CN115364245A - 一种荧光-磁共振双模态造影剂及其制备方法和用途 - Google Patents
一种荧光-磁共振双模态造影剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及医学诊断成像领域，具体公开了一种荧光‑磁共振双模态造影剂及其制备方法和用途，所述造影剂具有如下结构：X‑L‑Y,其中：
R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12各自独立的选自H，卤素，OH，NH2,COOH，CONH2，NO2，CN，低烷基，所述低烷基可以被卤素，OH，NH2，COOH，CONH2，SO3H，NO2，CN取代，其中R3与R4，R7与R8也可以各自独立的可以同它们所连接的碳原子环合成苯基或杂环。L为链接基团。Y为金属螯合物。
Description
技术领域
本发明涉及医学诊断成像领域，更具体地，本发明涉及一种荧光-磁共振双模态造影剂及其制备方法和用途。
背景技术
由于近年来疾病特别是癌症的早期诊断方面取得了长足的发展，传统的临床成像技术逐渐难以满足个体化癌症诊疗的新需求。传统的临床诊断技术，如正电子发射断层扫描(PET)，计算机断层扫描(CT)，X射线成像，超声成像(US)和磁共振扫描成像(MRI)，正受到特异性差、病变位置信息有限等固有缺陷制约。其中MRI是临床上应用最为广泛的影像诊断方法，MRI技术通常利用不同组织或器官中的质子的“自旋-晶格弛豫时间”和“自旋-自旋弛豫时间”的不同进行成像。MRI是一种非侵入性的不借助电离辐射的成像方式，能够提供活体动物的解剖、生理甚至分子信息。穿透深度足以在整个人体上成像，并且根据磁场强度，空间分辨率可达到10μm以下，MRI提供了其他影像学手段难以提供的图像信息。然后，虽然通常可以再不借助造影剂的条件下对解剖结构进行MRI成像，但如果需要分子水平的信息，则由于MRI的灵敏度低等原因，难以获得微小肿瘤病灶的清晰图像，不利于肿瘤的早发现早治疗，需要借助造影剂提升其图像质量。常用MRI的低灵敏度与信号检测的机制相关，难以通过自身的改进加以克服。目前常用的MRI造影剂钆喷酸葡胺(Gd-DTPA)弛豫率低，并且小分子造影剂在体内清除较快，因此提高MRI造影剂的弛豫效率是增强MRI对比度的关键步骤。
光学成像技术利用光的不同物理参数与组织相互作用来进行成像，已经报道了许多不同的光学成像方法。这些技术依赖于荧光、吸收光、反射光或生物发光作为对比的来源。光学成像技术主要包括近红外荧光成像(NIRF)，反射成像和生物发光成像。尽管出现的时间相对较晚，有关光学成像的各种临床研究和基础研究都进展迅速。光学成像的优点是使用简单，图像直观，能同时进行多个标记，适用于从亚细胞层面到组织层面的广泛空间尺度，还能用于生物实验，荧光引导手术和内镜成像。同时，大多数光学造影剂是无毒的，并且相对便宜、通用和灵敏。光学成像可以利用各种不同激发光波长下发出荧光的有机或无机荧光造影剂。早期用于癌症诊断的光学成像基于肿瘤组织内源性荧光的变化。然而，由于难以区分诊断信号成分与背景荧光，不得不开发出外源造影剂，以增强肿瘤组织和正常组织的对比度来进行荧光成像。光学成像所面临的主要问题是难以可靠地将信号和正常组织的背景噪音声区分开，这可能严重影响图像质量。同时组织穿透深度差和空间分辨率低也是光学成像技术需要解决的问题。吲哚菁绿(ICG)是目前临床一线荧光造影剂，最早是用来检查肝脏功能和肝有效血流量的染料药，但目前已经广泛的运用于肝脏手术的术中导航和乳腺癌的淋巴结扫荡。静脉注入体内后，立刻和血浆蛋白结合，随血循环迅速分布于全身血管内，高效率、选择性地被肝细胞摄取，又从肝细胞以游离形式排泄到胆汁中，经胆道入肠，随粪便排出体外。由于排泄快，一般正常人静脉注射20分钟后约有97％从血中排除、不参与体内化学反应、无肠肝循环、无淋巴逆流、不从肾等其他肝外脏器排泄。由于ICG的结构原因，灭菌注射用水是其首选的溶剂，但其水溶液的稳定性欠佳，另外在指导手术的过程中，由于肝硬化等情况，吲哚菁绿会在肝脏中呈现假阳性，降低肝脏切除手术的准确性。
