CN114656447A - 一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和应用 - Google Patents
一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和应用。所述近红外荧光、磁共振双模式成像探针分子具有式Ⅰ所示结构。另外,本发明还提供了所述近红外荧光、磁共振Aβ双模式成像探针在脑组织切片荧光标记和活体成像应用。研究结果表明,本发明提供的近红外荧光、磁共振双模式成像探针分子具有荧光发射波长长、光稳定性好、时空分辨率高、水溶性和生物相容性好等诸多优点,能够实现对APP/PS1转基因小鼠脑组织切片中Aβ斑块的精确定位,从而获取关于Aβ斑块分布、形态等高保真、可视化信息。
Description
技术领域
本发明属于精细化工技术领域,具体涉及一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和在生物活体上的双模式成像应用。
背景技术
阿尔茨海默症(AD,俗称老年痴呆症)是一种严重的中枢神经系统变性病。研究表明,大脑中β-淀粉样蛋白(Aβ)斑块被认为是该疾病早期诊断和治疗的重要病理学标志。目前,经FDA批准的、对Aβ斑块检测主要基于单一模式成像技术(荧光成像或正电子发射断层扫描等)。然而,基于这类单模式成像的Aβ探针并不能协同提升检测结果的时间、空间分辨率。因此,发展高性能的Aβ斑块成像剂,特别是将多模式成像优势集成于单一小分子探针中,对阿尔茨海默症的早期精准诊断具有非常重要的意义。
近红外荧光成像技术灵敏度高、成本低,具有高时间分辨率的特点;但是,其空间分辨率往往不足,难以获取高信号穿透深度的成像信号。磁共振成像(MRI) 技术信号穿透深,具有高空间分辨率的特点;然而MRI成像灵敏度往往不足,难以进行信号可激活响应。因此,将近红外荧光、磁共振双模式成像集成于单一小分子探针中,有助于协同提升对Aβ斑块检测的时间、空间分辨率,为Aβ斑块的活体精准成像提供一种标准化的方法。
发明内容
本发明提供了一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针及其制备方法和应用。该类近红外荧光、磁共振成像双功能探针以喹啉腈作为荧光染料母体单元,N,N-二甲基苯胺结构单元作为Aβ斑块结合基团,通过引入噻吩等基团延长染料荧光发射波长,引入含有Gd3+(钆离子)的DOTA环(或 DTPA、NOTA环)作为磁共振成像功能单元。基于以上分子理性设计,使染料具有荧光发射波长长(近红外荧光发射)、光稳定性好、时空分辨率高、水溶性/ 生物相容性好等诸多优点。在荧光成像方面:该染料水相生理环境中并不表现荧光发射,当其与Aβ斑块特异性结合后,染料呈现显著的(90倍,高信噪比)近红外荧光信号增强,在Aβ检测过程中具有高时间分辨率的特点。在MRI成像方面:该染料能够提供稳定的MRI信号,可用于高空间分辨率生物活体成像。更进一步,该类成像剂具有良好的血脑屏障穿透性,能够通过近红外荧光、MRI双模式成像实现对APP/PS1转基因小鼠Aβ斑块的精确定位和长时间示踪。
本发明还提供了上述基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针的制备方法。
本发明的目的通过下述方案实现:
一方面,本发明所述基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其结构为式Ⅰ所示:
式Ⅰ中,R1独立选自:氰基(-CN),羧基(-COOH)和式Ⅱ所示基团(其中曲线标记处为取代位,下同)中的任意一种;
曲线标记处为取代位(下同)。
R2为C1~C4的烃基或烃基磺酸盐;
R3独立选自式Ⅲ~式Ⅵ所示基团(其中曲线标记处为取代位,下同)中的任意一种,其中n为0-1中的整数;
R4独立选择式Ⅶ~式Ⅻ所示基团(其中X表示Br或Cl,曲线标记处为取代位,下同)中的任意一种,其中M为Gd3+、Nd3+、Tm3+、Ln3+、Yb3+、In3+中的任意一种,m为0-1中的整数;
在本发明一个优选的技术方案中:
R1独立选自氰基,羧基或式Ⅱ所示基团的任意一种;
