有効になるためには、適正なターゲット組織に効率よく送達されなければならない。送達は、付与経路および製剤組成を始めとするパラメーターによって影響を受ける場合がある。特定の適応症の処置に有効であることが示された経路および製剤によって投与されたオキシトシンの空間的および時間的分布を正確に決定することができると、前記適応症のための治療上有効な薬物動態プロファイルを決定することが可能になる。そうした薬物動態プロファイルの知識によって、投与経路と製剤の新たな組合せを評価して、治療有効性を最大にすることが可能になる。さらに、種々の適応症の処置についてオキシトシンの作用部位を発見することで、調査のための追加の治療ターゲットが得られる場合もある。
定義
13N−オキシトシン
調製方法
スキーム1における調製方法の調製実施形態をスキーム1aに示しており、スキーム1aにおいて、R1およびR2は、独立に、C1〜C6アルキルまたはC6〜C14アリールであり、R1およびR2のC1〜C6アルキルおよびC6〜C14アリールは、独立に、ハロゲン、シアノ、またはC1〜C6アルキルで必要に応じて置換されており、PG1は、アミン保護基(たとえば、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、2,2,2−トリクロロエチルホルミル(Troc)、カルボキシベンジル、およびアリルオキシカルボニル)であり、LGは、脱離基(たとえば、OH、O−アシル、OAt、OBt、Cl、1−イミダゾリルなど)である。
使用方法
画像化
放射断層撮影
処置
疾患および状態
オキシトシンペプチド製剤
オキシトシン投与
キット
例示的な実施形態
(実施例1)
ラットにおけるオキシトシンの静脈内投与後の分布
(実施例2)
ラットにおけるオキシトシンの経鼻投与後の分布
(実施例3)
健常ヒト対象におけるオキシトシンの経鼻投与後の分布および動態
(実施例4)
健常なヒトボランティア、神経精神医学的患者、または慢性片頭痛患者におけるオキシトシンの経鼻投与後の分布、動態、および薬力学
(実施例5)
13N−オキシトシンの合成方法
Claims (28)
- 配列番号1のアミノ酸配列を含む13N標識オキシトシンペプチド。
- 前記オキシトシンペプチドの1個の構成14N原子が13N放射性核種で置き換えられている、請求項1に記載の13N標識オキシトシンペプチド。
- 前記オキシトシンペプチドの1つの残基が、13N放射性核種を含む部分を含むように修飾されている、請求項1または2に記載の13N標識オキシトシンペプチド。
- 前記オキシトシンペプチドの1つの残基が、13NH2を含むように修飾されている、請求項3に記載の13N標識オキシトシンペプチド。
- 単一の13N放射性核種を含む、請求項1から4のいずれか一項に記載の13N標識オキシトシンペプチド。
- a)4位にあるグルタミン残基(配列番号2)、b)5位にあるアスパラギン残基(配列番号3)、またはc)9位にあるグリシン残基(配列番号4)に13N放射性核種を含む、請求項1から5のいずれか一項に記載の13N標識オキシトシンペプチド。
- 式(IV)の化合物である、請求項1に記載の13N標識オキシトシンペプチド。
- 配列番号1のアミノ酸配列を含む13N標識オキシトシンペプチドを製造する方法であって、
a)式(Ib)の化合物をシアノホスホン酸ジエチル(DECP)と反応させて、式(IIb)の化合物を提供することと、
b)前記式(IIb)の化合物を気体13NH3と反応させて、式(IIIb)の化合物を提供することと、
c)前記式(IIIb)の化合物を脱保護して、前記13N標識オキシトシンペプチドを提供することと
を含み、
前記13N標識オキシトシンペプチドは、式(IV)の化合物である、方法。 - 前記式(Ib)の化合物をDECPと反応させることが、ジメチルスルホキシド(DMSO)、テトラヒドロフラン(THF)、およびペンタメチルピペリジン(PMP)の存在下で実施される、請求項8に記載の方法。
- DECPの量が、約0.7当量〜約1.1当量の間である、請求項8または9に記載の方法。
