CN105753843A - 一种pet示踪剂前体2-硝基咪唑类化合物及其制备方法 - Google Patents
一种pet示踪剂前体2-硝基咪唑类化合物及其制备方法 Download PDFInfo
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K51/041—Heterocyclic compounds
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种PET示踪剂前体2硝基咪唑类化合物及其制备方法,该前体的化学名为2[4(羧甲基)7[2(2(2硝基1H咪唑1基)乙酰氨基)乙基]1,4,7三氮杂环壬烷1基]乙酸,结构式如式(Ⅰ)所示。本发明解决了现有乏氧显像剂标记操作复杂、标记率低的技术问题和亲脂性高的应用缺陷,特别适用于乏氧肿瘤的诊断、治疗及疗效监测等。
Description
技术领域
本发明涉及一种PET示踪剂前体,尤其涉及一种硝基咪唑类化合物及其制备方法,属于放射性药物合成技术领域。
背景技术
正电子发射计算机断层扫描(Positronemissiontomography,简称PET)在肿瘤诊断和治疗中的应用主要是因为绝大部分恶性肿瘤存在着对葡萄糖、蛋白质、核酸、氧等物质具有高代谢或高表达倾向。PET显像技术是将葡萄糖、蛋白质、核酸及其它小分子作为载体标记上短半衰期的正电子放射性核素(如18F、11C、13N、15O、64Cu或68Ga等)制成示踪剂,注入人体后随血液循环浓聚到脏器的靶向部位。PET探测系统通过断层扫描采集每个正电子核素发生湮灭辐射所产生的能量相同(511keV)、方向相反的两个γ光子,并将数据分析重建进行功能显像。由于PET探测系统具有高灵敏度(fmol)、高分辨率(4-10mm)和可被适当定量的组织堆积等优势,结合CT或MR的解剖学影像,可从体外无创、定量、动态地显示生物分子代谢、受体配体特异性结合及神经介质活动等。
乏氧是肿瘤异质性的表现之一。肿瘤细胞以血管为中心呈环状排列,靠近血管的肿瘤细胞由于氧和营养物质供应充分,细胞增殖迅速。随着肿瘤细胞与血管距离逐渐增大,氧扩散的速率逐渐减慢,氧张力下降,当细胞离血管半径超过200μm,细胞大量坏死形成坏死区。介于这两者之间有一层厚度约10μm~20μm的乏氧区域,诱导细胞周期阻滞及基因突变,不仅使肿瘤本身更具有侵袭性,而且增加肿瘤细胞对放化疗的抵抗性。因此,在对肿瘤进行治疗前,有必要检测其乏氧程度。采用体外无创伤非侵入性方法评估肿瘤的乏氧性具有重要的临床意义,其中乏氧显像剂的测定在临床应用较广泛。
18F具有接近100%的正电子效率,低正电子能量(0.64M电子伏)和相对较短的物理半衰期(T1/2=109.7min)等特点,是理想的PET显像核素。经文献报道的18F标记的PET乏氧显像剂以2-硝基咪唑衍生物为主。硝基咪唑具有亲脂性,很容易从血液扩散到组织中。细胞内硝基咪唑在黄嘌呤氧化酶作用下发生单电子还原,产生阴离子自由基。正常氧水平细胞中,该还原过程可逆,阴离子自由基重新氧化,并扩散到细胞外;而在乏氧细胞中,阴离子自由基可以在硝基还原酶的作用下进一步还原形成更活泼的中间体,与细胞内组分结合并滞留在细胞中。硝基咪唑类乏氧显像剂即利用上述特点使放射性核素浓聚于肿瘤乏氧区域。目前较为常见的硝基咪唑类乏氧组织显像剂包括:18F-氟硝基咪唑(18F-FMISO)、18F-1-α-D-[5’-脱氧-5’-呋喃糖基]-2-硝基咪唑(18F-FAZA)、18F-氟赤硝基咪唑(18F-FETNIM)等,其中18F-FMISO是应用最广、最具代表性的也是临床上最早的用18F标记的乏氧组织显像剂。
常规地,正电子核素通过连接碳原子结合至载体化合物,或者先标记低比活度试剂,HPLC纯化后缀合至目标肽再次纯化。但是以上方法通常涉及多步合成及纯化,总合成时间约1-3小时,相对于短半衰期核素无法保证显像时足够的比活度,图像清晰度欠佳。另一方面,现有乏氧显像剂在生物学性质上普遍存在神经毒性和软组织吸收,在肿瘤中浓聚较慢,靶/本底值低。
发明内容
鉴于现有技术存在的不足,本发明的目的在于提供一种成本低廉、成像清晰,具有乏氧显像特性的示踪剂前体及其制备方法,从而将该前体药物标记后通过无创观测肿瘤乏氧程度进行肿瘤诊断、治疗及预后评估。
为了实现本发明的目的,发明人通过大量试验研究并不懈探索,最终获得了如下技术方案:
一种PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1,其化学名为2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸,结构式如式(Ⅰ)所示:
