CN101133017A - 放射性卤素标记的苯氧基苯胺衍生物 - Google Patents
放射性卤素标记的苯氧基苯胺衍生物 Download PDFInfo
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- CN101133017A CN101133017A CNA2005800488048A CN200580048804A CN101133017A CN 101133017 A CN101133017 A CN 101133017A CN A2005800488048 A CNA2005800488048 A CN A2005800488048A CN 200580048804 A CN200580048804 A CN 200580048804A CN 101133017 A CN101133017 A CN 101133017A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
一种右式所示的放射性卤素标记的苯氧基苯胺衍生物，其中，R1代表的基团如烷基；X1、X2、X3和X4各自代表氢原子、烷基、烷氧基、其中导入有11C或携带了放射性卤原子的烷氧基，其条件是X1、X2、X3和X4中的至少一个代表其中导入了11C或携带了放射性卤原子的烷氧基；该化合物可用作具有很高亲和力和很高选择性的PBR配体。在PBR的体外测定中，将具有很高亲和力和很高的选择性的PBR配体用放射性卤素核素进行标记，以便能够使用包括PET以及SPECT的工具在体内测定PBR。因此，可以得到用于疾病如阿尔茨海默型痴呆症的早期诊断、预防和治疗的化合物。
Description
技术领域
本发明涉及对外周苯二氮卓类受体具有很高亲和性的放射性卤素标记的苯氧基苯胺(phenyloxyaniline)衍生物。
背景技术
苯二氮卓类受体(BZ)分为中枢和外周受体。首先在外周组织中观察到了苯二氮卓类受体(PBR)，但在中枢神经系统中也识别到了其存在。而且，已经揭示出，PBR在中枢神经系统中的密度很高，几乎与中枢苯二氮卓类受体(CBR)在相同区域中的密度一样高或者更高。迄今的研究报道，PBR与多种疾病相关，这些疾病如阿尔茨海默氏病(Alzheimer’s disease)、额颞叶痴呆症(front-temporal dementia)、弥漫性Lewy小体病(diffuse Lewy corpuscle disease)、血管病变、帕金森氏症(Parkinson’s disease)相关疾病、皮质延髓变性(corticobasilardegeneration)、帕金森氏症、惠廷顿氏舞蹈病(Huntington’s chorea)、多系统萎缩症、多发性硬化、癫痫症、脑膜炎、脑炎、外周神经损伤、喉癌、乳癌、卵巢肿瘤、肝癌、大肠癌、胃癌、肾上腺癌、神经胶质瘤、成胶质细胞瘤、成纤维细胞瘤、神经肉瘤、肺癌、子宫癌、淋巴瘤、前列腺癌、黑素瘤、睾丸肿瘤、星形细胞瘤、异位产生激素的肿瘤(ectopic hormone-producing tumor)。
在用正电子发射断层显像(PET)对活体人脑的脑内PBR分布进行成像时，使用常规的PBR配体11C-标记的N-甲基-N-(1-甲基丙基)-1-(2-氯苯基)-异喹啉-3-羧酰胺(下文中称作“PK 11195)来诊断脑神经胶质瘤和阿尔茨海默氏症。但由于该化合物在脑中的积累极少，并且在定量分析方面存在问题，需要开发出能给予很高信号的PBR配体。在此情况下，现在清楚的是，N-(2，5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺(下文中称作DAA1106)和N-(2-氟代甲基-5-甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺(下文中称作FMDAA1106)[专利文件2]和N-[2[(2-氟)乙基-5-甲氧基苄基]-N-(5-氟-2-苯氧基苯基)乙酰胺(下文中称作FEDAA1103)[专利文件2]均具有很强的亲和性和很高的选择性，因此它们非常适合于此用途。即，用11C标记的[11C]DAA1106，以及用18F标记的[18F]FMDAA1106和[18F]FEDAA1106作为PET示踪剂在脑内PBR的外部计数中均能给出很高的信号，这在定量分析中是高度准确的。
专利文件1：JP 11-171844A
专利文件2：JP 2004-231647A
发明内容
