JP2012516308A - 放射性ヨウ素化方法 - Google Patents
放射性ヨウ素化方法 Download PDFInfo
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- JP2012516308A JP2012516308A JP2011546852A JP2011546852A JP2012516308A JP 2012516308 A JP2012516308 A JP 2012516308A JP 2011546852 A JP2011546852 A JP 2011546852A JP 2011546852 A JP2011546852 A JP 2011546852A JP 2012516308 A JP2012516308 A JP 2012516308A
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- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
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Abstract
【選択図】なし
Description
一態様では、本発明は、下記の式Iの放射性ヨウ素化化合物又はその塩若しくは溶媒和物の合成方法であって、下記の式IIの化合物を下記の式IIIの化合物と反応させる段階を含んでなる方法に関する。
A1はNH又はOであり、
R1及びR2の一方は−L1−Ar1基であり、
(式中、
L1は化学結合又は1〜3のL*リンカー単位(式中、L*は−CO−、−CR'2−、−CR'=CR'−、−C≡C−、−CR'2CO2−、−CO2CR'2−、−NR'−、−NR'CO−、−CONR'−、−NR'−、−(C=O)NR'−、−NR'(C=S)NR'−、−SO2NR'−、−NR'SO2−、−CR'2OCR'2−、−CR'2SCR'2−、−CR'2NR'CR'2−、C5-12アリーレン基及びC3-12ヘテロアリーレン基から選択され、R'は水素又はC1-3アルキルである。)を含む二価リンカーであり、
Ar1は、放射性ヨウ素で置換され、かつC1-3アルキル、ハロ、アミノ、カルボキシル、ヒドロキシル及びこれらの保護バージョンから選択される0〜3の他の置換基で置換された六員のC3-6アリール基であり、前記アリール基はN、S及びOから選択される0〜3のヘテロ原子を有する。)
R1及びR2の他方は−L2−R*基であり、
(式中、
L2は化学結合又は1〜6のL*リンカー単位(式中、L*はL1に関して定義した通りである。)を含む二価リンカーであり、
R*は生体分子である。)
R1及びR2は任意には好適な保護基を含み、
Xは活性エステル基を表す。
「放射性ヨウ素化化合物」という用語は、放射性ヨウ素(即ち、1以上の放射性ヨウ素原子)を含む化合物、特に本発明に関して言えばラジオヨードアリール基を含む化合物を意味する。「ラジオヨードアリール基」とは、本明細書中で定義されるように、放射性ヨウ素原子を含むアリール基である。「放射性ヨウ素原子」は、ヨウ素の任意の放射性同位体、好ましくは123I、124I、125I又は131I、最も好ましくは123I、124I又は131Iであり得る。
式II及び式IIIの化合物は、当業者にとって公知の方法で得ることができる。
(a)トリアルキルスタンナン(例えば、トリメチルスタンニル又はトリブチルスタンニル)、トリアルキルシラン(例えば、トリメチルシリル)或いは有機ホウ素化合物(例えば、ボロネートエステル又はオルガノトリフルオロボレート)のような有機金属誘導体。
(b)求電子ヨウ素化に向けて活性化された芳香環(例えば、フェノール類)及び求核ヨウ素化に向けて活性化された芳香環(例えば、アリールヨードニウム塩、アリールジアゾニウム塩、アリールトリアルキルアンモニウム塩又はニトロアリール誘導体)。
好ましい実施形態では、式Iの化合物は下記の式Iaの化合物であり、式IIの化合物は下記の式IIaの化合物であり、式IIIの化合物は下記の式IIIaの化合物である。
(i)式Iの放射性ヨウ素化化合物から任意の保護基を除去する段階、及び/又は
(ii)式Iの放射性ヨウ素化化合物を生体適合性キャリヤーと混合して放射性医薬組成物を調製する段階、及び/又は
(iii)段階(ii)の放射性医薬組成物を滅菌する段階、及び/又は
(iv)段階(ii)の放射性医薬組成物から発熱物質を除去する段階。
好ましい態様では、本明細書中に好適なもの及び好ましいものとして定義される本発明の方法は自動化される。自動化プロセスは、オペレーターの放射線被曝が減少するので、放射性化合物の合成において特に有用である。現在、特にPETラジオトレーサーはしばしば自動化放射合成装置で簡便に製造されている。かかる装置には、TRACERlab(商標)及びFASTlab(商標)(いずれもGE Healthcare社製)をはじめとするいくつかの市販例が存在している。かかる装置は通常、放射化学を実施するための(しばしば使い捨ての)「カセット」を含んでいて、これは放射合成を実施するため装置に取り付けられる。このカセットは、普通、流体通路、反応器、及び試薬バイアルを受け入れるためのポート並びに放射合成後の清掃段階で使用される任意の固相抽出カートリッジを含んでいる。
