JP5618042B2 - アイソトープ標識化合物及びアイソトープ標識化合物前駆体 - Google Patents
アイソトープ標識化合物及びアイソトープ標識化合物前駆体 Download PDFInfo
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- JP5618042B2 JP5618042B2 JP2009218247A JP2009218247A JP5618042B2 JP 5618042 B2 JP5618042 B2 JP 5618042B2 JP 2009218247 A JP2009218247 A JP 2009218247A JP 2009218247 A JP2009218247 A JP 2009218247A JP 5618042 B2 JP5618042 B2 JP 5618042B2
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- prion
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/16—Measuring radiation intensity
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nuclear Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Physics & Mathematics (AREA)
- High Energy & Nuclear Physics (AREA)
- Molecular Biology (AREA)
- Spectroscopy & Molecular Physics (AREA)
Description
また、ステップ1における原料として、ベンゼン環に対する置換基の位置の異なる異性体を用いることによって、配位位置が有機スズ化合物4と異なる異性体を合成することもできる。
まず、o-トルイジンと2-ヨードアニリンとをパラホルムアルデヒドを用いてカップリングし、下記化合物1’を合成した。
1H NMR (CDCl3): δ 2.13 (s, 3H), 3.51 (s, 2H), 3.70 (s, 2H), 3.95 (s, 2H), 6.60 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.94 (dd, J = 1.7, 8.1 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H).
13C NMR (CDCl3): δ 17.4, 39.6, 84.5, 114.8, 115.1, 122.6, 127.2, 129.9, 130.9, 131.3, 133.9, 138.8, 142.7, 144.7.
MS (EI): m/z 338 (M+).
Anal. Calcd for C14H15IN2: C, 49.72; H, 4.47; N, 8.28. Found: C, 49.62; H, 4.57, N, 8.12.
1H NMR (CDCl3): δ 0.88 (t, J = 7.3 Hz, 9H), 1.05-1.08 (m, 6H), 1.32 (sextet, J = 7.3 Hz, 6H), 1.49-1.55 (m, 6H), 2.12 (s, 3H), 3.48 (s, 2H), 3.50 (s, 2H), 3.74 (s, 2H), 6.591 (d, J = 8.3 Hz, 1H), 6.593 (d, J = 8.1 Hz, 1H), 6.83-6.87 (m, 2H), 6.91 (dd, J = 2.2, 8.1 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H).
MS (EI) m/z: 502 (M+).
Anal. Calcd for C26H42N2Sn: C, 62.29; H, 8.44; N, 5.59. Found: C, 62.13; H, 8.45, N, 5.56.
1H NMR (CDCl3): δ 0.87 (t, J = 7.3 Hz, 9H), 1.08-1.12 (m, 6H), 1.31 (sextet, J = 7.5 Hz, 6H), 1.46-1.53 (m, 6H), 2.26 (s, 3H), 3.91 (s, 2H), 4.20 (s, 2H), 4.23 (s, 2H), 7.03 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 7.15 (dd, J = 2.0, 8.1 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
MS (EI) m/z: 597 [(M-Bu)+].
Anal. Calcd for C30H44Cl2N2O2Sn: C, 55.07; H, 6.78; N, 4.28. Found: C, 55.17; H, 6.72, N, 4.32.
1H NMR (CDCl3): δ 0.87 (t, J = 7.3 Hz, 9H), 1.07-1.10 (m, 6H), 1.30 (sextet, J = 7.4 Hz, 6H), 1.46-1.52 (m, 6H), 1.83-1.86 (m, 8H), 2.21 (s, 3H), 2.70-2.72 (m, 8H), 3.28 (s, 2H), 3.31 (s, 2H), 3.87 (s, 2H), 6.98 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.13 (dd, J = 2.0, 8.3 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 8.86 (s, 1H), 9.21 (s, 1H).
MS (EI) m/z: 667 [(M-Bu)+].
Anal. Calcd for C38H60N4O2Sn・0.5(H2O): C, 62.30; H, 8.39; N, 7.65. Found: C, 62.51; H, 8.33, N, 7.68.