本发明的目的是提供用作PBR配体的具有很强亲和性和很高选择性的化合物，以及能够通过在PBR的外部计数中用放射性卤素核素对具有很强亲和性和很高选择性的PBR配体进行标记，通过包括PET以及SPECT的技术测定活体内的PBR。
为解决上述问题，本发明人进行了广泛的研究，从而发现，通过改变JP 11-171844A中所述的化合物的烷基成为卤代烷基，可以实现优异的PBR亲和力，从而完成本发明。
即，本发明涉及一种式(I)所示的放射性卤素标记的苯氧基苯胺衍生物
[式1]
其中，R1代表氢原子、具有1-10个碳原子的取代或未取代烷基、具有1-10个碳原子的烷氧基、取代或未取代苯基、式-NR2(R3)所示的基团，其中R2和R3相同或者不同，并代表氢原子、具有1-10个碳原子的取代或未取代烷基，或者与相邻的氮原子一起形成4-10元环状氨基，且X1、X2、X3和X4相同或不同，各自代表氢原子、具有1-5个碳原子的烷基、具有1-5个碳原子的烷氧基、苯氧基、三氟甲基、氨基甲酰基、氨基磺酰基、卤原子或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，其条件是X1、X2、X3和X4中的至少一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子。
优选地，本发明涉及一种根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中，R1代表氢原子、具有1-10个碳原子的取代或未取代烷基，且X1、X2、X3和X4相同或不同，各自代表氢原子、具有1-5个碳原子的烷氧基、卤原子或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，其条件是X1、X2、X3和X4中的至少一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子。
更优选地，本发明涉及一种根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中，R1代表具有1-10个碳原子的取代或未取代烷基，X1和X2各自代表具有1-5个碳原子的烷氧基，X3代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，且X4代表氢原子。
最优选地，本发明涉及一种根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中，R1代表具有1-10个碳原子的取代或未取代烷基，X1和X2相同或不同，各自代表具有1-5个碳原子的烷氧基或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，其条件是X1和X2中的任一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，X3代表卤原子，且X4代表氢原子。
此外，本发明涉及阿尔茨海默氏病、额颞叶痴呆症、弥漫性Lewy小体病、血管病变、帕金森氏症相关疾病、皮质延髓变性、帕金森氏症、惠廷顿氏舞蹈病、多系统萎缩症、多发性硬化、癫痫症、脑膜炎、脑炎、外周神经损伤、喉癌、乳癌、卵巢肿瘤、肝癌、大肠癌、胃癌、肾上腺癌、神经胶质瘤、成胶质细胞瘤、成纤维细胞瘤、神经肉瘤、肺癌、子宫癌、淋巴瘤、前列腺癌、黑素瘤、睾丸肿瘤、星形细胞瘤或异位产生激素的肿瘤等的诊断剂，其包括式(I)所示的放射性卤素标记的苯氧基苯胺衍生物作为活性成分。
发明优势
根据本发明，提供了多种用作PBR配体的具有很强亲和性和很高选择性的化合物。此外，可以通过在PBR的外部计数中用放射性卤素核素对具有很强亲和性和很高选择性的PBR配体进行标记，通过包括PET以及SPECT的技术测定活体内的PBR。这样能够进行阿尔茨海默氏病、额颞叶痴呆症、弥漫性Lewy小体病、血管病变、帕金森氏症相关疾病、皮质延髓变性、帕金森氏症、惠廷顿氏舞蹈病、多系统萎缩症、多发性硬化、癫痫症、脑膜炎、脑炎、外周神经损伤、喉癌、乳癌、卵巢肿瘤、肝癌、大肠癌、胃癌、肾上腺癌、神经胶质瘤、成胶质细胞瘤、成纤维细胞瘤、神经肉瘤、肺癌、子宫癌、淋巴瘤、前列腺癌、黑素瘤、睾丸肿瘤、星形细胞瘤或异位产生激素的肿瘤等的早期诊断。此外，本发明的化合物可用作上述疾病的预防和治疗药物。
附图说明
图1是将[131I]2IDAA1106给予大鼠后30分钟内脑的离体放射自显影照片。
图2是将[131I]2IDAA1106给予大鼠后30分钟内脑的离体放射自显影照片。
具体实施方式