本発明の方法に関して本明細書中に好適なもの及び好ましいものとして定義される式Iの放射性ヨウ素化化合物は、Ar1の放射性ヨウ素置換基が123I、124I又は131Iからなるインビボイメージング剤である。「インビボイメージング剤」という用語は、哺乳動物における特定の生理学的又は病態生理学的状態を標的化するように設計され、哺乳動物体へのインビボ投与後に検出できる化合物を意味する。本発明の方法によって得られる放射性ヨウ素含有化合物がインビボイメージング剤である場合、ラジオヨードアリール部分中のヨウ素原子は123I、124I及び131Iから選択される。同位体123I及び131Iはγ線を放出し、これは単光子放出断層撮影法(SPECT)を用いて検出できる。同位体124Iは陽電子を放出し、これは陽電子放出断層撮影法(PET)を用いて検出できる。本発明のインビボイメージング剤にとって好ましいヨウ素同位体は123I及び124Iであり、最も好ましくは123Iである。
本発明の方法によって得られる放射性ヨウ素化化合物は、本明細書中に定義された式Iの放射性ヨウ素化化合物を、哺乳動物への投与に適した生体適合性キャリヤーと共に含んでなる放射性医薬組成物を製造するために使用できる。
本発明の方法はキットによって簡便に実施できる。したがって、別の態様では、本発明は本明細書中に好適なもの及び好ましいものとして定義される本発明の方法を実施するためのキットを提供する。前記キットは、
(i)本明細書中に定義される式IIの化合物又は本明細書中に定義される式IIaの化合物を含む第1の容器、及び
(ii)本明細書中に定義される式IIIの化合物又は本明細書中に定義される式IIIaの化合物を含む第2の容器
を含んでなる。
特記しない限り、下記実施例中に記載されるすべての試薬はSigma−Aldrich社又はBDH社から入手した。
Ac アセチル
DCC ジシクロヘキシルカルボジイミド
DMF ジメチルホルムアミド
h 時間
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー質量分析法
Lys リシン
MeOH メタノール
min 分
MS 質量分析法
m/z 質量/電荷比
NHS N−ヒドロキシスクシンイミド
NMR 核磁気共鳴
RCP 放射化学純度
TFA トリフルオロ酢酸
THF テトラヒドロフラン
Thr トレオニン
TLC 薄層クロマトグラフィー
tR 保持時間
UV 紫外
比較例1:N−[1−(4−ヨードフェニル)メチ−(E)−イリデン]−N’−ピリジン−2−イル−ヒドラジンの合成
生成物を精製し、質量分析法で分析してその正体を確認するため、4−ヨードベンズアルデヒド及び2−ヒドラジノピリジンの127Iコンジュゲーションを実施した。
10μlの2−ヒドラジノピリジン(9.2×10-8モル)。
170μlの50mM pH7.4リン酸塩緩衝液。
21μlの4−ヨードベンズアルデヒド(9.1×10-8モル)。
カラム−Phenomenex Luna C18(2) 5μ 4.6×150mm
流量−1ml/分
検出−UV254nm及びBioscan放射線検出器
溶媒A−水中0.1%TFA
溶媒B−アセトニトリル中0.1%TFA
勾配−
0分0%B
20分70%B
25分90%B
27分90%B
28分0%B
35分0%B
N−[1−(4−ヨードフェニル)メチ−(E)−イリデン]−N’−ピリジン−2−イル−ヒドラジンのピークをHPLCで精製した。質量分析法は324の位置にピークを示したが、これは予想される生成物の補正質量である。
2−ヒドラジノピリジンをエタノールに溶解して9.2mM溶液を得た。5μlの過酢酸を5mlの水で希釈して5mM溶液を得た。
(Sessler et al,J Am Chem Soc 1995;117(2):704−14の方法で製造した)4−トリ−n−ブチルスズベンズアルデヒドの2.8mMエタノール溶液37μl(1.0×10-7モル)を1.5mlのシラン化密封V形バイアルに添加した。200μlの0.2M pH4酢酸アンモニウム緩衝液及び10μlの0.05M NaOH中1mM Na127I(1.0×10-8モル)を123Iバイアルに添加した。10μlの5mM過酢酸を123Iバイアルに添加した。123Iバイアルの内容物を1.5mlのシラン化V形バイアルに移した。
4.4μlの2−ヒドラジノピリジン(4.0×10-8モル)、100μlの粗4−ヨードベンズアルデヒド及び100μlの50mM pH7.4リン酸塩緩衝液を10mlのシラン化密封ガラスバイアルに添加し、調製物を70℃で10分間加熱した。
3−ヨード安息香酸(1g、4mmol)、N−ヒドロキシスクシンイミド(464mg、4mmol)及びジシクロヘキシルカルボジイミド(DCC)(4mlの1Mジクロロメタン溶液、4mmol)の反応によって3−ヨード安息香酸2,5−ジオキソピロリジン−1−イルエステルを製造した。反応混合物を10mlのDMF中において室温で6時間撹拌した。得られた白色沈殿を濾別して廃棄し、得られた濾液を真空中で減容し、カラムクロマトグラフィーで精製したところ、29%の収率が得られた。
