JP2009541286A - 化学的方法及び装置 - Google Patents
化学的方法及び装置 Download PDFInfo
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- JP2009541286A JP2009541286A JP2009515948A JP2009515948A JP2009541286A JP 2009541286 A JP2009541286 A JP 2009541286A JP 2009515948 A JP2009515948 A JP 2009515948A JP 2009515948 A JP2009515948 A JP 2009515948A JP 2009541286 A JP2009541286 A JP 2009541286A
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- MGIUUAHJVPPFEV-ABXDCCGRSA-N magainin ii Chemical compound C([C@H](NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O)C1=CC=CC=C1 MGIUUAHJVPPFEV-ABXDCCGRSA-N 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
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- LDIPAETVPYDPHR-UHFFFAOYSA-N n-benzylpent-4-ynamide Chemical compound C#CCCC(=O)NCC1=CC=CC=C1 LDIPAETVPYDPHR-UHFFFAOYSA-N 0.000 description 1
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- 150000002791 naphthoquinones Chemical class 0.000 description 1
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- PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
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- 238000012856 packing Methods 0.000 description 1
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- 150000004686 pentahydrates Chemical class 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 229940043267 rhodamine b Drugs 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
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- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
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- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- COIVODZMVVUETJ-UHFFFAOYSA-N sulforhodamine 101 Chemical compound OS(=O)(=O)C1=CC(S([O-])(=O)=O)=CC=C1C1=C(C=C2C3=C4CCCN3CCC2)C4=[O+]C2=C1C=C1CCCN3CCCC2=C13 COIVODZMVVUETJ-UHFFFAOYSA-N 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WGTODYJZXSJIAG-UHFFFAOYSA-N tetramethylrhodamine chloride Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C(O)=O WGTODYJZXSJIAG-UHFFFAOYSA-N 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- 230000002227 vasoactive effect Effects 0.000 description 1