在本发明中，卤原子是氟原子、氯原子、溴原子或碘原子；优选其为氟原子、碘原子或溴原子；更优选其为氟原子或碘原子。
在本发明中，具有1-10个碳原子的烷基是指线性、支链或环状烷基；而且，例如，其包括甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、环丁基、环丙基甲基、戊基、异戊基、环戊基、环丁基甲基、1-乙基丙基、己基、异己基、环己基、环戊基甲基、1-乙基丁基、庚基、异庚基、环己基甲基、辛基、壬基和癸基。
在本发明中，具有1-10个碳原子的取代烷基是指被“羟基、烷酰氧基、烷酰基、烷氧基、卤原子、叠氮基、氨基、羧基”取代的烷基；并且，例如，其包括羟甲基、乙酰氧基甲基、甲氧基甲基、氯甲基、三氟甲基、叠氮甲基、氨基甲基、二甲基氨基甲基和吡咯烷甲基。
在本发明中，具有1-10个碳原子的烷氧基是指线性、支链或环状烷氧基；而且，例如，其包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、环丙基甲氧基、戊氧基、异戊氧基、己氧基、庚氧基、辛氧基、壬氧基和癸氧基。
在本发明中，取代苯基是指被1-3个选自如下基团的基团取代的苯基：具有1-10个碳原子的烷基、具有1-10个碳原子的被“卤原子、羟基、具有1-10个碳原子的烷酰氧基、羧基或烷氧基羰基”取代的烷基、具有2-10个碳原子的烯基、具有1-10个碳原子的烷氧基、具有1-10个碳原子的烷基硫代基(alkylthio group)、式-O-Z-R4所示的基团(其中Z代表具有1-10个碳原子的支链或直链烯基，R4代表氨基、被1或2个具有1-7个碳原子的烷基取代的氨基、具有2-7个碳原子的环状氨基、羟基、羧基或烷氧基羰基)、具有2-10个碳原子的烷酰基或其缩酮、甲酰基或其缩醛、羧基、具有2-10个碳原子的烷氧基羰基、氨基甲酰基、其中氮原子被1或2个具有1-10个碳原子的烷基取代的氨基甲酰基、氨基磺酰基、其中氮原子被1或2个具有1-10个碳原子的烷基取代的氨基磺酰基、卤原子和硝基；其包括，例如，2-甲基苯基、2-丙基苯基、2-异丙基苯基、2-环戊基苯基、2-(1-羟乙基)苯基、2-羧基甲基苯基、2-甲氧基羰基苯基、2-乙烯基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-乙氧基苯基、2-己氧基苯基、2-异丙氧基苯基、2-环戊氧基苯基、2，5-二甲氧基苯基、2，4，6-三甲氧基苯基、4-甲基硫代苯基(4-methylthiophenyl group)、2-异丙基硫代苯基、4-环己基硫代苯基、2-(2-二甲基氨基乙氧基)苯基、2-(2-羟基乙氧基)苯基、2-羧基甲氧基苯基、2-甲氧基羰基甲氧基苯基、2-乙酰基苯基、2-(2-甲基-1，3-二氧戊环-2-基)苯基、2-甲酰基苯基、2-(1，3-二氧戊环-2-基)苯基、2-羧基苯基、2-(N-甲基氨基羰基)苯基、2-(N，N-二甲基氨基羰基)苯基、2-氨基羰基苯基、2-氨基磺酰基苯基、4-氨基磺酰基苯基、2-甲基氨基磺酰基苯基、2-二甲基氨基磺酰基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2，4-二氟苯基、2-硝基苯基、2-氨基苯基、2-吡咯烷苯基、和4-二甲基氨基苯基。
在本发明中，式NR2(R3)所示的4-10元环状氨基是指可以含有氮原子或氧原子的环状氨基；其包括，例如，吡咯烷基、哌啶基、哌嗪基、N-甲基哌嗪基、吗啉基。
本发明的化合物可以通过如下所示的方法，从以JP 11-171844A所述的相同的方法制备的化合物来制备(在反应式中，X1、X2和R1所指与上文相同)。
[式2]
因此，可以将上式代表的具有各种非放射性卤原子的N-(2-苄氧基-5-烷氧基苄基)-N-(苯氧基苯基)酰胺化合物与钯复合物和有机锡化合物反应，从而将非放射性卤原子用有机锡取代基取代，然后与各种放射性卤试剂反应，得到用卤原子标记的苯氧基苯胺衍生物。在此，X1、X2、X3和X4中的至少一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子。
以下通过操作实施例和实验实施例对本发明进行更详细的说明。
实施例
(实施例1)
制备[131I]-N-(2，5-二甲氧基苄基)-N-(5-碘-2-苯氧基苯基)乙酰胺(下文中称为[131I]-1IDAA1106)
