CN111574438A - 红/近红外AIE探针及其制备方法和在检测Aβ聚集体及其纤维化斑块的应用 - Google Patents
红/近红外AIE探针及其制备方法和在检测Aβ聚集体及其纤维化斑块的应用 Download PDFInfo
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- CN111574438A CN111574438A CN202010489837.2A CN202010489837A CN111574438A CN 111574438 A CN111574438 A CN 111574438A CN 202010489837 A CN202010489837 A CN 202010489837A CN 111574438 A CN111574438 A CN 111574438A
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- NPAWNPCNZAPTKA-UHFFFAOYSA-M sodium;propane-1-sulfonate Chemical compound [Na+].CCCS([O-])(=O)=O NPAWNPCNZAPTKA-UHFFFAOYSA-M 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明属于生物成像技术领域，涉及一种红/近红外AIE探针及其制备方法和在检测Aβ聚集体及其纤维化斑块中的应用，所述探针具有以下通式：
制备方法为将溴取代的芳基乙腈与芳基硼酸进行Suzuki反应，再与直链卤代化合物发生取代或成盐反应，最后与醛基取代的芳香族化合物进行Knoevenagel缩合反应，得到目标化合物。与现有技术相比，本发明所述聚集诱导发光(AIE)探针克服了聚集导致荧光猝灭效应，从而有更高的发光效率和信噪比。并且此探针能够实现对Aβ聚集体高选择性和高灵敏度的检测。更重要的是，此探针能实现对活体内Aβ纤维化斑块的早期成像。
Description
技术领域
本发明涉及荧光探针领域，特别涉及一类新型红/近红外聚集诱导发光荧光探针及其制备方法和在检测Aβ聚集体及其纤维化斑块中的应用。
背景技术
阿尔茨海默症(AD)是一种神经系统退行性疾病，β-淀粉样蛋白(Aβ)的聚集及其形成的纤维化斑块是AD的主要病症之一。因此，在临床上，早期检测Aβ聚集体和纤维化斑块对于诊断和治疗AD患者起到至关重要的作用。荧光检测技术拥有高灵敏度、高选择性及成本低廉等优点，在诊断和治疗阿尔茨海默症方面拥有十分广阔的应用前景。目前市售的检测Aβ聚集体及其纤维化斑块的探针，例如金标准探针硫黄素T(ThT)和刚果红等在活体成像方面还存在明显缺陷：首先这类探针往往拥有良好的水溶性，从而导致探针穿透血脑屏障的能力有限，无法在脑部病灶区域聚集足量的探针剂量；其次这些探针的激发和发射波长较短，因而，其激发光源和发射光难以穿过颅骨，进一步削弱探针的成像效果；再次这些探针均为聚集导致荧光猝灭型(ACQ)探针，多数ACQ探针光稳定性差，不耐光漂白且信噪比低，这就导致了探针的荧光成像寿命短、检测效果有限。因此目前市售的这些探针难以实现Aβ聚集体和纤维化斑块的早期成像和检测。
相较于传统的聚集导致荧光猝灭型(ACQ)探针，聚集诱导发光型(AIE)探针往往拥有良好的光稳定性、高信噪比和耐光漂白等优点，并且由于探针的AIE特性，大大提高了探针的成像效果和荧光成像寿命。但目前已开发的多数AIE探针的发射波长处于相对短波的区域，一方面会影响成像过程中探针的组织穿透性，另一方面生物体的背景荧光易与探针的发射重叠进而影响成像效果。更为重要的是，现有的工作大多只能在体外能实现很好的检测，体内和活体实验结果仍不理想。虽然已有一些红/近红外发光的AIE探针，但目前已经开发的AIE探针的合成原材料价格昂贵，合成步骤繁琐，因此难以开发商用。此外，以Aβ42聚集体及纤维化斑块为例，即使已有少数基于AIE探针的活体成像结果，但却无法实现对Aβ42聚集体及纤维化斑块的早期检测和成像，而早期检测恰恰是诊断和治疗阿尔茨海默症的重中之重。总之，现有的荧光检测体系还无法很好地做到对Aβ聚集体和纤维化斑块的早期检测，因此亟需研发新型的荧光探针来实现对Aβ聚集体和纤维化斑块的早期检测和成像，从而有效地诊断和治疗阿尔茨海默症。
发明内容
本发明的目的是为了克服上述现有技术存在的缺陷而提供一种红/近红外AIE探针及其制备方法，并将其应用于检测Aβ聚集体及其纤维化斑块，实现对Aβ聚集体及纤维化斑块的早期检测和高分辨率及高信噪比成像，且该探针兼具合成简便、原料廉价易得和污染小等优点。
本发明的目的可以通过以下技术方案来实现：一种红/近红外AIE探针，其特征在于，该探针具有以下通式：
X，Y为均为杂原子，包括C、N、O或S；
m、n、k为自然数，且不同时为0；进一步优选地，所述的m为1～3，n为0～5，k为0～5；
R1，R2分别为氢，直链烷基，环烷基，羟基取代烷基，苯基或各类取代芳环；进一步优选地，R1，R2分别为CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2OH、CH2CH2OH、CH2CH2CH2OH、4-CH3OPh或4-NH2Ph；