20μlの2−ヒドラジノピリジン(1.8×10-7モル)。
180μlの50mM pH7.4リン酸塩緩衝液。
63μlの2.9mM 3−ヨード安息香酸2,5−ジオキソピロリジン−1−イルエステル(1.8×10-7モル)。
2(ii)(a) シントンの製造
2−ヒドラジノピリジンをエタノールに溶解して17mM溶液を得た。10μlの過酢酸を5mlの水で希釈し、次いで100μlのこの溶液を水で1mlに基質して1mM溶液を得た。(下記例3に記載するようにして合成した)3−トリメチルスタンニル安息香酸2,5−ジオキソピロリジン−1−イルエステルをメタノール中1%酢酸に溶解して0.26mM溶液を得た。C18 SepPakを5mlのアセトニトリルでコンディショニングし、次いで10mlの水でコンディショニングした。
6μlの2−ヒドラジノピリジン(1.0×10-7モル)及び194μlの50mM pH7.4リン酸塩緩衝液を乾燥したシントンに添加し、調製物を37℃で30分間加熱した。
3(i) 3−ヨード安息香酸メチル(2)
Claims (22)
- 下記の式Iの放射性ヨウ素化化合物又はその塩若しくは溶媒和物の合成方法であって、下記の式IIの化合物を下記の式IIIの化合物と反応させる段階を含んでなる方法。
A1はNH又はOであり、
R1及びR2の一方は−L1−Ar1基であり、
(式中、
L1は化学結合又は1〜3のL*リンカー単位(式中、L*は−CO−、−CR'2−、−CR'=CR'−、−C≡C−、−CR'2CO2−、−CO2CR'2−、−NR'−、−NR'CO−、−CONR'−、−NR'−、−(C=O)NR'−、−NR'(C=S)NR'−、−SO2NR'−、−NR'SO2−、−CR'2OCR'2−、−CR'2SCR'2−、−CR'2NR'CR'2−、C5-12アリーレン基及びC3-12ヘテロアリーレン基から選択され、R'は水素又はC1-3アルキルである。)を含む二価リンカーであり、
Ar1は、放射性ヨウ素で置換され、かつC1-3アルキル、ハロ、アミノ、カルボキシル、ヒドロキシル及びこれらの保護バージョンから選択される0〜3の他の置換基で置換された六員のC3-6アリール基であり、前記アリール基はN、S及びOから選択される0〜3のヘテロ原子を有する。)
R1及びR2の他方は−L2−R*基であり、
(式中、
L2は化学結合又は1〜6のL*リンカー単位(式中、L*はL1に関して定義した通りである。)を含む二価リンカーであり、
R*は生体分子である。)
R1及びR2は任意には適当な保護基を含み、
Xは活性エステル基を表す。 - A1がNHである、請求項1記載の方法。
- A1がOである、請求項1記載の方法。
- L1が化学結合又はC1-3アルキレンリンカーである、請求項1乃至請求項3のいずれか1項記載の方法。
- L2が化学結合又はC1-3アルキレンリンカーである、請求項1乃至請求項4のいずれか1項記載の方法。
- R1が−L2−R*基であり、R2が−L1−Ar1基である、請求項1乃至請求項5のいずれか1項記載の方法。
- Ar1が、放射性ヨウ素で置換されかつ任意にはヒドロキシル又はグアニジンで置換されたフェニルである、請求項1乃至請求項6のいずれか1項記載の方法。
- R*が、抗体、ペプチド又はタンパク質である生体分子である、請求項1乃至請求項7のいずれか1項記載の方法。
- 式Iの化合物が下記の式Iaの化合物であり、式IIの化合物が下記の式IIaの化合物であり、式IIIの化合物が下記の式IIIaの化合物である、請求項1記載の方法。
- A1がNHである、請求項9記載の方法。
- A1がOである、請求項9記載の方法。
- A3がCHである、請求項9乃至請求項11のいずれか1項記載の方法。
- R4及びR5の一方が放射性ヨウ素であり、他方が水素である、請求項9乃至請求項12のいずれか1項記載の方法。
- 前記放射性ヨウ素化化合物がインビボイメージング剤であり、Ar1の放射性ヨウ素置換基が123I、124I又は131Iからなる、請求項1乃至請求項13のいずれか1項記載の方法。
- さらに下記の段階の1以上を任意の順序で含む、請求項1乃至請求項14のいずれか1項記載の方法。
(i)式Iの放射性ヨウ素化化合物から任意の保護基を除去する段階、及び/又は
(ii)式Iの放射性ヨウ素化化合物を生体適合性キャリヤーと混合して放射性医薬組成物を調製する段階、及び/又は
(iii)段階(ii)の放射性医薬組成物を滅菌する段階、及び/又は
(iv)段階(ii)の放射性医薬組成物から発熱物質を除去する段階。 - 自動化される、請求項1乃至請求項14のいずれか1項記載の方法。
- 自動合成装置で実施される、請求項16記載の方法。
- 請求項1乃至請求項14のいずれか1項記載の方法で定義した式Iの放射性ヨウ素化化合物を、哺乳動物への投与に適した形態の生体適合性キャリヤーと共に含んでなる放射性医薬組成物。
- 請求項1乃至請求項17のいずれか1項記載の方法を実施するためのキットであって、