一种上述PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1的制备方法,该方法包括如下步骤:
(1)1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷的制备:将溴乙酸叔丁酯溶于CHCl3,在室温下用注射泵加入1,4,7三氮环杂壬烷的CHCl3溶液中,反应18-30h,过滤,滤液蒸干,加入蒸馏水,调pH=2.8-3.2,以乙醚萃取2-5次,蒸干有机层得到1,4,7-三氮杂环壬烷的三叔丁氧羰甲基取代物,水层调pH=10.5-11.2,以CH2Cl2萃取2-5次,合并有机相,加入正己烷重结晶,得到二取代物1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷;
(2)2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯的制备:将2-硝基咪唑、溴乙酸叔丁酯、碳酸钾加入乙腈中,氮气保护下升温至回流搅拌反应2-4小时,TLC检测反应完全,过滤,滤液旋干得到黄色油状物,乙酸乙酯/正己烷重结晶,得到白色固体产物;
(3)N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺的制备:将2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯溶于三氟乙酸/二氯甲烷溶液,室温搅拌3-4h,TLC检测反应完全,旋干后不经处理直接加入到处理过的二氯甲烷和DMF,加入溴乙胺溴酸盐、HATU、DIEA,25℃搅拌过夜,TLC检测反应完全,真空蒸除溶剂,加入水,乙酸乙酯萃取,合并的有机相,水洗,5%K2CO3洗涤,5%盐酸洗涤,干燥,旋干得到N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺;
(4)2-{4-[2-(叔丁氧基)-2-羰乙基]-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基}乙酸叔丁酯的制备:向反应容器中加入1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷,碳酸钾和乙腈,滴加N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺的乙腈溶液,滴加完毕后,室温搅拌过夜,减压旋去乙腈,搅拌后分层,有机相无水硫酸钠干燥,旋干,柱层析得到产物;
(5)2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸的制备:将步骤(4)所得产物溶于三氟乙酸,室温搅拌4-5小时,蒸干溶剂,乙醚洗涤,加入水、氯仿洗涤,蒸干水相得到纯品。
优选地,上述PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1的制备方法,其中1,4,7-三氮杂环壬烷和2-硝基咪唑的摩尔比例为5:1~10:1。
本领域技术人员可以根据各自熟知的技术手段选择合适的方法对产物进行纯化及检测,本发明选择以制备型HPLC进行对产物的纯化,并以分析型HPLC方法对产物的纯度进行检测分析。该方法简单、高效,且纯化及检测精度高。
另外,本发明还提供了一种用于制备上述PET示踪剂的药盒,该药盒内包含上述的NOTA-Nitro1,同时含有氯化铝,NOTA-Nitro1和氯化铝的摩尔比为(1-10):1。
优选地,如上所述用于制备PET示踪剂的药盒,该药盒内还包含醋酸-醋酸钠缓冲液。或者,如上所述用于制备PET示踪剂的药盒,所述的NOTA-Nitro1和氯化铝以冻干粉形式存在。
再者,本发明还提供上述用于制备PET示踪剂的药盒的制备方法,该方法包括如下步骤:1)将NOTA-Nitro1溶于醋酸-醋酸钠缓冲液;2)将氯化铝溶于冰醋酸-醋酸钠缓冲液;3)将步骤(1)和步骤(2)的两种溶液混合均匀;4)所得混合溶液无菌过滤后,分装于容器中,冷冻干燥即得所述药盒。
需要说明的是,本发明所述的PET示踪剂是通过对硝基咪唑类化合物进行正电子核素标记得到的。该正电子显像核素可以为本领域中常使用的正电子显现核素,优选18F。基于此,上述PET示踪剂具有如下所示的结构:18F-FAl-NOTA-Nitro1;其中所述NOTA为螯合剂1,4,7-三氮杂环壬烷,Nitro1为所述硝基咪唑类化合物。上述螯合剂为本领域技术人员熟知的可起到连接作用的基团,均可购自法国Chematech公司或美国Macrocyclics公司,各型号产品并无明显区别,对本发明的技术效果不产生影响,本发明中均选用100mg包装。