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- 238000005406 washing Methods 0.000 description 1
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 1
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- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/13—Labelling of peptides
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- 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
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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Abstract
Description
R1A、R2A、R3A及びR4Aは各々独立にRA基であり、
RA基は各々独立にH、C1-10アルキル、C3-10アルキルアリール、C2-10アルコキシアルキル、C1-10ヒドロキシアルキル、C1-10アルキルアミン又はC1-10フルオロアルキルであるか、或いは2以上のRA基がこれらに結合した原子と共に炭素環式又は複素環式の飽和又は不飽和環を形成する。
或いは、R*は下記の式(i)、(ii)、(iii)又は(iv)で表されるキレート剤を含み得る。
HPLC:高速液体クロマトグラフィー
DMF:N,N−ジメチルホルムアミド
DMSO:ジメチルスルホキシド
ESI−MS:エレクトロスプレーイオン化質量分析法
rt:室温
TOF−ESI−MS:飛行時間型エレクトロスプレーイオン化質量分析法
FT−IR:フーリエ変換赤外
ppm:百万分率
TFA:トリフルオロ酢酸
ACN:アセトニトリル
実施例1:銅ループ反応器を用いる[ 18 F]−4−(2−フルオロエチル)−トリアゾール−1−イル−[KGFGK]の製造
本実施例は図1を参照しながら説明する。加熱銅管は1.0mの長さ及び0.56mmの内径(246μlの管容積)を有している。
化合物19(2.9mg、2.04μmol)を、ジメチルホルムアミド(25μl)の添加物と共にリン酸ナトリウム緩衝液(100μl、pH6.0、100mM)に溶解した。アセトニトリル(100μl)中の化合物11(518μCi/19MBq)を添加した後、混合物を0.1ml/分の流量で80℃の予熱銅ループ反応器にポンプ送入した。次いで、系を水(0.5ml)でフラッシュした。第1及び第2の画分のHPLC分析により、それぞれ9%及び34%の標識効率が判明した。系からの放射能の総回収率は53%であった。
モデルペプチド1(2.4mg、4.08μmol)、リン酸ナトリウム緩衝液(0.2ml、pH6.0、250mM)及びDMF(0.05ml)の溶液を、アセトニトリル(0.2ml)中の[18F]2−フルオロエチルアジド(0.9mCi、34MBq)と混合する。0.1ml/分の流量を用いる点を除き、実施例1に記載したようにして混合物を加熱銅ループにポンプ送入する。混合物の通過時間は3分であり、総反応時間は10分である。標識ペプチド2を77%の回収率(崩壊補正)で捕集する。放射化学純度は>99%である。水(1ml)、水/TFA(1/1、2ml)、水(2ml)及びアセトニトリル(3ml)を用いて銅ループ反応器を洗浄し、窒素流(1分、50ml/分)を用いて乾燥する。同じ初期放射能の[18F]2−フルオロエチルアジドを用いて実験を繰り返す。単離された2の放射化学収率は71%(崩壊補正)であり、放射化学純度は98%である。
トルエン−4−スルホン酸2−フルオロエチルエステル(化合物(1))をE.U.T.van Velzen et al.,Synthesis(1995)989−997に記載されたようにして製造した。化合物(1)(128mg、0.586mmol)及びアジ化ナトリウム(114mg、1.758mmol)を無水DMF(10ml)と混合し、室温で48時間撹拌した。反応混合物を濾過したが、生成物(2)は反応溶液から単離されなかった。