(i)請求項1乃至請求項8のいずれか1項記載の方法で定義した式IIの化合物、又は請求項9乃至請求項12のいずれか1項記載の方法で定義した式IIaの化合物を含む第1の容器、及び
(ii)請求項1及び請求項4乃至請求項8のいずれか1項記載の方法で定義した式IIIの化合物、又は請求項9又は請求項13記載の方法で定義した式IIIaの化合物を含む第2の容器
を含んでなるキット。 - 請求項17記載の方法を実施するためのカセットであって、請求項19記載のキットに関して定義した第1及び第2の容器を含んでなるカセット。
- 請求項1乃至請求項17のいずれか1項記載の方法を実施するための、請求項19記載のキットの使用。
- 請求項17記載の方法を実施するための、請求項20記載のカセットの使用。
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GBGB0901483.8A GB0901483D0 (en) | 2009-01-29 | 2009-01-29 | Radioiodination method |
GB0901483.8 | 2009-01-29 | ||
US14841009P | 2009-01-30 | 2009-01-30 | |
US61/148,410 | 2009-01-30 | ||
PCT/EP2010/051053 WO2010086398A1 (en) | 2009-01-29 | 2010-01-29 | Radioiodination method |
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US11589960B2 (en) | 2015-07-13 | 2023-02-28 | Iucf-Hyu (Industry-University Cooperation Foundation Hanyang University) | Customized alveolar bone tissue and method of forming the same |
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US5206370A (en) * | 1989-02-24 | 1993-04-27 | Johnson Matthey, Inc. | Certain pyridyl hydrazines and hydrazides useful for protein labeling |
EP1315699B1 (en) * | 2000-03-22 | 2013-01-02 | Solulink, Incorporated | Hydrazine-based and carbonyl-based bifunctional crosslinking reagents |
GB0305704D0 (en) * | 2003-03-13 | 2003-04-16 | Amersham Plc | Radiofluorination methods |
GB0520529D0 (en) * | 2005-10-10 | 2005-11-16 | Ge Healthcare Ltd | Automated radiolabelling method |
TW200806326A (en) * | 2006-07-28 | 2008-02-01 | Inst Nuclear Energy Res Aec | Method for manufacturing iodine-123-ADAM and automatic manufacturing device thereof |
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JP2008507562A (ja) * | 2004-07-23 | 2008-03-13 | オンコロジック, インコーポレイテッド | がんへのホットスポット放射線の多段階送達のための組成物 |
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US11589960B2 (en) | 2015-07-13 | 2023-02-28 | Iucf-Hyu (Industry-University Cooperation Foundation Hanyang University) | Customized alveolar bone tissue and method of forming the same |
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GB0901483D0 (en) | 2009-03-11 |
US20110280803A1 (en) | 2011-11-17 |
WO2010086398A1 (en) | 2010-08-05 |
BRPI1007020A2 (pt) | 2016-03-29 |
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