JP6336695B2 - 画像化および治療のためのエチレンジシステイン−糖接合体の効率的な合成 - Google Patents
画像化および治療のためのエチレンジシステイン−糖接合体の効率的な合成 Download PDFInfo
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- JP6336695B2 JP6336695B2 JP2015503472A JP2015503472A JP6336695B2 JP 6336695 B2 JP6336695 B2 JP 6336695B2 JP 2015503472 A JP2015503472 A JP 2015503472A JP 2015503472 A JP2015503472 A JP 2015503472A JP 6336695 B2 JP6336695 B2 JP 6336695B2
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- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
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- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001043 yellow dye Substances 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or 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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- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- 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
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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
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Description
本発明は、例えば、以下を提供する。
(項目1)
アミノ糖とチアゾリジンカルボン酸を混合することによって、チアゾリジン−糖接合体を与えることを含む、チアゾリジン−糖接合体を調製する方法。
(項目2)
チアゾリジン−糖接合体を、アルカリ金属および電子源を含む還元剤で還元することによって、エチレンジシステイン−糖接合体を与えることをさらに含む、項目1に記載の方法。
(項目3)
アミノ糖は、アミノヘキソースまたはアミノペントースである、項目1に記載の方法。
(項目4)
アミノヘキソースは、グルコース、ガラクトース、マンノース、イドース、タロース、アルトロース、アロース、グロースまたはフルクトースのアミノ誘導体である、項目3に記載の方法。
(項目5)
アミノヘキソースはグルコサミンである、項目4に記載の方法。
(項目6)
アミノペントースは、リボース、キシロース、アラビノースまたはリキソースのアミノ誘導体である、項目3に記載の方法。
(項目7)
アミノ糖は、糖の2’位に配置されたアミノ基を有する糖である、項目1に記載の方法。
(項目8)
アミノ糖のヒドロキシル基が保護されている、項目1に記載の方法。
(項目9)
アミノ糖が、1,3,4,6−テトラ−O−アセチル−2−アミノ−α−D−グルコピラノース塩酸塩である、項目8に記載の方法。
(項目10)
前記混合が、有機溶媒中で行われる、項目1に記載の方法。
(項目11)
有機溶媒が、ジメチルホルムアミド、ジメチルスルホキシド、ジオキサン、メタノール、エタノール、ヘキサン、塩化メチレン、アセトニトリル、テトラヒドロフラン、またはこれらの混合物である、項目10に記載の方法。