1-1)将N-(2，5-二甲氧基苄基)-N-(5-溴-2-苯氧基苯基)乙酰胺(510mg，1.12mmol)溶解在甲苯中，并用六丁基二锡(IV)和二氯二(三苯基膦)钯(0)回流4天。除去甲苯后，反应产物通过硅胶柱层析(通过己烷∶乙酸乙酯＝1∶4洗脱)提纯，得到320mg(43％)N-(2，5-二甲氧基苄基)-N-(5-三丁基甲锡烷基-2-苯氧基苯基)乙酰胺。
FABMS C36H48FNO3Sn(m/z)680.5(m++1)
向N-(2，5-二甲氧基苄基)-N-(5-三丁基甲锡烷基-2-苯氧基苯基)乙酰胺(55mg，0.083mmol)的氯仿溶液中加入100mg固体碘，生成的反应液在室温下搅拌1小时，然后向反应液中加入饱和硫代硫酸钠水溶液，直至反应液变为无色。分离有机层，用饱和盐水溶液洗涤，并用无水硫酸镁干燥。将减压蒸发溶剂得到的粗产品通过硅胶柱层析(通过己烷∶乙酸乙酯＝1∶4洗脱)提纯，得到32mg(77％)题述化合物。
1-2)将100μL乙酸/30％过氧化氢(3/1)加入到N-(2-三丁基甲锡烷基-5-甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺(0.1mg)的乙酸乙酯(100μL)中并混合。向混合物中加入[131I]NaI(0.1mCi)，静置1分钟。反应完成后，将反应混合物注射到反相半制备性HPLC(YMC J’sphere ODS-H80柱，10mmID×250mm)中。在4mL/min的流速下使用CH3CN/H2O(9/1)作为流动相，得到[131I]1IDAA1106的馏分。减压蒸馏从该馏分中除去溶剂，残余物溶解在生理盐水(1mL)中，然后使其通过0.22μm Millipore滤器，成功地得到[131I]1IDAA1106(0.091mCi)。
(实施例2)
制备N-(2-[131I]碘-甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺(下文中称为[131I]-2IDAA1106)
将100μL乙酸/30％过氧化氢(3/1)加入到N-(2-三丁基甲锡烷基-5-甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺(0.1mg)的乙酸乙酯(100μL)溶液中并混合。向其中加入[131I]NaI(0.1mCi)，静置1分钟。反应完成后，将反应混合物注射到反相半制备性HPLC(YMC J’sphereODS-H80柱，10mmID×250mm)中。在4mL/min的流速下使用CH3CN/H2O(9/1)作为流动相，得到[131I]1IDAA1106的馏分。减压蒸馏从该馏分中除去溶剂，残余物溶解在生理盐水(1mL)中，然后使其通过0.22μm Millipore滤器，成功地得到[131I]2IDAA1106(0.095mCi)。
(实验实施例)
离体放射自显影
图1和图2显示了将[131I]2IDAA1106给予大鼠后30分钟内脑的离体放射自显影照片。如图1所示，[131I]2IDAA1106显示出相对很高的脑渗透特性，符合放射性配体的基本要求。嗅球、脉络丛和小脑处存在相对很高的放射性分布，这种分布图谱与外周苯二氮卓类受体的脑内分布相一致。此外，如图2所示，将DAA1106和[131I]2IDAA1106同时给药时，整个脑内的放射性分布降低。具体来说，嗅球、脉络丛和小脑处的放射性水平显著降低，等于或小于图1的20％。这些事实说明，[131I]2IDAA1106是对外周苯二氮卓类受体有特异性的放射性配体。此外，表明[131I]2IDAA1106可以对外周苯二氮卓类受体进行成像。
下面，显示了引入11C的具有烷氧基的本发明化合物的合成。
DAA1106(2)：R＝CH3 DAA1097(3)：R＝CH(CH3)2
[11C]DAA1106([11C]2)：R＝11CH3 [11C]3：R＝11CH(CH3)2
[11C]7：R＝11CH2CH3
[11C]8：R＝11CH3
DAA1097(3)：R＝CH(CH3)2
[11C]3：R＝11CH(CH3)2
[11C]7：R＝11CH2CH3
[11C]8：R＝11CH3
9：R＝OH
(实施例3)
N-(4-氯-2-苯氧基苯基)-N-(2-[2-11C]异丙氧基苄基)乙酰胺([11C]3)
对含有0.01％氧气的超高纯氮气(1.5MPa)进行来自回旋加速器的18.5MeV质子的辐射，通过14N(p，α)11C核反应产生无载体[11C]CO2。