因此，更丰富和全面的诊断信息有利于提升诊断的准确度，而单纯的形态图像难以提供足够丰富的信息。另一方面光学成像技术、PET、单光电子发射计算机断层扫描(SPECT)等灵敏度较高又能在影像之外提供更多信息的影响技术却受制于空间分辨率低的缺陷。虽然同时单独使用多种造影剂能够在每种成像方式中获得更优的造影效果，但是建立双模态造影剂能够有助于确保各个模式的信号的药代动力学均相同，且能进行共定位，还能避免对身体的血液清除机制造成额外压力。设计多模态造影剂时应注意避免所选择的成像模式的功能和优势相互重叠，并注意弥补每种成像方式的弱点，最大限度的发挥协同作用。
发明内容
针对现有技术中存在的不足，本发明提供了一种荧光-磁共振双模态造影剂，所述造影剂具有如下结构：
X-L-Y,
其中：
X具有如下结构：
R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12各自独立的选自H，卤素，OH，NH2,COOH，CONH2，NO2，CN，低烷基，所述低烷基可以被卤素，OH，NH2，COOH，CONH2，SO3H，NO2，CN取代，其中R3与R4，R7与R8也可以各自独立的可以同它们所连接的碳原子环合成苯基或杂环。
其中所述卤素为氟、氯、溴或碘离子。
所述低烷基优选为C1-6烷基，如甲基，乙基，正丙基，异丙基，叔丁基，正丁基，戊基，环丙基，环戊基或环己基。
优选的，所述低烷基为C1-3烷基，如甲基，乙基，正丙基，异丙基。
该双模态造影剂具有良好的磁共振T1加权成像造影能力和活体荧光成像能力，具有高的弛豫率。
优选的，所述X具有如下结构：
其中R9,R10,R11和R12的定义与前文定义相同。
进一步优选的，所述X具有如下结构：
L为链接基团，具有如下结构：
其中：A选自S，N或O，优选的A为N或O。
L1为8-20长度的碳链组成，所述碳链中的碳原子可以被氧原子或氮原子取代；所述碳链中可以含有双键；所述碳链上的氢原子可以被1-5个R13取代，所述R13各自独立的为苄基、羧基，C1-3烷基或者相邻R13可以与它们相连的原子形成环状结构，示例性的如形成
所述碳链上的碳可以进一步被羰基替换，示例性如碳链中含有
进一步优选的，L为如下结构：
其中A的定义与上文相同；
L2的定义与L1相同。
该双模态造影剂具有高的弛豫率、优良的热稳定性，较低的毒副作用，良好的荧光与磁共振信号对应性等优点，可以有效应用于活体细胞和活体的磁共振成像和荧光成像。
进一步优选的，L2为
其中n为8-20，更优选的n为10-15。
本发明提供的荧光-磁共振双模态造影剂是利用磁共振信号实时监控荧光染料在人体组织中分布及代谢情况，经过大量的实验验证，有些链接基团容易分解，会造成两种组分在体内很快分离，影响最后的监控效果，当本发明选择L2为
时，得到的荧光-磁共振双模态造影剂稳定好，能够实现优异的检测效果，预期可以满足临床的需求。
Y为金属螯合物。
优选的，所述金属螯合物与Gd络合形成Gd络合物(Z)。
进一步优选的，所述Gd络合物具有如下结构：
进一步优选的，本发明所述荧光-磁共振双模态造影剂具有如下结构：
另一方面，本发明提供了所述荧光-磁共振双模态造影剂的制备方法，反应方程式如下，
所述方法为式I化合物与式II化合物缩合得到目标化合物III。
其中所述式II化合物由
与氯化钆水合物进行络合得到。
其中R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12，Y，A，L和Z的定义与前文相同。
或者,本发明提供的荧光-磁共振双模态造影剂也可以由式III-1化合物与氯化钆水合物进行络合得到，其反应方程式如下：
进一步的，所述式III-1化合物由式I-2化合物与式II-2缩合制备得到，其反应方程式如下：