11Cで標識したアイソトープ標識化合物5’の合成では、以下の装置及び試薬を用いた。
標識用合成装置は、理化学研究所 分子イメージング科学研究センターに設置してある標準型標識用自動合成装置を用いた。化学薬品は市販のものをそのまま用いた。高速液体クロマトグラフィー用アセトニトリル(ナカライ社製)、脱水N,N-ジメチルホロムアミド(DMF)(関東化学社製)、脱水N-メチル-2-ピロリジノン(NMP)(関東化学社製)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(Aldrich社製)、トリ-o-トリルホスフィン(Aldrich社製)、塩化銅(和光社製)、炭酸カリウム(和光社製)、重炭酸アンモニウム(東京化成社製)を使用した。
11C核の製造は住友重機械工業社製サイクロトロンCYPRIS HM-12Sを使用し、14N(p,α)11Cの核反応により製造した。[11C]ヨウ化メチルの合成は専用の標識用合成装置を用いて、11CO2ガスを出発物質として、11CO2→11CH3OH→11CH3Iの順に変換して調製した。
トリスジベンジリデンアセトンジパラジウム(1.6 mg, 1.7 μmol)および、トリ-o-トリルホスフィン(2.1 mg, 6.8μmol)のNMP溶液(0.3 mL)を標識用合成装置の反応容器(A)に準備し、室温に設置した。反応容器(A)中の溶液は、[11C]ヨウ化メチルを吹き込む10-20分前に設置した。また、スズ前駆体4’(2.3 mg, 3.2 μmol)、CuCl(1.7 mg, 17.5 μmol)、およびK2CO3(1.2 mg, 8.8 μmol)のNMP溶液(80 μL)を反応容器(B)に準備し、室温に設置した。続いて反応容器(A)に[11C]ヨウ化メチルを60-80 mL/minのガス流量で吹き込み、その後1分間静置した。得られた溶液を反応容器(B)に移送し、さらに反応容器(A)の内部を少量のNMP溶液(60 μL)を用いて洗浄して、この洗浄液も反応容器(B)に移送した。続いて、反応容器(B)中の混合溶液を80 ℃で5分間加熱した。得られた反応溶液を0.3 mLの洗浄液(アセトニトリル:水=4:1溶液)で希釈した後、綿栓あるいはフィルターを用いてろ過し、分取HPLCにて分取した。分取用カラムはPhenomenex 社製Gemini 5μ C18 110A 10mm×250mm、ガードカラムはPhenomenex 社製 Semiprep Guard Cartridge System (AJO-7220)およびSUMIKA社製スミパックスフイルター PG-ODSを使用した。流量は5ml/minで、移動層は100mM NH4HCO3(pH=7.8):CH3CN(5% H2O添加)=40:60を使用した。UV検出波長254 nmおよびγ線検出器で測定した結果、アイソトープ標識化合物5’の保持時間は約14.3分であった(図1)。分取したアイソトープ標識化合物5’を含むフラクションをエバポレーターを用いて減圧濃縮した。濃縮液は臨床用投与溶液(生理食塩水:4ml、propylene glycol:0.3 ml、Tween80:0.05 ml)を用いて希釈し、無菌バイアルに入れた。
本溶液の一部(20μL)を分析HPLCに供して、目的化合物の同定、純度検定、および比放射能の算出を行った。分析カラムはPhenomenex 社製Gemini 4.6mm×150mm を使用し、カラム温度30℃で分析を行った。流量は1ml/minで、移動層は100mM NH4HCO3(pH=7.8):CH3CN=40:60を使用した。UV検出波長254 nmおよびγ線検出器で測定した結果、アイソトープ標識化合物5’の保持時間は約8.0分であった。なお、アイソトープ標識化合物5’の同定はアイソトープ標識化合物5’の非標識体(5’(a))を用いて行った。アイソトープ標識化合物5’の総放射能は0.5−2.0GBq、[11C]ヨウ化メチルに基づく崩壊補正放射化学収率は20%であった。合成時間は43分、放射化学純度は95%以上で、化学的純度は82%−92%、比放射能は 98−110GBq/μmolであった。
1H NMR (CDCl3): δ 1.85 (quint, J = 3.3 Hz, 8H), 2.20 (s, 6H), 2.72 (br, 8H), 3.30 (s, 4H), 3.85 (s, 2H), 6.97 (s, 2H), 7.04 (dd, J = 1.7, 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 9.21 (s, 2H).