R2为C1~C4的直链或支链烷基,C2~C4的直链或支链炔基,C1-C4的直链烃基磺酸盐;R3为式Ⅲ~式Ⅵ所示基团中的任意一种,n为0-1中的整数;R4为式Ⅶ~式Ⅻ所示基团(其中X表示Br或Cl,下同)所示基团中的任意一种, M为Gd3+、Nd3+、Tm3+、Ln3+、Yb3+、In3+中的任意一种,m为0-1中的整数;
在优选的技术方案中,R1独立选自氰基或式Ⅱ所示基团的任意一种,R2为乙基,和丙磺酸盐;R3为式Ⅴ所示基团,其中n为0;R4为式Ⅶ~式Ⅻ所示基团中的任意一种,M为Gd3+、Nd3+、Tm3+、Ln3+、Yb3+、In3+中的任意一种,m为 0-1中的整数;
更进一步优选的R1独立选自氰基,R2为乙基,R3为式Ⅴ所示基团,其中n为 0;R4为式Ⅹ所示基团,M为Gd3+、Nd3+、Tm3+、Ln3+、Yb3+、In3+中的任意一种,其中m为0;
更进一步优选的R4为式Ⅹ所示基团且M为Gd3+。
本发明另一个目的在于,提供了一类上述基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针的制备方法,其主要步骤包括:由A所示化合物与溴乙酰溴的酰化反应;B所示化合物与DOTA-tBe的取代反应;C所示化合物和5- (N,N-二甲基苯胺)-2-噻吩醛的Knoevenagel缩合反应;D所示化合物的水解反应及其之后的金属络合反应。
具体步骤如下:
第一步:在氩气条件保护下,将A所示化合物和溴乙酰溴置于反应容器中,以DCM作为溶剂常温搅拌反应制得中间化合物B;
第二步:在氩气条件保护下,由B所示化合物和DOTA-tBe置于反应容器中,以CH3CN作为溶剂常温搅拌反应制得中间化合物C;
第三步:在氩气条件保护下,由C所示化合物和5-(N,N-二甲基苯胺)-2-噻吩醛置于反应容器中,以CH3CN作为溶剂加热回流搅拌反应制得中间化合物D;
第四步:在氩气条件保护下,将D所示化合物置于反应容器中,以TFA和 DCM(TFA/DCM,V/V,1:1)作为混合溶剂,常温搅拌反应后,通过旋蒸除去溶剂,干燥得到固体;将固体溶于超纯水中,调节pH至6~7,加入GdCl3水溶液,常温搅拌反应后得到目标化合物E;
其中,式中:
R1独立选自氰基;R2独立选自乙基;R3独立选自式Ⅴ所示基团,n为0。
本发明还提出一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在脑组织切片上作为荧光标记的应用。
本发明还提出一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在活体脑部荧光成像和磁共振成像上的应用。
本发明还提出一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在诊断或治疗阿尔茨海默症的产品上的应用。
研究结果表明,本发明提供的近红外荧光、磁共振双模式成像探针分子具有荧光发射波长长(近红外荧光发射)、光稳定性好、时空分辨率高、水溶性和生物相容性好等诸多优点,能够实现对APP/PS1转基因小鼠脑组织切片中Aβ斑块的精确定位,从而获取关于Aβ斑块分布、形态等高保真、可视化信息。此外,该类探针具有良好的血脑屏障穿透性,基于其高时空分辨率的近红外荧光、磁共振双模式成像性能,成功用于活体检测APP/PS1转基因小鼠脑部中的Aβ斑块。
附图说明
图1.式Ⅰ-1所示化合物(详见实施例1)在四氢呋喃和水混合溶剂中不断增加四氢呋喃的荧光发射光谱图(10-5mol·L-1);
其中,横坐标为波长(nm),纵坐标为荧光强度(a.u.)。
图2.染料Ⅰ-1(浓度为10-6mol·L-1)随着加入不同浓度的Aβ42蛋白纤维(0-10 μM)后荧光光谱的变化;
其中,横坐标为波长(nm),纵坐标为荧光强度(a.u.)。
图3.染料Ⅰ-1水溶液的浓度与弛豫时间的关系曲线
其中,横坐标为染料Ⅰ-1浓度(mmol/L),纵坐标为弛豫时间(ms)。
图4.染料Ⅰ-1细胞毒性表征。
图5.染料Ⅰ-1与商业化染料ThS在APP/PS1转基因鼠同一脑组织切片上的荧光共定位标记图。
其中,图5(A)与(D)为野生型小鼠脑切片图片;图5(B)与(E)分别为市售染料ThS与染料Ⅰ-1染色的APP/PS1转基因小鼠脑切片大脑皮层区域;(C)与 (F)为对APP/PS1小鼠大脑皮层区域染色后放大40倍的图片。
图6.染料Ⅰ-1在野生型小鼠与APP/PS1转基因小鼠上的活体荧光成像应用。
图7.染料Ⅰ-1在野生型小鼠与APP/PS1转基因小鼠上的活体脑部MRI成像应用。
具体实施方式