辐射之后，通过N2(50mL/min)从气体靶标收集的[11C]CO2，并浓缩，直至在液N2中冷却至-150℃的不锈钢线圈中整个线圈中的放射性达到稳定状态。当升温时排出浓缩的[11C]CO2，使干燥N2(2mL/min)在-5℃下流入含有CH3MgBr的回路中。当完成放射性的转移后，停止N2流，然后将该回路在25℃下保持5分钟，以进行格利雅(Grignard)反应。随后，使LiAlH4的THF溶液(0.2M，500μL)通过回路，将反应混合物移动至180℃的加热反应器1分钟。反应器在50-60℃下冷却后，向该反应器加入HI水溶液(57％，800μL)。反应混合物加热至180℃，生成的放射性馏分用N2(50mL/min)吹扫，并在室温下引入至Porapak(商品名)柱的入口。N2流持续3分钟，直至柱入口中的放射性水平变稳定。当该柱被加热时(加热速率：15℃/30秒)，[11C]10开始在6分钟内丛柱出口流出，其被收集到含有无水DMF(1mL)的罐中。然后该[11C]CO2被用于与格氏试剂MeMgBr的反应中，然后通过气相色谱分离，得到放射化学纯度＞95％的[11C]10(3.7-4.4GBq，n＝3)。
将9(1.0mg)、[11C]10(3.0-3.2GBq)和NaH(7μL，0.5g/20mLDMF)的DMF悬液加热至130℃，并将其保持10分钟。加入CH3CN/H2O(90-10，0.5mL)使含有[11C]3的反应混合物淬火，然后使其通过装在JASCO HPLC系统中的半分馏柱(内径10mm×250mm，CAPCELLPAK C18，SHISEIDO)。在该柱上使用CH3CN/H2O进行洗脱，流速为5.0mL/min，将所需的馏分(tR＝8.8min)收集在烧瓶中。将溶剂在90℃下丛烧瓶中减压蒸去后，残余物收集在10mL无菌盐水溶液中。使[11C]3的盐水溶液通过无菌0.22μm滤器，进入无菌瓶中。在合成结束时，得到放射化学纯度＞98％的[11C]3(180-310MBq，n＝3)。
(实施例4)
N-(4-氯-2-苯氧基苯基)-N-(2-[2-11C]乙氧基苄基)乙酰胺([11C]7)
通过进行CH3MgBr与[11C]CO2的反应，在合成结束时，得到放射化学纯度＞95％的[11C]11(3.9-5.3GBq，n＝3)。
将9(1.0mg)、[11C]11(3.0-3.2GBq)和NaH(7μL，0.5g/20mLDMF)在DMF(1mL)中的悬液加热至50℃，并将其保持5分钟。反应混合物通过上述使用的相同柱子进行提纯，不同之处在于使用CH3CN/H2O(80/20)，得到所需的放射性馏分(tR＝8.1min)。通过如在[11C]3上进行的相同方法处理之后，在合成结束时，得到放射化学纯度＞98％的[11C]7(300-350MBq，n＝3)。
(实施例5)
N-(4-氯-2-苯氧基苯基)-N-(2-[2-11C]甲氧基苄基)乙酰胺([11C]8)[11C]12的制备以及随后[11C]9甲基化为[11C]8在自动合成仪上进行。将由此形成的[11C]12蒸馏，通过烧碱石棉和P2O5柱，并收集在含有9(1.0mg)、NaH(7μL，0.5g/20mL DMF)和DMF(1mL)的容器中，在-15至-20℃下保持1.5分钟。然后将反应容器加热至30℃，保持5分钟。反应混合物通过上述使用的相同柱子进行提纯，不同之处在于使用CH3CN/H2O(70-30)，得到所需的放射性馏分(tR＝9.5min)。通过如在[11C]3上进行的相同方法处理之后，在合成结束时，得到放射化学纯度＞98％的[11C]8(1.0-1.3GBq，n＝3)。
(实施例6)
N-(5-氟-2-苯氧基苯基)-N-(2-[11C]甲氧基-5-甲氧基苄基)乙酰胺([11C]2)
通过与实施例5中所用方法类似的方法，得到了题述的化合物。
工业应用性
本发明的化合物可以用作多种疾病如阿尔茨海默氏病、额颞叶痴呆症、弥漫性Lewy小体病、血管病变、帕金森氏症相关疾病、皮质延髓变性、帕金森氏症、惠廷顿氏舞蹈病、多系统萎缩症、多发性硬化、癫痫症、脑膜炎、脑炎、外周神经损伤、喉癌、乳癌、卵巢肿瘤、肝癌、大肠癌、胃癌、肾上腺癌、神经胶质瘤、成胶质细胞瘤、成纤维细胞瘤、神经肉瘤、肺癌、子宫癌、淋巴瘤、前列腺癌、黑素瘤、睾丸肿瘤、星形细胞瘤和异位产生激素的肿瘤的早期诊断剂，也可用作上述疾病的预防和治疗药物。
Claims (5)
1.一种式(I)所示的放射性卤素标记的苯氧基苯胺衍生物：
[式1]