13C NMR (CDCl3): δ 17.5, 24.1, 40.8, 54.5, 59.5, 121.4, 127.3, 127.7, 130.8, 133.8, 137.3, 168.9.
MS (EI) m/z: 448 (M+).
Anal. Calcd for C27H36N4O2・0.25(H2O): C, 71.57; H, 8.12; N, 12.37. Found: C, 71.63; H, 7.85, N, 12.33.
50 mLナス型フラスコにm-トルイジン塩酸塩 (1.43 g, 10.0 mmol)、メタノール (10 mL) を、m-トルイジン(1.43 g, 10.0 mmol)、パラホルムアルデヒド (0.30 g, 10.0 mmol) を順に加え、加熱還流下で2日間撹拌した。室温に戻したのち、減圧濃縮した。得られた残渣に蒸留水(10 mL)を加え、1N水酸化ナトリウム水溶液を用いて中和した。ジクロロメタン(10 mL×4)で抽出し、有機層を蒸留水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (シリカゲル 250 g, 展開溶媒;ヘキサン/酢酸エチル = 1/1) で精製し、茶色結晶の(6)(518 mg, 22.9%) を得た。
TLC Rf 0.30 (ヘキサン/酢酸エチル = 1/1)
1H NMR (400 MHz, CDCl3): δ 2.17 (s, 6H, CH 3), 3.51 (br s, 4H, NH 2), 3.70 (s, 2H, CH 2), 6.45 (dd, J = 2.4, 8.3 Hz, 2H, Ar-H), 6.55 (d, J = 2.4 Hz, 2H, Ar-H), 6.68 (d, J = 8.3 Hz, 2H, Ar-H).
10 mL 二口ナス型フラスコにアルゴン雰囲気下で、化合物(6) (283 mg, 1.25 mmol) 、4-ジメチルアミノピリジン (15 mg, 0.13 mmol) を加え、脱水ジクロロメタン (7 mL) に溶解した。脱水ピリジン (243 mL, 3.01 mmol) を加え、得られた混合溶液を0 °Cに冷却し、臭化ブロモアセチル (239 mL, 2.76 mmol) を滴下し、10分間撹拌した後、室温に戻し5時間撹拌した。析出した固体を濾取し、ジクロロメタン (30 mL)およびジエチルエーテル (20 mL) で洗浄し、白色結晶の化合物(7) (453 mg, 77.3%) を得た。
1H NMR (400 MHz, CD3SOCD3,): δ 2.17 (s, 6H, CH 3), 3.80 (s, 2H, CH 2), 4.00 (s, 4H, CH 2), 6.77 (d, J = 8.3 Hz, 2H, Ar-H,), 7.28 (dd, J = 2.0, 8.3 Hz, 2H, Ar-H,), 7.42 (d, J = 2.0 Hz, 2H, Ar-H,), 10.27 (s, 2H, NH).
TLC Rf 0.35 (ジクロロメタン/メタノール = 10/1)
1H NMR (400 MHz, CDCl3,): δ 1.84-1.87 (m, 8H, CH 2), 2,25 (s, 6H, CH 3), 2.60-2.69 (m, 8H, CH 2), 3.27 (s, 4H, NH 2), 3.83 (s, 2H, CH 2), 6.84 (d, J = 8.2Hz, 2H, Ar-H), 7.28 (dd, J = 1.9, 8.2 Hz, 2H, Ar-H), 7.44 (d, J = 1.9 Hz, 2H, Ar-H), 9.00 (s, 2H, NH).