下面通过实施例对本发明作进一步的阐述,其目的仅在于更好地理解本发明的内容。因此,所举之例并不限制本发明的保护范围:
实施例1
染料Ⅰ-1的合成:
(A-1表示属于A类结构化合物,下同)将A-1所示结构化合物(500mg,2 mmol)和溴乙酰溴(600mg,3mmol)置于100mL圆底烧瓶中,以25mL超干 DCM作为溶剂,室温搅拌2h。反应结束后抽滤,DCM洗三次滤饼后再用水洗三次滤饼,干燥得到土黄色固体产物428mg,产率57.9%。
1H NMR(DMSO-d6,400MHz,ppm)δ:10.81(s,1H,-NH-),9.01(d,J=2.0Hz, 1H,phenyl-H),8.13(q,J=9.6Hz,1H,phenyl-H),8.07(d,J=9.6Hz,1H,phenyl-H), 6.80(s,1H,alkene-H),4.44(q,J=14.0Hz,2H,-NCH2CH3),4.11(s,2H,-CH2Br), 2.65(s,3H,-CH3),1.35(t,J=6.8Hz,3H,-NCH2CH3);Mass spectrometry(ESI-MS, m/z):[M+Na]+calcd.for[C17H15N4OBr+Na]+393.0327;found,393.0324.
将B-1所示结构化合物(428mg,1.16mmol)和DOTA-tBe(540mg,1.06 mmol)置于100mL两口瓶中,以15mL超干CH3CN作为溶剂,室温搅拌24h。反应结束后旋干溶剂,柱层析分离(DCM/MeOH,V/V,99:1),干燥得到黄色固体产物373mg,产率70.2%。
1H NMR(CDCl3,400MHz,ppm)δ:10.67(s,1H,-NH-),9.72(d,J=1.6Hz,1H, phenyl-H),8.05(t,J=9.6Hz,1H,phenyl-H),7.57(d,J=9.2Hz,1H,phenyl-H),6.82 (s,1H,alkene-H),4.30(q,J=14.0Hz,2H,-NCH2CH3),3.31(s,2H,-NCH2Boc),3.27 (s,2H,-NCH2Boc),3.16(s,4H,-NCH2Boc),2.90(s,8H,-NCH2CH2N-),2.80(s,4H, -NCH2CH2N-),2.70(s,4H,-NCH2CH2N-)2.56(s,3H,-CH3),1.48(t,J=7.2Hz,3H, -NCH2CH3),1.48(s,9H,-O(CH3)3),1.39(s,18H,-O(CH3)3);Mass spectrometry(ESI- MS,m/z):[M+Na]+calcd.for[C43H64N8O7+Na]+827.4796;found,827.4780.
将C-1所示结构化合物(373mg,0.463mmol)和5-(N,N-二甲基苯胺)-2-噻吩醛(107mg,0.463mmol)置于50mL的两口瓶,以20mL超干CH3CN作为溶剂,缓慢滴加1mL哌啶,在氩气保护条件下90℃加热回流2h。反应结束后旋干溶剂,柱层析分离(DCM/MeOH,V/V,99:1),干燥得到红黑色固体236mg,产率51.3%。
1H NMR(CDCl3,400MHz,ppm)δ:11.26(s,1H,-NH-),9.54(d,J=2.4Hz,1H, phenyl-H),8.23(dd,J=9.2Hz,1H,phenyl-H),7.50(d,J=8.8Hz,3H,phenyl-H), 7.42(d,J=15.2Hz,1H,alkene-H),7.18(d,J=3.6Hz,1H,thioph-H)7.12(d,J=3.6 Hz,1H,thioph-H),7.08(s,1H,phenyl-H),6.70(m,3H,phenyl-H),4.33(q,J=14.4 Hz,2H,-NCH2CH3),3.71(m,4H,-NCH2Boc),3.00(s,6H,-CH3),2.83(m,8H,- NCH2CH2N-),2.30(m,8H,-NCH2CH2N-),1.88(m,4H,-NCH2Boc),1.50(m,3H,- NCH2CH3),1.50(m,27H,-O(CH3)3);Mass spectrometry(ESI-MS,m/z):[M+Na]+ calcd.for[C56H75N9O7S+Na]+1040.5408;found,1040.5410.