(項目12)
還元前にチアゾリジン−糖接合体を精製することをさらに含む、項目2に記載の方法。
(項目13)
チアゾリジン−糖接合体が、シリカゲルカラムクロマトグラフィー、HPLC、またはこれらの組合せによって精製される、項目12に記載の方法。
(項目14)
アルカリ金属が、リチウム、ナトリウムまたはカリウムである、項目2に記載の方法。
(項目15)
電子源が、液体アンモニア、メチルアミン、エチルアミン、エチレンジアミン、またはこれらの組合せである、項目2に記載の方法。
(項目16)
金属イオンをエチレンジシステイン−糖接合体にキレート化し、金属イオンで標識されたエチレンジシステイン(EC)−糖接合体を生成することをさらに含む、項目2に記載の方法。
(項目17)
金属イオンが、テクネチウムイオン、スズイオン、銅イオン、インジウムイオン、タリウムイオン、ガリウムイオン、ヒ素イオン、レニウムイオン、ホルミウムイオン、イットリウムイオン、サマリウムイオン、セレニウムイオン、ストロンチウムイオン、ガドリニウムイオン、ビスマスイオン、鉄イオン、マンガンイオン、ルテチウムイオン、コバルトイオン、白金イオン、カルシウムイオンおよびロジウムイオンからなる金属イオン群から選択される、項目16に記載の方法。
(項目18)
金属イオンが放射性核種である、項目16に記載の方法。
(項目19)
放射性核種が、 99m Tc、 117m Sn、 177 Lu、 188 Re、 186 Re、 153 Sm、 166 Ho、 90 Y、 89 Sr、 67 Ga、 68 Ga、 111 In、 183 Gd、 59 Fe、 225 Ac、 212 Bi、 211 At、 45 Ti、 60 Cu、 61 Cu、 67 Cu、 64 Cuおよび 62 Cuからなる群から選択される、項目18に記載の方法。
(項目20)
金属イオンが非放射性金属である、項目16に記載の方法。
(項目21)
非放射性金属が 187 Reである、項目20に記載の方法。
(項目22)
被検体の中の部位を画像化し、疾患を診断するか、または疾患を治療する方法であって、
(a)項目16に記載の方法によって作られる、金属イオンで標識されたエチレンジシステイン(EC)−糖接合体を得ることと;
(b)薬学的または診断的に有効な量の金属イオンで標識されたエチレンジシステイン(EC)−糖接合体を被検体に投与し、部位が画像化され、疾患が診断されるか、または疾患が治療されることとを含む方法。
(項目23)
前記方法が、癌被検体を治療する方法としてさらに定義される、項目22に記載の方法。
(項目24)
癌が、中皮腫、乳癌、肺癌、前立腺癌、卵巣癌、脳癌、肝臓癌、子宮頸癌、結腸癌、腎臓癌、皮膚癌、頭頸部癌、骨癌、食道癌、膀胱癌、子宮体癌、リンパ系の癌、胃癌、膵臓癌、精巣癌、リンパ腫、または白血病である、項目23に記載の方法。
(項目25)
前記方法が、二重放射線療法/化学療法併用療法を行うための方法としてさらに定義される、項目22に記載の方法。
(項目26)
前記方法が、部位に局在化した、金属イオンで標識されたエチレンジシステイン−糖接合体からのシグナルを検出することを含む、被検体の中の部位を画像化する方法としてさらに定義される、項目22に記載の方法。
(項目27)
シグナルが、PET、PET/CT、CT、SPECT、SPECT/CT、MRI、PET/MRI、SPECT/MRI、光学イメージングおよび超音波からなる群から選択される技術を用いて検出される、項目26に記載の方法。
(項目28)
画像化される部位が、腫瘍または心臓である、項目22に記載の方法。
(項目29)
心血管疾患被検体を画像化し、診断するか、または治療する方法としてさらに定義される、項目22に記載の方法。
(項目30)
心血管疾患が、心筋梗塞、鬱血性心不全、心筋症、心臓弁膜症、不整脈、先天性心疾患、狭心症、非心臓の循環性鬱血、収縮期心不全、正常な収縮機能を有する心不全、または右側心不全である、項目29に記載の方法。