DMF(1ml)中のフェニルアセチレン(105μl、0.977mmol)を窒素下で水(0.3ml)中の硫酸銅(II)五水塩(12mg、0.0489mmol)及びL−アスコルビン酸(16mg、0.0977mmol)の撹拌溶液に添加した。DMF(5ml)中の化合物(2)(1.172mmol)を添加した後、室温で21時間攪拌を続けた。反応混合物を水(5ml)で希釈し、粗生成物をジクロロメタン(3×5ml)で抽出し、重炭酸ナトリウム溶液(10%、3×10ml)及び塩水(1×5ml)で洗浄した。硫酸ナトリウム上で乾燥した後、溶媒を減圧下で除去し、粗標品をフラッシュクロマトグラフィー(シリカ、ヘキサン/酢酸エチル)を用いて精製した。
収量:32mg(17%)、白色結晶、m.p.83〜85℃。
1H−NMR(CDCl3):δ=4.70(m,1H,CH2)、4.76(m,1H,CH2)、4.80(m,1H,CH2)、4.89(m,1H,CH2)、7.35(tt,1.0Hz,7.5Hz,1H,HAr)、7.44(m,2H,HAr)、7.84(m,2H,HAr)、7.89(d,1Hz,1H,CH−トリアゾール)ppm。
GC−MS:m/z=191。
TOF−ESI−MS:実測値 m/z=192.0935[MH]+、C10H10N3Fの計算値[MH]+ m/z=192.0932。
DMF(0.7ml)中の4−エチニルアニリン(40mg、0.344mmol)を窒素下で水(1.2ml)中の硫酸銅(II)五水塩(129mg、0.516mmol)及びL−アスコルビン酸(182mg、1.032mmol)の撹拌溶液に添加した。DMF(2.45ml)中の化合物(2)(0.287mmol)を添加した後、室温で4時間攪拌を続けた。反応混合物を水酸化ナトリウム溶液(1M、5ml)で奪活した。生成物を酢酸エチル(3×5ml)で抽出し、水(5ml)及び塩水(2ml)で洗浄した。硫酸ナトリウム上で乾燥した後、溶媒を減圧下で除去し、粗標品をフラッシュクロマトグラフィー(シリカ、ヘキサン/酢酸エチル)を用いて精製した。収量:15mg(25%)、ベージュ色結晶、m.p.79〜82℃。
1H−NMR(CDCl3):δ=4.70(m,1H,CH2)、4.72(m,1H,CH2)、4.77(m,1H,CH2)、4.88(m,1H,CH2)、6.74(m,2H,HAr)、7.63(m,2H,HAr)、7.74(d,0.1Hz,1H,CH−トリアゾール)ppm。
TOF−ESI−MS:実測値 m/z=207.1030[MH]+、C10H11N4Fの計算値[MH]+ m/z=207.1040。
G.M.Coppola & R.E.Damon,Synthetic Communications,23(1993)2003−2010のプロトコルに従って製造したプロピン酸ベンジルアミド(50mg、0.314mmol)をDMF(1ml)に溶解し、窒素下で水(0.4ml)中の硫酸銅(II)五水塩(3.9mg、0.0157mmol)及びL−アスコルビン酸(11mg、0.0628mmol)の撹拌溶液に添加した。DMF(3.2ml)中の化合物(2)(0.377mmol)を添加した後、室温で48時間攪拌を続けた。反応混合物を重炭酸ナトリウム(10%、5ml)で希釈し、粗生成物をジクロロメタン(3×5ml)で抽出し、塩水(5ml)で洗浄した。硫酸ナトリウム上で乾燥した後、溶媒を減圧下で除去し、粗標品を酢酸エチル/ジエチルエーテルからの再結晶によって精製した。
収量:8mg(10%)、白色結晶、m.p.165〜167℃。
1H−NMR(CDCl3):δ=4.70(m,6H,CH2)、7.34(m,5H,HAr)、7.46(m,1H,NH)、8.20(s,1H,CH−トリアゾール)ppm。
TOF−ESI−MS:実測値 m/z=249.1143[MH]+、C12H13N4OFの計算値[MH]+ m/z=249.1146。
ペント−4−イン酸ベンジルアミド:この化合物は、N−スクシンイミジル中間体の単離以外は、G.M.Coppola及びR.E.Damon(比較例4参照)によって記載された方法と同様な方法を用いて合成した。
収量:100mg(53%)、白色針状晶、m.p.50〜55℃。
1H−NMR(CDCl3):δ=1.98(m,1H,アルキン−CH)、2.44(m,2H,CH2)、2.56(m,2H,CH2)、4.46(d,2H,CH2N)、7.29〜7.25(m,5H,HAr)ppm。
FT−IR(フィルム):1651、1629cm-1。