将式D-1所示结构化合物(236mg,0.23mmol)置于50mL单口瓶中,以 TFA和DCM共6mL作为混合溶剂(TFA/DCM,V/V,1:1)室温下反应3h。反应结束后,旋蒸除去TFA得到粗产物。将粗产物溶于5mL超纯水中,用1M氢氧化钠水溶液调节pH至6~7,逐滴滴加GdCl3·6H2O(104mg,0.28mmol)水溶液, 反应过夜。反应结束后旋干溶剂,进行HPLC纯化,得到红黑色固体175mg,产率76.4%。
Mass spectrometry(ESI-MS,m/z):[M+H]+calcd.for[C44H51N9O7S+H]+ 850.3710;found,850.3711;[M+H]+calcd.for[C44H48N9O7SGd+Na]+1027.2520; found,1027.5366.
实施例2
染料Ⅰ-1在聚集态的荧光光谱
取实施例1制备的染料Ⅰ-1溶于分析纯二甲基亚砜中,制成1.0×10-3M的储备液。然后制备四氢呋喃(THF)含量为90%、70%、50%、30%、10%、0%的 THF/H2O混合溶剂2mL。取20μL上述储备液加入到已制备的THF/H2O混合溶剂中,混合均匀后转移至光学石英比色皿(10×10mm)中测试其荧光光谱。如图1所示,以450nm作为激发波长,染料Ⅰ-1的最大发射峰大约位于720nm处位于近红外区域,斯托克斯位移达到270nm;并且染料Ⅰ-1在混合溶剂中聚集导致其荧光增强,具有典型的聚集荧光增强特性。
实施例3
染料Ⅰ-1对Aβ42纤维的光谱响应
取实施例1制备的染料Ⅰ-1溶于分析纯二甲基亚砜中,制成1.0×10-4M的储备液。然后制备PBS缓冲液1.97mL。取20μL上述储备液加入到已制备的PBS 缓冲液中,再加入10μL Aβ42纤维储存液(2×10-4M)。混合液在37℃下孵育 30min,混合均匀后转移至光学石英比色皿(10×10mm)中测试荧光光谱。如图2所示,未加入Aβ42纤维时,染料Ⅰ-1基本没有荧光信号;当加入Aβ42纤维后,以450nm作为激发波长,在近红外区域665nm处出现最大发射峰,荧光强度增加90倍左右,表现出极高的信噪比。
实施例4
染料Ⅰ-1浓度与弛豫时间关系测试
取实施例1制备的染料Ⅰ-1溶于超纯水中,制成1.0×10-3M的储备液。然后稀释成0.01、0.05、0.1、0.2、0.4mmol/L不同浓度的水溶液。取1.5mL上述不同浓度水溶液转移至2mL玻璃管中测试其弛豫时间。如图3所示,随着染料Ⅰ- 1浓度不断上升,弛豫时间不断减小。当浓度达到0.4mmol/L时,弛豫时间降为 180ms,表明染料Ⅰ-1较好的MRI造影功能。
实施例5
染料Ⅰ-1细胞毒性测试
我们采用标准的MTT方法测试聚集诱导发光染料Ⅰ-1的细胞毒性。具体实验步骤如下:首先将HeLa细胞铺到96孔板中,细胞密度为1×104细胞/孔,并在细胞培养箱中培养过夜。不同浓度的染料Ⅰ-1(0-32μM,100μL/孔)分别加入到不同的孔中,培养基稀释的DMSO(0.5%,100μL/孔)作为阴性对照组。细胞在细胞培养箱中培养24h,然后在每孔中加入10μLMTT溶液(5mg/mL)。孵育4小时后,除去96孔板中的液体,并加入DMSO(100μL/孔),最后用酶标仪进行测定。由图4中细胞毒性数据所示,当染料Ⅰ-1的浓度增大到32μM时,细胞存活率大约为90%,表明染料Ⅰ-1的细胞毒性很低。
实施例6
染料Ⅰ-1对APP/PS1转基因小鼠脑组织切片的荧光标记
为了研究染料Ⅰ-1对阿尔茨海默小鼠脑组织切片是否具有荧光标记能力,我们选取APP/PS1转基因小鼠脑组织切片作为切片模型,同时选取商业化市售染料硫黄素S(ThS)作为金标染料。具体实验步骤如下:取实施例1中染料Ⅰ-1储备液或者硫黄素S(ThS)储备液(10mg/mL)在室温条件下滴加到同一脑组织切片上孵育30min(染料Ⅰ-1最终浓度为100μM),接着用40%的乙醇溶液浸泡 2min,洗涤两次,再用去离子水冲洗一次。最后用共聚焦显微镜进行组织切片成像。成像结果如图5所示,发现染料Ⅰ-1能够清楚地对Aβ斑块进行荧光标记,定位结果与市售染料硫黄素S(ThS)标记的相邻切片基本一致。证明了染料Ⅰ-1 能够准确的与Aβ斑块结合;相比于市售染料硫黄素S(ThS),染料Ⅰ-1具有更高的灵敏度和信噪比。
实施例7