- DMSOのTHFに対する比が、約1:7〜約1:11の間である、請求項9または10に記載の方法。
- 前記脱保護することが、前記式(IIIb)の化合物をHCl/ジオキサンと反応させることを含む、請求項8から11のいずれか一項に記載の方法。
- ステップc)において提供された前記13N標識オキシトシンペプチドを精製して、試薬、有機溶媒、および前駆体を除去することをさらに含む、請求項8から12のいずれか一項に記載の方法。
- 前記精製することが、固相抽出(SPE)による精製を含む、請求項13に記載の方法。
- SPEによる精製が、
a)前記13N標識オキシトシンペプチドを第1の疎水性SPEカラムに付与して、13N−オキシトシンおよび前駆体が第1の疎水性SPEカラム上に保持されるようにすることと、
b)水性イオン対試薬を含む溶液を前記第1の疎水性SPEカラムに付与して、前記13N−オキシトシンが第1の溶出液中に溶離するようにすることと、
c)前記第1の溶出液を第2の疎水性SPEカラムに付与して、前記第1の溶出液の前記13N−オキシトシンが、前記第2の疎水性SPEカラム上に保持されるようにすることと、
d)前記13N−オキシトシンを第2の溶出液中に溶離させることと
を含む、請求項14に記載の方法。 - 前記第1および/または第2の疎水性SPEカラムが、強い疎水性を有する、シリカを主体とする結合相を含む、請求項15に記載の方法。
- 前記水性イオン対試薬を含む溶液が、約15%〜約25%の間のアセトニトリルを含む、請求項15または16に記載の方法。
- 請求項8から17のいずれか一項に記載の方法を含むプロセスによって調製された13N標識オキシトシンペプチド。
- 個体において、外因的に投与されたオキシトシンの分布を決定する方法であって、
a)前記個体に、請求項1から8および18のいずれか一項に記載の13N標識オキシトシンペプチドを投与することと、
b)前記13N標識オキシトシンペプチドが組織または細胞部位で蓄積して画像化されるのを可能にすることと、
c)前記細胞または組織を非侵襲性の画像化技術によって画像化することと
を含む方法。 - 個体においてオキシトシン受容体の分布を決定する方法であって、
a)前記個体に、請求項1から8および18のいずれか一項に記載の13N標識オキシトシンペプチドを投与することと、
b)前記13N標識オキシトシンペプチドがオキシトシン受容体に結合するのを可能にすることと、
c)前記個体における前記13N標識オキシトシンペプチドを非侵襲性の画像化技術によって画像化することと
を含む方法。 - 個体において、外因的に投与されたオキシトシンの動態を決定する方法であって、
a)前記個体に、請求項1から8および18のいずれか一項に記載の13N標識オキシトシンペプチドを投与することと、
b)前記個体における前記13N標識オキシトシンペプチドを、非侵襲性の画像化技術によって所定の期間にわたり画像化することと
を含む方法。 - 前記非侵襲性の画像化技術が陽電子放出断層撮影イメージングを含む、請求項19から21のいずれか一項に記載の方法。
- 前記非侵襲性の画像化技術が、コンピュータ断層撮影イメージングを用いた陽電子放出断層撮影、または磁気共鳴画像法を用いた陽電子放出断層撮影を含む、請求項22に記載の方法。
- 前記13N標識オキシトシンペプチドが、頭蓋顔面粘膜投与によって投与される、請求項19から23のいずれか一項に記載の方法。
- 前記13N標識オキシトシンペプチドが鼻腔内投与される、請求項24に記載の方法。
- 前記13N標識オキシトシンペプチドが、静脈内、動脈内、腹腔内、小胞内、皮下、くも膜下腔内、肺内、筋肉内、気管内、眼科、経皮、または坐剤投与される、請求項19から23のいずれか一項に記載の方法。
- 前記13N標識オキシトシンペプチドが静脈内投与される、請求項26に記載の方法。
- 請求項1から7および18のいずれか一項に記載の13N標識オキシトシンペプチドを含むキット。
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