大量研究表明,临床上理想的PET肿瘤乏氧组织显像剂需具备以下条件:①无毒、体内稳定、制备简单及可重复性;②易选择性地浓聚于乏氧组织或细胞中,靶/本底值尽可能大,一般要求大于3:1;③生物半衰期适于显像,且在乏氧组织中有一定的滞留时间;④在血液及正常组织中分布均匀、清除速率快;⑤在患者可承受的辐射剂量内显像质量高,注射与显像时间间隔短,并具有提供量化的能力。本发明相比现有技术具有以下优点:(1)对本发明的硝基咪唑类化合物进行正电子核素标记后作为乏氧显像剂,荷瘤鼠microPET显像表明,肿瘤清晰可见,与背景对比度高,尾静脉注射1小时后,瘤肌比大于5,提示特异性结合。实验证实经正电子断层扫描显像,此类显像剂于肿瘤部位浓聚,与18F-FDG图像相比着重显示乏氧区域,并可进行肿瘤乏氧程度的定量分析,为肿瘤肿瘤诊治、预后评估及放疗靶区勾画提供了较可靠的依据。(2)由于本发明的硝基咪唑化合物经标记后与肿瘤乏氧区域高度特异性浓聚且组织渗透迅速,因此具有灵敏、快速的优点。(3)本发明所述的标记方法选用适宜的螯合剂标记,方法简单快捷,标记率和放化纯均可达到满意的效果。(4)本发明所述的方法以HPLC法对标记前体和标记产物进行提纯和纯度分析,不仅分离效果好,且与杂质明显区分。
附图说明:
图1为所述PET示踪剂的标记前体的分析型HPLC图;
图2为所述PET示踪剂放射性化学纯度指控结果,6小时内放射性化学纯度均大于99%;
图3为ECa109食管癌荷瘤裸鼠模型经尾静脉注射所述PET示踪剂的microPET显像图,白色箭头指示为ECa109种植瘤;
图4为通过ROI计算所述ECa109食管癌荷瘤裸鼠的主要器官对PET示踪剂的摄取值;
图5为实施例3中所述ECa109食管癌荷瘤裸鼠的靶/非靶值。
具体实施方式
为了使本发明的内容更容易被清楚的理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,本发明的优点和特点将会随着描述而更为清楚。但是应理解以下实施例仅是范例性的,不对本发明的保护范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神下可以对技术方案的细节和形式进行修改或替换,但这些修改或替换均落入本发明的保护范围。
实施例1:NOTA-Nitro1的制备:
(1)1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷的制备:溴乙酸叔丁酯(21.4g,55mmol)溶于CHCl3(100mL),室温下,用注射泵1h加入1,4,7-三氮环杂壬烷(6.5g,50mmol)的CHCl3(50mL)溶液中反应24h。过滤,滤液蒸干,加入蒸馏水50mL,用1MHCl调pH至3。以50mL乙醚萃取3次。蒸干有机层得到1,4,7-三氮杂环壬烷的三叔丁氧羰甲基取代物。水层用1MNaOH调pH11。以50mLCH2Cl2萃取3次,合并有机相,加入正己烷重结晶,得到二取代产物1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷。产率为61%。
(2)2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯的制备:将2-硝基咪唑1g,溴乙酸叔丁酯1.8g,碳酸钾1.3g加入20mL乙腈悬浮液中。氮气保护下升温至回流搅拌反应3小时。TLC检测反应完全,过滤,滤液旋干得到黄色油状物。乙酸乙酯/正己烷重结晶,得到白色固体产物2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯。产率约71%。
(3)N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺的制备:将第(2)步的反应产物2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯(1.32g,5.8mmol)溶于三氟乙酸(17mL)/二氯甲烷溶液(39mL),室温搅拌搅拌3.5h,TLC检测反应完全。旋干后不经处理直接到加入到处理过的二氯甲烷200mL,DMF20mL。加入溴乙胺溴酸盐1.1g,HATU2g,DIEA5mL。25℃搅拌过夜。TLC检测反应完全。真空蒸除溶剂,加入水,乙酸乙酯萃取(50mL×3),合并的有机相,水洗,5%K2CO3洗涤。5%盐酸洗涤。经干燥,旋干,柱层析得到产物N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺。产率为32%。