TOF−ESI−MS:実測値 m/z=188.1073[MH]+、C12H13NOの計算値[MH]+ m/z=188.1070。
収量:19mg(26%)、白色結晶、m.p.127〜133℃。
1H−NMR(CDCl3):δ=2.66(t,7.0Hz,2H,CH2)、3.09(t,7.0Hz,2H,CH2)、4.40(d,5.7Hz,2H,ベンジル−CH2)、4.56(m,2H,CH2)、4.61(m,2H,CH2)、4.70(m,2H,CH2)、4.80(m,2H,CH2)、6.0(s,1H,NH)、7.0〜7.3(m,5H,HAr)、7.44(s,1H,CH−トリアゾール)ppm。
TOF−ESI−MS:実測値 m/z=277.1474[MH]+、C12H13N4OFの計算値[MH]+ m/z=277.1459。
DMF(1.5ml)中の4−エチニル安息香酸ナトリウム(50mg、0.297mmol)を窒素下で水(0.2ml)中の硫酸銅(II)五水塩(3.7mg、0.0149mmol)及びL−アスコルビン酸(10.5mg、0.0595mmol)の撹拌溶液に添加した。DMF(0.76ml)中の化合物(2)(0.356mmol)を添加した後、室温で12時間攪拌を続けた。反応混合物をHCl(20ml、1M)で希釈した。粗生成物を酢酸エチル(3×10ml)で抽出し、塩水(10ml)で洗浄した。硫酸ナトリウム上で乾燥した後、溶媒を減圧下で除去し、粗標品を酢酸エチル/ヘキサンから再結晶した。
収量:37mg(52%)、白色結晶、m.p.236〜240℃。
1H−NMR(DMSO−d6):δ=4.74(m,1H,CH2)、4.80(m,2H,CH2)、4.90(m,1H,CH2)、8.70(s,1Hz,1H,CH−トリアゾール)ppm。
TOF−ESI−MS:実測値 m/z=236.0838[MH]+、C11H10N3O2Fの計算値[MH]+ m/z=236.0830。
DMF(0.5ml)中のプロピオル酸(60μl、0.977mmol)を窒素下で水(0.4ml)中の硫酸銅(II)五水塩(12mg、0.0489mmol)及びL−アスコルビン酸(34mg、0.135mmol)の撹拌溶液に添加した。DMF(2.5ml)中の化合物(2)(1.172mmol)を添加した後、室温で4時間攪拌を続けた。反応混合物をHCl(20ml、1M)で奪活し、粗生成物を酢酸エチル(3×20ml)で抽出した。塩水(5ml)で洗浄し、硫酸ナトリウム上で乾燥した後、溶媒を減圧下で除去し、生成物を酢酸エチル/ヘキサンからの再結晶によって精製した。
収量:16mg(10%)、白色結晶、m.p.160〜165℃。
1H−NMR(DMSO−d6):δ=4.74(m,1H,CH2)、4.80(m,2H,CH2)、4.90(m,1H,CH2)、8.71(s,1H,CH−トリアゾール)ppm。
TOF−ESI−MS:実測値 m/z=160.0518[MH]+、C5H6N3O2Fの計算値[MH]+ m/z=160.0517。
メタノール(1ml)中の2−アセチルアミノペント−4−イン酸エチルエステル(200mg、1.09mmol)を窒素下で銅粉(200mg、40メッシュ)に添加した後、DMF(3ml)中の化合物(2)(1.09mmol)の溶液を添加した。混合物を90分間撹拌した後、80℃で3時間加熱した。化合物(9)を逆相フラッシュクロマトグラフィー(アセトニトリル/水)で単離した。
収量:145mg(49%)、油、4℃での保存で結晶、m.p.55〜60℃。
1H−NMR(CDCl3):δ=1.13(t,3H,CH2CH3)、1.82(s,3H,CH3)、2.97(dd,2J=14.9Hz,3J=8.5Hz,1H,プロピオン酸−CH2)、3.07(dd,2J=14.9Hz,3J=6.0Hz,1H,プロピオン酸−CH2)、4.05(m,2H,OCH2CH3)、4.47(m,1H,CH)、4.46(m,1H,CH2)、4.64(m,1H,CH2)、4.70(m,1H,CH2)、4.81(m,1H,CH2)、7.89(s,1H,トリアゾール−CH)、8.31(d,1H,NH)ppm。
TOF−ESI−MS:実測値 m/z=273.1372[MH]+、C11H17N4O3Fの計算値[MH]+ m/z=273.1357。