其中R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12，A，L2和Y的定义与前文相同。
同时，本发明提供所述荧光-磁共振双模态造影剂的用途，所述用途主要为医用诊断，具体为进行医用磁共振增强成像，测定肝功能，辅助术前规划，手术中荧光导航，通过磁共振图像对内脏荧光分布进行预测，测定肝功能，测定肾功能，监测体内循环情况以及标记细胞，同时可用作体外细胞分析标记物。
本发明的有益效果为：本发明提供的双模态造影剂具有良好的磁共振T1加权成像造影能力和活体荧光成像能力，具有高的弛豫率、优良的热稳定性，较低的毒副作用，良好的荧光与磁共振信号对应性等优点，可以有效应用于活体细胞和活体的磁共振成像和荧光成像，给药6h后仍能够显著增强肝脏及肾脏磁共振信号，显著提高脏器边界分辨率，磁共振型号强度与荧光强度具有较高对应关系，具备临床所需肿瘤诊断及手术导航的磁共振-荧光双模态造影剂的效果。在临床应用中具有巨大的潜能。
附图说明
图1中A为化合物PL-001在小鼠磁共振T1增强成像；图B为T1增强肝肾磁共振图像信号均值柱状图；图C为PL-001给药6h后肝脏及肾脏荧光成像图像，图D为肝肾荧光效率值柱状图。
图2为流式细胞仪测量H22细胞中造影剂入胞速率结果。
图3为造影剂注射前后小鼠肝脏原位瘤磁共振T1增强成像横断位图像，虚线内为肿瘤组织。
图4为肝脏原位瘤小鼠主要组织荧光成像结果。
图5为PL-003HPLC纯度谱图。
具体实施方式
为了更好地理解本发明的技术方案，下面结合具体的实施例对本发明的技术方案做进一步说明，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1：化合物PL-001的制备
反应路线如下：
反应步骤：
1.IR-820(新吲哚菁绿)与1,11-二氨基-3,6,9-三氧杂十一烷以1:1-1:5比例加入DMSO溶液中，以三乙胺作为缚酸剂，20-80℃加热反应2h，沉淀后得到目标产物B01。
2.B01与DOTA-NHS(NBS为N-羟基琥珀酰亚胺)以1:1-1:3比例溶解在DMSO溶液中，加入1-20倍当量的三乙胺，10-40℃反应24h，沉淀后得到目标产物B02。
3.B02与0.5-2倍当量的水合氯化钆在DMSO中10-50℃下反应10h-50h，沉淀后得到目标产物PL-001，收率83％，纯度91％。
4.所得产品溶于纯水中配置为溶液。通过尾静脉注射的方式，分别以5mg/kg及30mg/kg剂量，对ICR小鼠进行给药。并在给药前后，分别对小鼠肝脏及肾脏主要层面进行磁共振T1增强成像(SE序列)。磁共振成像完成后，取出肝脏、肾脏进行荧光成像。所得图像通过ImageJ软件进行分析，结果如图1所示：A为化合物PL-001在小鼠磁共振T1增强成像，肝脏肾脏有显著增强；图B为T1增强肝肾磁共振图像信号均值柱状图；图C为PL-001给药6h后肝脏及肾脏荧光成像图像，肝脏肾脏有明显荧光；图D为肝肾荧光效率值柱状图。由图中可知肝脏肾脏的磁共振增强与荧光成像结果基本一致。
实施例2：化合物PL-002的制备
反应路线：
反应步骤：
1.IR-820与对氧钠苯丙酸钠以1:1-1:5当量溶解于DMSO，20-80℃下反应1-8h，沉淀后得到目标中间体C01；
2.C01与二吡咯烷基(N-琥珀酰亚氨氧基)碳鎓六氟磷酸盐以1:05-1:3当量下溶解于DMSO中，加入1当量N,N-二异丙基乙胺，10-50℃下反应10-30h，沉淀后获得目标中间体C02；
3.N-Boc-1,11-二氨基-3,6,9-三氧杂十一烷与DOTA-NHS以1:1-1:3比例溶解于DMSO中，加入1-3当量三乙胺，室温反应24h，沉淀后得到目标中间体D01；
4.D01加入三氟乙酸与二氯甲烷混合溶液中，0-40℃下反应24h，乙醚沉淀后得到目标中间体D02；