(4)2-{4-[2-(叔丁氧基)-2-羰乙基]-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基}乙酸叔丁酯的制备:向三口烧瓶中加入第(1)步的二取代产物1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷(715mg,2mmol),碳酸钾(331mg,2.4mmol)和10mL干燥乙腈。滴加N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺(665mg,2.4mmol)的干燥乙腈(7mL)溶液,滴加完毕后,室温搅拌过夜。减压旋去乙腈,搅拌后分层,有机相无水硫酸钠干燥,旋干。柱层析得到2-{4-[2-(叔丁氧基)-2-羰乙基]-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基}乙酸叔丁酯。(CH2Cl2/MeOH=9:1)
(5)2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸的制备:将上一步产物(354mg,0.64mmol)溶于三氟乙酸(2mL),室温搅拌4.5小时。蒸干溶剂,乙醚洗涤。加入2mL水,氯仿洗涤。蒸干水相得到纯品(254mg,90%)。经鉴定,其化学结构式如下式(Ⅰ)所示:
化学名为2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸,碳谱氢谱数据为:1HNMR(D2O,500MHz):δ7.37(d,1H,J=1.5Hz),7.16(d,1H,J=1.5Hz),5.36(s,1H),5.18(s,2H),3.75(s,4H),3.65(t,2H,J=6.0Hz),3.51-3.53(m,4H),3.45(t,2H,J=6.0Hz),3.35(m,4H),3.18(s,4H)。
实施例2:PET示踪剂18F-FAl-NOTA-Nitro1的制备
(1)18F溶液的制备:医用加速器中采用质子速轰击H2 18得到18F溶液。采用CRC-15R活度计(CAPINTEC)测定其放射剂量为20mCi。
(2)PET示踪剂18F-FAl-NOTA-Nitro1的制备:取实施例1制备的前体NOTA-Nitro10.1mg于西林瓶中,加入10μL冰醋酸、0.005mg三氯化铝(醋酸/醋酸钠缓冲溶液溶解)、200μL乙腈,继续加入50μL18F离子溶液,与100℃下密闭反应20min,反应结束后冷却至室温再加入超纯水,让反应液加压通过预先活化好的氯化铝柱,未反应的18F离子被吸附,收集洗脱液,再加热除去所用溶液,用生理盐水溶解得到目标产物,合成时间约20min。采用CRC-15R活度计(CAPINETC)测定其放射剂量为10.1mCi,因此,计算其标记率(未校正)为49.4±3.0%。所述PET示踪剂18F-FAl-NOTA-Nitro1的结构式如下:
采用步骤2中所述的分析型HPLC条件对该示踪剂进行检测,产品保留时间:15.5min(HPLC图谱见图2所示),放射化学纯度>95%。
实施例3:MicroPET显像试验
取荷人移植瘤(ECa109食管癌)模型鼠置于小动物PET床板上,异氟烷麻醉模型鼠,经胶带固定。模型鼠经尾静脉注射上述实施例2制备的示踪剂生理盐水溶液(1.85MBq,0.2ml)。注射后2小时动态扫描,分别进行MicroPET显像,结果分别如图3所示。
采用二维有序子集期望最大化法进行图像重建。在肿瘤、肌肉、肝等器官用感兴趣区(ROI)法计算放射性活度(MBq/ml),所得值除以注射剂量获得各组织对PET示踪剂摄取值(%ID/g)(假定组织密度为1g/ml)。计算结果分别如图4所示。靶/非靶比值(T/M)分别如图5所示。
如图3所示,ECa109食管癌移植瘤在注射后30min到60min均清晰可见。从图中可以看到,肿瘤与对侧相比具有良好的对比度。
所述PET示踪剂在模型鼠的肾中具有显著的浓聚,这表明其主要通过肾代谢。随着时间的延长,所述PET示踪剂在模型鼠体内的浓聚逐渐降低,显示所述PET示踪剂逐渐代谢排出体外,这表明所述PET示踪剂是安全的,不会持久的存于鼠体内,且半衰期较短,不会对模型鼠造成伤害。