18Fフッ化物は、濃縮[18O]H2Oターゲットの19MeVプロトン照射による18O(p,n)18F核反応を用いてサイクロトロンで生成させた。照射後、Kryptofix(登録商標)(5mg)、炭酸カリウム(1mg)及びアセトニトリル(1ml)の混合物を18F水(1ml)に添加した。窒素流(100ml/分)下において80℃で加熱して溶媒を除去した。その後、アセトニトリル(0.5ml)を添加し、加熱及び窒素流下で蒸発させた。この操作を2回繰り返した。室温に冷却した後、無水アセトニトリル(0.2ml)中の化合物(10)の溶液[1.5μl、Z.P.Demko and K.B.Sharpless,Org.Lett.3(2001)4091に記載の方法に従って調製]を添加した。反応混合物を80℃で30分間撹拌した。化合物(11)を、蒸留(効率76±8%(n=7))により、40±14%(n=7)の崩壊補正放射化学収率で単離した。
Ac−DL−Pra−OH(31mg)、(7−アザベンゾトリアゾール−1−イルオキシ)トリピロリジノホスホニウムヘキサフルオロホスフェート(PyAOP)(104mg)及びN−メチルモルホリン(NMM)(88μL)をジメチルホルムアミド(DMF)(3mL)に溶解し、混合物を5分撹拌した後、国際公開第2005/003166号に記載されたようにして製造してDMF(4ml)に溶解したClCH2CO−Lys−Cys(tBu)−Arg−Gly−Asp−Cys(tBu)−Phe−Cys−PEG−NH2(126mg)を添加した。反応混合物を45分間撹拌した。追加のClCH2CO−Lys−Cys(tBu)−Arg−Gly−Asp−Cys(tBu)−Phe−Cys−PEG−NH2(132mg)及びNMM(44μL)を添加し、45分間攪拌を続けた。次いでDMFを真空中で蒸発させ、残留物(5ml)を10%アセトニトリル(ACN)/水(100ml)で希釈し、分取HPLCを用いて生成物を精製した。
分取HPLC(勾配:A=H2O/0.1%TFA及びB=ACN/0.1%TFAの場合に60分で10〜40%B、流量:50mL/分、カラム:Phenomenex Luna 5μ C18(2)250×50mm、検出:UV214nm、生成物保持時間:31.3分)による希釈残留物の精製で、170mgの純粋AH−112145を得た。
化合物(19)(0.5mg、0.35μmol)をリン酸ナトリウム緩衝液(pH6.0、50mM)に溶解し、化合物(11)の溶液(25μl、728μCi/25MBq)及び銅粉(200mg、40メッシュ)と混合した。70℃で15分間加熱した後、混合物を放射性HPLCで分析する。
一般的手順:緩衝液(50μl、緩衝液A:リン酸ナトリウム、pH6.0、50mM;緩衝液B:炭酸ナトリウム、pH9.3、50mM)中の化合物(19)(0.5mg、0.35μmol)の溶液に、アセトニトリル(100μl)中の化合物(11)(0.1mCi、3.7MBq)を添加した後、銅触媒(触媒1:銅顆粒10+40メッシュ、触媒2:銅粉−40メッシュ、触媒3:銅粉、樹枝状、3μm)を添加する。混合物を80℃で15分間インキュベートした後、HPLCで分析した。
2 銅ループ
3 電気加熱シリンダー
4 加熱モジュール
5 温度制御ユニット
6 バイアル
7 ベント
Claims (12)
- R*が放射性核種を含む、請求項1記載の方法。
- R*が陽電子放出型放射性核種、好ましくは11C又は18Fを含む、請求項1又は請求項2記載の方法。
- ベクターがペプチド、タンパク質、ホルモン、細胞、細菌、ウイルス又は薬物様低分子であり、最も好適にはペプチドである、請求項1乃至請求項3のいずれか1項記載の方法。
- ベクターがArg−Gly−Aspペプチド又はその類似体である、請求項1乃至請求項4のいずれか1項記載の方法。
- 請求項1乃至請求項7のいずれか1項記載の方法を実施するためのミクロ流体装置であって、当該装置は第1の開口、第2の開口及びそれらを流体連通する1以上の細長いミクロ流体通路を画成する装置本体を含み、ミクロ流体通路の少なくとも一部は装置本体の金属銅部分によって画成されているミクロ流体装置。
- 1以上のミクロ流体通路を画成する装置本体が金属銅で形成されている、請求項8記載のミクロ流体装置。
- 装置本体がさらに、第1の開口、第2の開口及びそれらを流体連通する1以上の細長いミクロ流体通路を画成するベース部とカバー部とを含む、請求項8又は請求項9記載のミクロ流体装置。
- ミクロ流体通路が、ベース部又はカバー部のいずれか或いはそれらの間に上下に整合して形成された流路からなる、請求項10記載のミクロ流体装置。
- ミクロ流体通路が、請求項1乃至請求項7のいずれか1項に定義した式(I)、(II)、(III)又は(IV)の化合物を含む、請求項8乃至請求項11のいずれか1項記載のミクロ流体装置。
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