染料Ⅰ-1对APP/PS1转基因小鼠活体荧光成像测试
本发明中所有活体即APP/PS1转基因小鼠和C57对照组小鼠均购自南京君科生物工程有限公司,实验用的小鼠均由该公司工作人员饲养在其无菌室中层流通风橱内的无菌鼠笼中,使用高压蒸汽处理过的食物和水进行喂食。
对APP/PS1转基因鼠和对照组野生型小鼠进行一次剂量为2.35mg/kg的Ⅰ-1 的尾静脉注射。注射后,使用IVIS○RSpectrum CT In Vivo Imaging System对两类小鼠进行整体的光学成像,激发波长和接收波长分别为500nm和720nm。成像实验前,对小鼠进行腹腔注射含1.25%三溴乙醇的生理盐水溶液(0.02mL/g)使之麻醉。
如图6所示,尾静脉注射化合物Ⅰ-1后,APP/PS1转基因小鼠的大脑区域出现明显的荧光信号。而对照组野生型小鼠脑部无明显的荧光信号。表明化合物Ⅰ- 1具有很好的血脑屏障穿透性和活体荧光成像特性,可进一步应用于生物活体测试中。
实施例8
染料Ⅰ-1对APP/PS1转基因小鼠活体脑部MRI成像测试
对APP/PS1转基因鼠和对照组野生型小鼠进行一次剂量为5μmol/kg的Ⅰ-1 的尾静脉注射。注射后,使用CG NOVILA7.0T对两类小鼠进行整体的脑部MRI 成像。成像实验前,对小鼠进行含2.5%的异氟烷气体麻醉。
如图7所示,尾静脉注射化合物Ⅰ-1后,APP/PS1转基因小鼠的大脑区域出现明显的MRI信号增强现象,而对照组野生型小鼠脑部无明显的MRI增强现象。表明化合物Ⅰ-1具有很好活体脑部MRI成像特性,可进一步应用于生物活体测试中。
Claims (10)
2.根据权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其特征在于,所述R1为氰基。
3.根据权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其特征在于,所述R2为乙基或正丁基。
4.根据权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其特征在于,所述R3为式Ⅴ所示基团,其中n为0。
5.根据权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其特征在于,所述R4为式Ⅹ所示基团,其中m为0。
6.根据权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针,其特征在于,R1为氰基,R2为乙基,R3为式Ⅴ所示基团,其中n为0,R4为式Ⅹ所示基团,其中m为0,M为Gd3+。
7.一种如权利要求6所述的基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针制备方法,其特征在于,步骤如下:
第一步:在氩气条件保护下,将A所示化合物和溴乙酰溴置于反应容器中,以DCM作为溶剂常温搅拌反应制得中间化合物B;
第二步:在氩气条件保护下,由B所示化合物和DOTA-tBe置于反应容器中,以CH3CN作为溶剂常温搅拌反应制得中间化合物C;
第三步:在氩气条件保护下,由C所示化合物和5-(N,N-二甲基苯胺)-2-噻吩醛置于反应容器中,以CH3CN作为溶剂加热回流搅拌反应制得中间化合物D;
第四步:在氩气条件保护下,将D所示化合物置于反应容器中,以TFA和DCM(TFA/DCM,V/V,1:1)作为混合溶剂,常温搅拌反应后,通过旋蒸除去溶剂,干燥得到固体;将固体溶于超纯水中,调节pH至6~7,加入GdCl3水溶液,常温搅拌反应后得到目标化合物E;
其中,式中:
R1独立选自氰基;R2独立选自乙基;R3独立选自式Ⅴ所示基团,n为0。
8.如权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在脑组织切片上作为荧光标记的应用。
9.如权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在活体脑部荧光成像和磁共振成像上的应用。
10.如权利要求1所述的一类基于高时空分辨率的近红外荧光、磁共振Aβ双模式成像探针在诊断或治疗阿尔茨海默症的产品上的应用。
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