(項目31)
エチレンジシステイン−糖接合体と、ネオマイシンとを含む、接合体組成物。
(項目32)
エチレンジシステイン−糖接合体1mgあたり約0.1mg〜約1.0mgのネオマイシンを含む、項目31に記載の組成物。
(項目33)
エチレンジシステイン−糖接合体が、項目1に記載の方法によって作られる、項目31に記載の組成物。
(項目34)
酸化防止剤をさらに含む、項目31に記載の組成物。
(項目35)
アスコルビン酸、システイン、または塩化スズ(II)をさらに含む、項目31に記載の組成物。
(項目36)
(a)エチレンジシステイン−糖接合体1mgあたり約0.5〜2.0mgのアスコルビン酸;
(b)エチレンジシステイン−糖接合体1mgあたり約0.1〜1.0mgのシステイン;または
(c)エチレンジシステイン−糖接合体1mgあたり約0.05〜0.5mgの塩化スズ(II)を含む、項目35に記載の組成物。
(項目37)
前記組成物が凍結乾燥される、項目31に記載の組成物。
(項目38)
(a)エチレンジシステイン−糖接合体およびネオマイシンを水溶液に溶解することと;
(b)この溶液を凍結乾燥し、エチレンジシステイン−糖接合体組成物を提供することとを含む、接合体組成物を製造する方法。
(項目39)
被検体の中の部位を画像化し、疾患を診断するか、または疾患を治療する方法であって、
(a)金属イオンで標識されたエチレンジシステイン(EC)−糖接合体およびネオマイシンを含む組成物を得ることと;
(b)薬学的または診断的に有効な量の組成物を被検体に投与し、部位が画像化され、疾患が診断されるか、または疾患が治療されることとを含む、方法。
(項目40)
金属イオンで標識されたエチレンジシステイン−糖接合体と、ネオマイシンとを含む、組成物。
(項目41)
エチレンジシステイン−糖接合体1mgあたり約0.1mg〜約1.0mgのネオマイシンを含む、項目40に記載の組成物。
(項目42)
被検体の中の部位を画像化し、疾患を診断するか、または疾患を治療することに使用するための、項目40に記載の組成物。
図1を参照。
(概要)
あらゆる化学物質および溶媒は、Sigma−Aldrich(セントルイス、MO)から得た。Bruker 300MHz Spectrometerで核磁気共鳴(NMR)を行い、University of Texas MD Anderson Cancer Center(UTMDACC;Houston、TX)のコア設備でWaters Q−TOF Ultima Mass Spectrometer(Milford、MA)で質量分析を行った。化学シフトをδ(ppm)およびHz単位のJ値で測定した。FDGを、UTMDACCにあるDepartment of Nuclear Medicineから得た。
(工程1。T−G−(Ac)4の合成)
チアゾリジン−4−カルボン酸(T)(2.6g、0.02mol)のDMF(20ml)および5.0mlのトリメチルアミン溶液に、1−ヒドロキシベンゾトリアゾール水和物2.7g(0.02mol)を加えた。30分後、1,3,4,6−テトラ−O−アセチル−2−アミノ−α−D−グルコピラノース塩酸塩(G−(Ac)4)(7.7g、0.02mol)、N,N’−ジシクロヘキシルカルボジイミド(DCC;4.2g、0.02mol)および4−ジメチルアミノピリジン(DMAP;1.2g、0.01mol)を混合物に加え、室温で一晩攪拌した。溶液を高減圧下で乾燥するまで蒸発させた。ジクロロメタン(CH2Cl2)(50ml)を残渣に加え、4℃で一晩保持し、次いで濾過した。生成物を、CH2Cl2/MeOH(95/5、V/V)で溶出させることによって、シリカゲルによって精製し、白色生成物T−G−(Ac)4 4.08g(44.2%)を得た。NMRおよび質量分析法を使用し、T−G−(Ac)4の構造を確認した。