5.D02与氯化钆水合物以1:0.5-1:3当量溶解于水中，室温反应1-5天，过柱提纯后得到中间体D03；
6.D03与C02以1:0.5-1:3当量溶解于DMSO中，加入1-5当量N,N-二异丙基乙胺,0-50℃下反应8h，过柱提纯后得到目标产物PL-002，纯度91.2％，收率55％。
实施例3：化合物PL-003的制备
反应路线：
反应步骤：
N-Boc-1,10-二氨基癸烷与DOTA-NHS以1:1-1:3比例溶解于DMSO中，加入1-3当量三乙胺，室温反应24h，沉淀后得到目标中间体E01；
D01加入三氟乙酸与二氯甲烷混合溶液中，0-40℃下反应24h，乙醚沉淀后得到目标中间体E02；
D02与氯化钆水合物以1:0.5-1:3当量溶解于水中，室温反应1-5天，过柱提纯后得到中间体E03；
D03与C02以1:0.5-1:3当量溶解于DMSO中，加入1-5当量N,N-二异丙基乙胺,0-50℃下反应8h，过柱提纯后得到目标产物PL-003，纯度96.3％，收率51％，其HPLC谱图见图5，其对应的数据如表1：
表1
其HPLC方法如下：流速0.8mL/min,进样量10μL，检测波长254nm，色谱柱XtimateC18Welch 250×4.6mm×3um，洗脱剂A为120mM乙酸按+5mM柠檬酸溶液(pH6.0)，洗脱剂B为乙腈，稀释剂为甲醇，流动相梯度如下：
实施例4：化合物PL-004的制备
反应方程
反应步骤
N-Boc-2,2′-(乙烯二氧)双(乙胺)与DOTA-NHS以1:1-1:3比例溶解于DMSO中，加入1-3当量三乙胺，室温反应24h，沉淀后得到目标中间体F01；
F01加入三氟乙酸与二氯甲烷混合溶液中，0-40℃下反应24h，乙醚沉淀后得到目标中间体F02；
F02与氯化钆水合物以1:0.5-1:3当量溶解于水中，室温反应1-5天，过柱提纯后得到中间体F03；
F03与C02以1:0.5-1:3当量溶解于DMSO中，加入1-5当量N,N-二异丙基乙胺,0-50℃下反应8h，过柱提纯后得到目标产物PL-003，纯度93.3％，收率43％。
实施例5：
反应方程
反应步骤
N1-Boc-N4-N9-二甲基精胺与DOTA-NHS以1:1-1:3比例溶解于DMSO中，加入1-3当量三乙胺，室温反应24h，沉淀后得到目标中间体J01；
J01加入三氟乙酸与二氯甲烷混合溶液中，0-40℃下反应24h，乙醚沉淀后得到目标中间体J02；
J02与氯化钆水合物以1:0.5-1:3当量溶解于水中，室温反应1-5天，过柱提纯后得到中间体J03；
J03与C02以1:0.5-1:3当量溶解于DMSO中，加入1-5当量N,N-二异丙基乙胺,0-50℃下反应8h，过柱提纯后得到目标产物PL-005。
以下表2中实施例6-13获得的化合物为替换反应中间体后按照实施例2的方法制备得到。
表2
制备得到PL-005，PL-008，PL-013后，发现此化合物易溶于高极性有机溶剂(甲醇、N,N-二甲基甲酰胺、二甲亚砜等)，难溶于水(<0.1mg/mL)。
实施例13
造影剂的纵向弛豫率(r1)在0.35T小型核磁共振成像系统中采用IR反应序列测定。在纯水中及牛血清蛋白溶液(1％，w/w)中不同溶媒中造影剂的弛豫率如下表3所示。
表3
实施例14
造影剂水溶液(0.1mg/mL)室温放置，并在不同时间点通过HPLC方法标定其相对含量，测得其稳定性，造影剂稳定性通过如表4。
表4
实施例15
通过小鼠尾静脉给药初步测定了造影剂的最大耐受剂量(MTD)。选择ICR雌鼠(8周龄)每组4只，以25，50，75，100，125，150mg/kg进行尾静脉给药，并连续临床观察一周，结果如表5所示。
表5
实施例16
造影剂在细胞水平的入胞速率由流失细胞仪测定。收集对数生长鼠源肝癌细胞H22均匀铺于12孔板中，每孔细胞数大概为1.5×105，24h贴壁完全后，各孔分别加入PBS、PL-002、PL-003、PL-004以及PL-006,孵育一定时间后，胰酶消化细胞，并用PBS洗2次，最后重悬于0.5mL的PBS溶液中，并用流式细胞仪检测其入胞情况。结果如图2所示，PL-003入胞速度最快。