其中，R1代表氢原子、具有1-10个碳原子的取代或未取代烷基、具有1-10个碳原子的烷氧基、取代或未取代苯基、式-NR2(R3)所示的基团，其中R2和R3相同或者不同，并代表氢原子、具有1-10个碳原子的烷基，或者与相邻的氮原子一起形成4-10元环状氨基，且X1、X2、X3和X4相同或不同，各自代表氢原子、具有1-5个碳原子的烷基、具有1-5个碳原子的烷氧基、苯氧基、三氟甲基、氨基甲酰基、氨基磺酰基、卤原子、具有1-5个碳原子的用11C或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子标记的烷氧基，其条件是X1、X2、X3和X4中的至少一个代表具有1-5个碳原子的用11C或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子标记的烷氧基。
2.根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中，R1代表氢原子、具有1-10个碳原子的取代或未取代烷基，且X1、X2、X3和X4相同或不同，各自代表氢原子、具有1-5个碳原子的烷氧基、卤原子或具有1-5个碳原子的用11C或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子标记的烷氧基，其条件是X1、X2、X3和X4中的至少一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子。
3.根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中
R1代表具有1-10个碳原子的烷基，
X1和X2各自代表具有1-5个碳原子的烷氧基，
X3代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，
且X4代表氢原子。
4.根据权利要求1所述的放射性卤素标记的苯氧基苯胺衍生物，其中，
R1代表具有1-10个碳原子的烷基，
X1和X2相同或不同，各自代表具有1-5个碳原子的烷氧基或选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，其条件是X1和X2中的任一个代表选自121I、123I、124I、125I、131I、75Br、76Br、77Br和34mCl的放射性卤原子，
X3代表卤原子，
且X4代表氢原子。
5.一种阿尔茨海默氏病、额颞叶痴呆症、弥漫性Lewy小体病、血管病变、帕金森氏症相关疾病、皮质延髓变性、帕金森氏症、惠廷顿氏舞蹈病、多系统萎缩症、多发性硬化、癫痫症、脑膜炎、脑炎、外周神经损伤、喉癌、乳癌、卵巢肿瘤、肝癌、大肠癌、胃癌、肾上腺癌、神经胶质瘤、成胶质细胞瘤、成纤维细胞瘤、神经肉瘤、肺癌、子宫癌、淋巴瘤、前列腺癌、黑素瘤、睾丸肿瘤、星形细胞瘤或异位产生激素的肿瘤的诊断剂，其包括根据权利要求1-4中任意一项所述的放射性卤素标记的苯氧基苯胺衍生物作为活性成分。
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| EP1997515A1 (en) * | 2007-05-30 | 2008-12-03 | Bayer Schering Pharma Aktiengesellschaft | Use of radiolabelled phenyloxyaniline derivatives for imaging diseases associated with peripheral benzodiazepin receptor's activation |
| EP2228363A4 (en) * | 2007-10-31 | 2011-06-01 | Riken | KIT FOR USE IN THE MANUFACTURE OF A MOLECULAR PROBE FOR PET MEDICINE SCREENING |
| GB0722779D0 (en) * | 2007-11-20 | 2008-01-02 | Sterix Ltd | Compound |
| GB0904715D0 (en) | 2009-03-19 | 2009-05-06 | Ge Healthcare Ltd | Aryloxyanilide derivataives |
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| CN107412788B (zh) * | 2012-12-21 | 2021-06-18 | 国立研究开发法人量子科学技术研究开发机构 | 用于对脑内所蓄积的Tau蛋白质进行成像的新的化合物 |
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