T−G−(Ac)4(4.08g、8.8mmol)の液体アンモニア(170g)溶液に、ナトリウムを片ごとに加えた。溶液の色は、ゆっくりと暗青色に変化した。30分後、少量の塩化アンモニウムを加えた。液体アンモニアを減圧によって除去した。残渣固体をメタノール(100ml)で磨砕した。次いで、固体を濾過し、さらなるメタノール(50ml)で洗浄し、未精製生成物4.16gを得た。分析的に純粋なECGを得るために、未精製生成物(0.1g)を1.0mlのHCl(0.1N)に溶解し、SephadexカラムでH2Oを用いて溶出させることによって精製した。水性フラクションを合わせ、凍結乾燥し、EC−G 0.029g(46.7%)を得た。NMR、質量分析法およびHPLCを用い、ECGの構造を確認した。
合成スキームを図1に示す。ECGを2工程反応で合成した。第1の工程では、1−ヒドロキシベンゾトリアゾール水和物、DCCおよびDMAP存在下、チアゾリジン−4−カルボン酸(T)を1,3,4,6−テトラ−O−アセチル−2−アミノ−α−D−グルコピラノース塩酸塩(G−(Ac)4)と反応させた。精製した後、生成物T−G−(Ac)4の収率は44.2%であった。1H NMR(D2O,δ):1.97−2.14(m,12H),3.88(t,1H),3.93(s,2H,),4.05−4.10(m,6H) 4.22−4.30(m,2H,),5.09(t,1H),5.34(t,1H),5.80(d,1H),6.93(d,1H,).13C NMR(D2O,δ):171.19,171.00,170.65,169.35,166.35,141.76,92.05,82.45,72.79,72.02,68.02,61.73,60.39,53.21,42.32,20.84,20.68,20.58,20.55.FAB MS m/z:462.5。
69GaCl3(20mg、0.11mmol)を0.2mlのH2Oに溶かし、これをECG(60mg、0.1mmol)の0.5ml H2O溶液に加えた。0.1N NaOH(50μl)を用い、pH値を4〜5に調節した。この溶液を60℃で30分間加熱した。生成物をSephadex columnでH2Oを用いて溶出させて精製し、Ga−ECGを得た。凍結乾燥後、Ga−ECGを白色固体として得た(52mg、78.1%)。NMR、質量分析計およびHPLCを使用し、69Ga−ECGの構造を確認した。
68Ge/68Ga生成器(Eckert Ziegler、Valencia、CA)から、0.1N HClを用いて溶出させ、68GaCl3を得た。68GaCl3(120μl、300μCi)を、ECG(1.2mg)の0.1ml H2O溶液に加え、NaHCO3(40μl、0.1N)を用い、pHを4〜5に調節した。この溶液を60℃で15分間加熱した。Covidien(Houston、TX)製の99Mo/99mTc生成器から過テクネチウム酸ナトリウム(Na99mTcO4)を得た。99mTc−ECGのラジオシンセシス(radiosynthesis)は、99mTc−過テクネチウム酸塩(40〜50mCi)を、ECGの凍結乾燥した残基(5mg)および塩化スズ(II)(SnCl2、100μg)に加えることによって達成された。ECGと99mTcとの錯体化は、pH6.5で行った。放射線化学物質の純度は、TLC(Waterman 1番、Aldrich−Sigma、セントルイス、MO)によって、食塩水を用いて溶出させて決定された。高性能液体クロマトグラフィー(HPLC)にNaI検出器およびUV検出器(210nm)を取付け、C−18逆相カラム(C18−extend、Agilent、Santa Clara、CA)で、アセトニトリル/水(1:9、V/V)を流速0.5ml/分で溶出させた。冷69Ga−ECGのHPLCを用い、68Ga−ECGの構造を確認した。