实施例17
造影剂的肝脏原位瘤磁共振成像使用GE 3.0T磁共振成像系统完成。H22细胞通过肝脏原位注射接种于Balb/c小鼠，通过磁共振观察肝脏情况，成瘤后通过尾静脉注射1mg/mL造影剂溶液(5mL/kg),并在给药后不同时间点对肝脏进行磁共振T1增强成像，结果如图3所示。造影剂注射后能够显著增强肿瘤部位成像效果，其中PL-003整体增强效果较好。
实施例18
肝脏原位瘤小鼠组织荧光由小动物活体成像分析仪(Perkin Elmer)进行观察。磁共振成像后取出小鼠主要脏器通过活体成像仪观察，结果如图4所示。造影剂在肝脏中均有较明显的荧光，主要荧光范围与磁共振成像结果吻合，其中PL-003肿瘤与正常组织有一定区分且荧光强度较好。该图谱表明本发明的造影剂在成像中能够有效提高正常组织与肿瘤组织的区分度，从而有利于辅助术前规划，手术中荧光导航。
Claims (10)
1.一种荧光-磁共振双模态造影剂，所述造影剂具有如下结构：
X-L-Y,
其中：
X具有如下结构：
R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12各自独立的选自H，卤素，OH，NH2,COOH，CONH2，NO2，CN，低烷基，所述低烷基可以被卤素，OH，NH2，COOH，CONH2，SO3H，NO2，CN取代，其中R3与R4，R7与R8也可以各自独立的可以同它们所连接的碳原子环合成苯基或杂环；
L为链接基团，具有如下结构：
A选自S，N或O，优选的A为N或O；
L1为8-20长度的碳链组成，所述碳链中的碳原子可以被氧原子或氮原子取代；所述碳链中可以含有双键；所述碳链上的氢原子可以被1-5个R13取代，所述R13各自独立的为苄基、羧基、C1-3烷基或者相邻R13可以与它们相连的原子形成环状结构，所述碳链中的碳可以进一步被羰基替换；
Y为金属螯合物。
2.根据权利要求1所述的双模态造影剂，其中所述X具有如下结构：
其中R9,R10,R11和R12的定义与权利要求1相同。
3.根据权利要求1所述的双模态造影剂，其中所述X具有如下结构：
4.根据权利要求1所述的双模态造影剂，其中所述L为如下结构：
其中A的定义与权利要求1相同；
L2的定义与L1相同。
5.根据权利要求4所述的双模态造影剂，其中所述L2为
其中n为8-20。
6.根据权利要求1所述的双模态造影剂，其中所述金属螯合物与Gd络合形成Gd络合物。
7.根据权利要求6所述的双模态造影剂，其中所述Gd络合物具有如下结构：
8.根据权利要求1所述的双模态造影剂，选自如下结构：
9.一种荧光-磁共振双模态造影剂的制备方法，为式I化合物与式II化合物缩合得到荧光-磁共振双模态造影剂III，其中所述式II化合物由
与氯化钆水合物进行络合得到，
其中R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12，Y，A，L和Z的定义与权利要求1-8任一项权利要求的定义相同；
或者,由式III-1化合物与氯化钆水合物进行络合得到，
所述式III-1化合物由式I-2化合物与式II-2缩合制备得到，
其中R1,R2,R3,R4,R5,R6,R7,R8，R9,R10,R11和R12，A，L2和Y的定义与权利要求1-8任一项权利要求的定义相同。
10.一种荧光-磁共振双模态造影剂的在制备医用磁共振增强成像，测定肝功能，辅助术前规划，手术中荧光导航，通过磁共振图像对内脏荧光分布进行预测，测定肝功能，测定肾功能，监测体内循环情况以及标记细胞，体外细胞分析标记物等试剂中的用途，所述荧光-磁共振双模态造影剂与权利要求1-8任一项权利要求的定义相同。
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