[培養細胞]
マウス視床下部神経細胞系列GT1は、マウスプリオンに感染し得る。化合物の抗プリオン作用を評価する目的で、我々はGTFK-1細胞系列を用いた(N. Nishida et al., J. Virol, 74, 320-325 (2000))。これらはGSS由来の(O. Milhavet et al., Proc. Natl. Acad. Sci. U. S. A., 97, 13937-13942 (2000))マウス適合プリオンFukuoka-1株である。
GT1-7細胞は、ペニシリンおよびストレプトマイシンを含むDMEM培地(Invitrogen社製)で培養した。3〜4日ごとに、細胞をトリプシン処理し、1:5に希釈して継代した。安定にFukuoka-1または22L株に感染したGT1-7細胞については、O.Milhavet et al., Proc. Natl. Acad. Sci. U.S.A. 97, 13937-13942 (2000)に記載されている。化合物のストック溶液は、10mMのDMSO中に調製し室温で保存した。使用前に、化合物を培地で希釈した。対照細胞を溶媒のみを含む(0.1%)培地で処理した。約2×105の細胞を6ウェルプレートの各ウェルに入れ、15時間後に化合物を添加して薬剤処理を開始した。72時間のインキュベーションの後に、細胞を回収した。
回収した細胞を、1×Triton/DOC溶解バッファー(0.5% TritonX-100, 0.5% deoxycholic acid, 150mM NaCl, 50mM Tris HCl[pH7.5])150μl中に溶解させた。タンパク質濃度をBCAプロテインアッセイキット(Pierce社製)で測定し、各細胞溶解液を2mg/mlに標準化した。感染型プリオンタンパク質の産生を分析するため、タンパク質1mgあたり20μgの濃度のプロテイナーゼKを用いて30分間37℃で消化した。消化を阻害剤AEBSF(3mM)で止めた後、サンプルについて15% ポリアクリルアミドゲルを用いてSDS-PAGEを行った。次いで、タンパク質をPVDF膜(Immobilon-P, ミリポア社製)に転写した。ウェスタンブロットによるタンパク質のバンド検出に、抗マウスPrP抗体M-20(SANTA CRUZ社製)を一次抗体として用いた。バンドのシグナルはSuper Signal(Pierce社製)で可視化し、曝露およびシグナルの定量は、膜をLAS-1000 UVmini(富士フイルム社製)でスキャンすることにより行った。
(PET撮影1)
PET撮影1では、健常ラット頭頚部のPET撮像を行った。以下に詳細を示す。
なお、撮像結果からの画像の再構成はASIPro(SIEMENS社製のソフトウェア)を用いて次のように行った。PETプローブの投与直後は当該PETプローブが拡散中である。よって、投与後5分程度の間に撮像した画像で見られるPETプローブの集積は、ソマトスタチン受容体と特異的結合したものよりも血中にある未結合のPETプローブの影響が強い。このため、PETプローブの投与後5分から90分までに得られたデータをMaximum a Posteriori Expectation Maximization法(MAP-EM法:参考文献/Qi J, Leahy R, Resolution and noise properties of MAP reconstruction for fully 3-D PET, IEEE Trans Med Imag vol 19, 493-506(2000))にて画像再構成を行った。再構成した画像を図2及び図3に示す。
PET撮影2では、健常ラットでのEx Vivo オートラジオグラフィー(Ex Vivo ARG)を行った。詳細を以下に示す。
PET撮影1から得られたtTACにより、組織に十分取り込ませるのに必要な時間が分かっていたため、投与後40分間PETプローブを取りこませることとした。その後、安楽死させ脱血灌流後に脳を取り出し、2mm厚のスライス切片を作って、イメージングプレート(BAS-SR2040、FUJIFILM社製)に20分間露光させた。イメージングプレートをイメージアナライザー(FLA-7000,FUJIFILM社製)にセットし、PETプローブの集積部位を検出した。
Claims (4)
- 下記一般式(a)(式中、R0は11CH3、CH2 18F及びCF2 18Fのいずれかであり、R1及びR2は同一又は異なって、水素原子又は炭化水素基を示す。)、又はその薬学上許容される塩、水和物、若しくは溶媒和物からなることを特徴とするアイソトープ標識化合物。
- 下記一般式(b)(式中、R 1 及びR 2 は同一又は異なって、水素原子又は炭化水素基を示す。)で示される請求項1記載のアイソトープ標識化合物。
- 下記有機スズ化合物(c)(式中、R 1 及びR 2 は同一又は異なって、水素原子又は炭化水素基を示し、Rはアルキル基を示す。)からなることを特徴とするアイソトープ標識化合物前駆体。
- 請求項1又は2に記載のアイソトープ標識化合物を含有することを特徴とするPET用分子プローブ。
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