雌のFischer 344ラット(150±25g)(Harlan Sprague−Dawley、インディアナポリス、IN)(n=3ラット/時間点)に、IL−45細胞株から抽出された悪性の胸膜中皮腫細胞を接種した。腫瘍細胞(106細胞/ラット)を後ろ足に注入した(筋肉内)。腫瘍が直径約1cmになったら、接種から14〜17日後に、試験を行った。組織分布試験において、各動物に99mTc−ECG、68Ga−ECGおよび18F−FDGを注射した(静脈内、10μCi/ラット、10μg/ラット)。ラットを0.5〜4時間時に殺した。選択した組織を切断し、秤量し、ガンマカウンター(Packard Instruments、Downers Grove、IL)を用い、放射性活性を計測した。各サンプルのトレーサーの生体内分布を、濡れた組織の重量あたりの注射した投薬量のパーセント(%ID/g)として計算した。
IL−45細胞株から誘導される悪性の胸膜中皮腫を(後足に)有する雌のFischer 344ラット(150±25g)をイメージング試験に使用した。腫瘍が直径約1cmになったら、接種から14〜17日後に、試験を行った。ガントリー連動型PET/CTデータ獲得に組み込まれたマイクロ−PET(Inveon)から、または低エネルギーの平行穴コリメーターを備えるM−ガンマカメラ(Siemens Medical Systems,Inc.、Hoffman Estates、IL)からシンチグラフィー画像を得た。各動物に99mTc−ECG(300μCi/ラット、静脈内)、68Ga−ECGおよび18F−FDG(400μCi/ラット、静脈内)を投与し、0.5〜4時間時に画像を得た。68Ga−ECGを画像によって導かれる処理に使用することができることを示すために、腫瘍の容積が1.5cmの同じ中皮腫を有するラット(n=3)をパクリタキセル(20mg/kg、静脈内、1回注射)で処理した。処理前およびパクリタキセルで処理した後、7日目に、腫瘍を有するラットから、68Ga−ECGを用いて画像化した。コンピュータによって輪郭を作成した関心領域(ROI)(ピクセルあたりの計測数)を使用し、99mTc−ECGについて、バックグラウンドに対する腫瘍の計測数の密度比を決定した。腫瘍および筋肉について、対応する時間間隔でコンピュータによって輪郭を作成した関心領域(ROI)(ピクセルあたりの計測数)を使用し、68Ga−ECGおよび18F−FDGの動的プロットを作成した。動的プロットは0〜45分であった。細胞株試験において、グルコーストランスポーター(Glut−1)の阻害によって増殖防止効果を与えるため、パクリタキセルを選択した(Rastogiら、2007)。さらに、動物モデルにおいて、パクリタキセル処理に対して中皮腫が応答することが報告されている(Schulzら、2011)。
1.0mgのEC−Gを0.1mLの水に溶解することによって、1個のキットEC−Gを製造した。これに、1mgのL−アスコルビン酸の0.1mL水溶液、0.5mgのネオマイシンの0.1mL、0.5mg L−システインおよび0.1mLの1mg/mLの塩化スズ(II)溶液を加えた。1個の冷たいキットのために、生成物を凍結乾燥した。即時薄層クロマトグラフィーで、食塩水を移動相として用い、このキットを用いて作られる99mTc−EC−Gを分析した。この結果は、キット製品および標準的な99mTc−EC−G生成物の両方について、同じ保持力を示した(図16)。このキット製品および標準製品も、HPLCによってH2O/MeCN(9:1)を溶出液として用い、流速0.50mL/分で分析した(図17および18)。キット製品および標準製品の取り込みは、13762ラット哺乳動物腫瘍細胞への取り込みについて分析した。キット製品は、標準製品よりも5倍良好に取り込むことがわかった(図19)。
以下の参考文献は、例示、手順、または本明細書に記載するものの補助となる他の詳細を与える程度まで、本明細書に全体的に参照により組み込まれる。
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Henson et al.、Am.J.Neuroradiol.、25(6):969−972、2004.
Kundra et al.、J.Nucl.Med.、43(3):406−412、2002.
Rastogi et al.、Cancer Lett.、257(2):244−251、2007.