如图4所示,注射后30-60min,肿瘤对所述PET示踪剂摄取值保持较高水平,约6-8%ID/g,后随着时间的变化,摄取值逐渐降低。此外,如图5所示,肿瘤较正常组织如肌肉对所述PET示踪剂摄取显著,注射60min后肿瘤与肌肉摄取比值大于3,这有利于获得高清晰度的肿瘤PET图像,便于肿瘤的诊断和治疗。
Claims (7)
1.一种PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1,其化学名为2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸,结构式如式(Ⅰ)所示:
2.一种根据权利要求1所述PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1的制备方法,其特征在于该方法包括如下步骤:
(1)1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷的制备:将溴乙酸叔丁酯溶于CHCl3,在室温下用注射泵加入1,4,7三氮环杂壬烷的CHCl3溶液中,反应18-30h,过滤,滤液蒸干,加入蒸馏水,调pH=2.8-3.2,以乙醚萃取2-5次,蒸干有机层得到1,4,7-三氮杂环壬烷的三叔丁氧羰甲基取代物,水层调pH=10.5-11.2,以CH2Cl2萃取2-5次,合并有机相,加入正己烷重结晶,得到二取代物1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷;
(2)2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯的制备:将2-硝基咪唑、溴乙酸叔丁酯、碳酸钾加入乙腈中,氮气保护下升温至回流搅拌反应2-4小时,TLC检测反应完全,过滤,滤液旋干得到黄色油状物,乙酸乙酯/正己烷重结晶,得到白色固体产物;
(3)N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺的制备:将2-(2-硝基-1H-咪唑-1-基)乙酸叔丁酯溶于三氟乙酸/二氯甲烷溶液,室温搅拌3-4h,TLC检测反应完全,旋干后不经处理直接加入到处理过的二氯甲烷和DMF,加入溴乙胺溴酸盐、HATU、DIEA,25℃搅拌过夜,TLC检测反应完全,真空蒸除溶剂,加入水,乙酸乙酯萃取,合并的有机相,水洗,5%K2CO3洗涤,5%盐酸洗涤,干燥,旋干得到N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺;
(4)2-{4-[2-(叔丁氧基)-2-羰乙基]-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基}乙酸叔丁酯的制备:向反应容器中加入1,4–二(叔丁氧羰甲基)1,4,7-三氮杂环壬烷,碳酸钾和乙腈,滴加N-(2-溴乙基)-2-(2-硝基-1H-咪唑-1-基)乙酰胺的乙腈溶液,滴加完毕后,室温搅拌过夜,减压旋去乙腈,搅拌后分层,有机相无水硫酸钠干燥,旋干,柱层析得到产物;
(5)2-[4-(羧甲基)-7-[2-(2-(2-硝基-1H-咪唑-1-基)乙酰氨基)乙基]-1,4,7-三氮杂环壬烷-1-基]乙酸的制备:将步骤(4)所得产物溶于三氟乙酸,室温搅拌4-5小时,蒸干溶剂,乙醚洗涤,加入水、氯仿洗涤,蒸干水相得到纯品。
3.根据权利要求2所述PET示踪剂前体2-硝基咪唑类化合物NOTA-Nitro1的制备方法,其特征在于,所述1,4,7-三氮杂环壬烷和2-硝基咪唑的摩尔比例为5:1~10:1。
4.一种用于制备PET示踪剂的药盒,其特征在于,所述药盒内包含权利要求1所述的NOTA-Nitro1,同时含有氯化铝,NOTA-Nitro1和氯化铝的摩尔比为(1-10):1。
5.根据权利要求4所述用于制备PET示踪剂的药盒,其特征在于,所述药盒内还包含醋酸-醋酸钠缓冲液。
6.根据权利要求4所述用于制备PET示踪剂的药盒,其特征在于,所述的NOTA-Nitro1和氯化铝以冻干粉形式存在。
7.一种根据权利要求4所述用于制备PET示踪剂的药盒的制备方法,其特征在于,该方法包括如下步骤:1)将NOTA-Nitro1溶于醋酸-醋酸钠缓冲液;2)将氯化铝溶于冰醋酸-醋酸钠缓冲液;3)将步骤(1)和步骤(2)的两种溶液混合均匀;4)所得混合溶液无菌过滤后,分装于容器中,冷冻干燥即得所述药盒。
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