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Claims (24)
- カップリング剤の存在下でアミノ糖と保護されていないチアゾリジンカルボン酸を混合することによって、ペプチド結合によるチアゾリジン−糖接合体を与えることを含む、チアゾリジン−糖接合体を調製する方法。
- 請求項1に記載の方法に従ってチアゾリジン−糖接合体を調製すること、および該チアゾリジン−糖接合体を、アルカリ金属および電子源を含む還元剤で還元することによって、エチレンジシステイン−糖接合体を与えることを含む、エチレンジシステイン−糖接合体を調製する方法。
- アミノ糖は、アミノヘキソースまたはアミノペントースである、請求項1に記載の方法。
- アミノヘキソースは、グルコース、ガラクトース、マンノース、イドース、タロース、アルトロース、アロース、グロースまたはフルクトースのアミノ誘導体である、請求項3に記載の方法。
- アミノヘキソースはグルコサミンである、請求項4に記載の方法。
- アミノペントースは、リボース、キシロース、アラビノースまたはリキソースのアミノ誘導体である、請求項3に記載の方法。
- アミノ糖は、糖の2’位に配置されたアミノ基を有する糖である、請求項1に記載の方法。
- アミノ糖のヒドロキシル基が保護されている、請求項1に記載の方法。
- アミノ糖が、1,3,4,6−テトラ−O−アセチル−2−アミノ−α−D−グルコピラノース塩酸塩である、請求項8に記載の方法。
- 前記混合が、有機溶媒中で行われる、請求項1に記載の方法。
- 有機溶媒が、ジメチルホルムアミド、ジメチルスルホキシド、ジオキサン、メタノール、エタノール、ヘキサン、塩化メチレン、アセトニトリル、テトラヒドロフラン、またはこれらの混合物である、請求項10に記載の方法。
- 還元前にチアゾリジン−糖接合体を精製することをさらに含む、請求項2に記載の方法。
- チアゾリジン−糖接合体が、シリカゲルカラムクロマトグラフィー、HPLC、またはこれらの組合せによって精製される、請求項12に記載の方法。
- アルカリ金属が、リチウム、ナトリウムまたはカリウムである、請求項2に記載の方法。
- 電子源が、液体アンモニア、メチルアミン、エチルアミン、エチレンジアミン、またはこれらの組合せである、請求項2に記載の方法。
- 金属イオンをエチレンジシステイン−糖接合体にキレート化し、金属イオンで標識されたエチレンジシステイン(EC)−糖接合体を生成することをさらに含む、請求項2に記載の方法。
- 金属イオンが、テクネチウムイオン、スズイオン、銅イオン、インジウムイオン、タリウムイオン、ガリウムイオン、ヒ素イオン、レニウムイオン、ホルミウムイオン、イットリウムイオン、サマリウムイオン、セレニウムイオン、ストロンチウムイオン、ガドリニウムイオン、ビスマスイオン、鉄イオン、マンガンイオン、ルテチウムイオン、コバルトイオン、白金イオン、カルシウムイオンおよびロジウムイオンからなる金属イオン群から選択される、請求項16に記載の方法。
- 金属イオンが放射性核種である、請求項16に記載の方法。
- 放射性核種が、99mTc、117mSn、177Lu、188Re、186Re、153Sm、166Ho、90Y、89Sr、67Ga、68Ga、111In、183Gd、59Fe、225Ac、212Bi、211At、45Ti、60Cu、61Cu、67Cu、64Cuおよび62Cuからなる群から選択される、請求項18に記載の方法。
- 金属イオンが非放射性金属である、請求項16に記載の方法。
- 非放射性金属が187Reである、請求項20に記載の方法。
- 請求項1に記載の方法であって、前記チアゾリジンカルボン酸が、
- 請求項1に記載の方法であって、前記カップリング剤が、N,N’−ジシクロヘキシルカルボジイミド(DCC)である、方法。
- 請求項23に記載の方法であって、前記カップリング剤が、4−ジメチルアミノピリジン(DMAP)をさらに含む、方法。
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PL2830666T3 (pl) | 2021-03-08 |
KR102040476B1 (ko) | 2019-11-06 |
ZA201407213B (en) | 2017-08-30 |
CN104321083A (zh) | 2015-01-28 |
EP2830666A1 (en) | 2015-02-04 |
EP2830666B1 (en) | 2020-01-08 |
AU2013239870A1 (en) | 2014-10-23 |
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IL234858A (en) | 2017-03-30 |
AU2013239870B2 (en) | 2017-07-20 |
RS60085B1 (sr) | 2020-05-29 |
BR112014023988B1 (pt) | 2021-02-02 |
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EP2830666A4 (en) | 2015-11-04 |
IN2014DN08487A (ja) | 2015-05-08 |
RU2674673C2 (ru) | 2018-12-12 |
PT2830666T (pt) | 2020-04-02 |
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