Ar为芳香环或其相应的取代芳环，包括苯环，吡咯，吡啶，喹啉，咪唑，吡唑，噻唑，噁唑，喹喔啉；进一步优选地，Ar为
R3为离子基团，包括SO3H、SO3 –Na+、COOH、COONa+、PO(OH)2、PO2Na+、PO3 2Na2 +、P+Ph3Br；进一步优选地，R3为SO3 –Na+，COO–Na+，PO3 2–Na2 +。
本发明还提供一种红/近红外AIE探针的制备方法，包括以下步骤：
上述第一步，将溴取代的芳基乙腈与芳基硼酸进行Suzuki反应，
Suzuki反应是在惰性气体保护下，将溴取代的芳基乙腈与芳基硼酸加入钯催化剂的碱性溶液中，于80–120℃回流反应；回流温度优选为85–100℃。溴取代的芳基乙腈与芳基硼酸的用量比为1:1.1～1:1.5
进一步优选地，所述的钯催化剂的碱性溶液中钯催化剂的用量为0.01–0.1当量；惰性气体为氮气。
进一步优选地，所述的钯催化剂为四三苯基膦钯(0)，所述的碱性溶液为以1–2M碳酸钾或碳酸钠水溶液为母液，四氢呋喃，乙醇，甲苯中至少一种溶剂配置(水溶液：有机溶剂体积比为1:3～1:5)的混合溶液；上述第二步，再与卤代烃发生取代或成盐反应；该反应是在惰性气体保护下，反应物在纯溶剂中90–150℃回流反应；卤代烃的加入量为2～5当量；惰性气体为氮气，纯溶剂为乙腈，N,N′-二甲基甲酰胺，二甲亚砜中的一种。
上述第三步，最后与醛基取代的芳香族化合物进行Knoevenagel缩合反应，得到目标化合物。Knoevenagel缩合反应是在惰性气体保护下，加入碱作为催化剂的溶液中室温反应；催化剂用量为0.5–1当量；
惰性气体为氮气，催化剂为氢氧化钾或氢氧化钠，配置催化剂的溶液采用的溶剂为二氧六环，乙醇，N,N′-二甲基甲酰胺，二甲亚砜中至少一种，室温为20–25℃。
本发明还提供一种红/近红外AIE探针在检测Aβ聚集体的应用。
本发明还提供一种红/近红外AIE探针在小鼠体内检测Aβ聚集体和纤维化斑块并成像的应用。
与现有技术相比，本发明具有以下有益效果：
1.探针特点：本发明设计并合成了一类用于早期检测Aβ聚集体以及纤维化斑块的具有红光/近红外发光的AIE探针。从探针结构来说，本发明以苯丙烯腈为结构基元，同时引入强吸电子基团和给电子基团并辅以柔性的离子团，一方面吸电子基(A)和给电子基团(D)能够增强D-π-A效应使探针拥有红光/近红外发光，另一方面柔性离子基团又能使得探针具有一定的水溶性和合适的油水分配系数(LogP)，从而让探针既能在生物体中不会因过早聚集而影响检测和成像效果又能很好的穿过血脑屏障。从探针性能来说，相较于ACQ探针来说，本发明开发得AIE探针因其AIE特性，使得其在检测过程中拥有更低的背景荧光噪声和更高的信噪比和分辨率，且其光稳定性和耐光漂白性亦大大优于ACQ探针。而且，由于其红/近红外发光，也使得探针具有非常优异的穿透颅骨的能力，从而赋予其极佳的活体成像性能，可以实现颅脑中Aβ聚集体和纤维化斑块的早期显影与追踪。
2.本发明提供了能有效获取新型红/近红外光AIE荧光探针的方法，且原料易得、合成简便。本发明中的荧光探针能够高选择性地检测Aβ聚集体，并且细胞毒性小。本发明中的探针实现了对活体小鼠颅内Aβ42纤维化斑块的早期检测和成像，拥有组织穿透性优良和成像信噪比高等优点。
附图说明
图1.制备的聚集诱导发光荧光探针在二甲亚砜溶液中的紫外吸收光谱(10–5mol/L)和荧光发射光谱(10–4mol/L)；
图2.A)相同浓度(10–5mol/L)荧光探针在四氢呋喃含量不断增大的二甲亚砜/四氢呋喃混合溶液中的发射光谱；B)相同浓度(10–5mol/L)荧光探针在不同含量四氢呋喃的二甲亚砜/四氢呋喃混合溶液中的荧光强度与探针在纯二甲亚砜溶液中荧光强度比值变化图；
图3.荧光探针在不同pH环境下的荧光图(10–5mol/L)；
图4.Aβ42聚集体的透射电镜图；
图5.荧光探针(5μM)对不同浓度Aβ42聚集体(0–35μM)响应的荧光工作曲线图；
图6.荧光探针(5μM)与市售ThT(5μM)对相同浓度的(30μM)Aβ42聚集体的信噪比对比图；
图7.荧光探针(5μM)对相同浓度(30μM)的不同生物物种的选择响应柱状图；
图8.逐渐向ThT/Aβ42聚集体复合溶液(c＝15μM，pH＝7.4)中滴加的荧光探针(λex＝455nm，c＝5μM)，荧光探针和ThT(λex＝420nm，c＝5μM)的荧光变化图；
图9.细胞毒性图；
图10.APP/PS1小鼠和5*FAD小鼠活体成像图。
具体实施方式
下面结合附图和实施例对本方明进行详细说明，应当理解，此处所描述的具体实施例仅用以解释本发明，并不限制本发明。下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明采用以下方法制得红/近红外AIE探针：
第一步，在氮气保护下，将溴取代的芳基乙腈与芳基硼酸加入钯催化剂的碱性溶液中，于80–120℃回流反应。
第二步，在氮气保护下，将第一步反应得到的产物加入直链卤代化合物和纯溶剂，90–150℃回流反应；
第三步，在氮气保护下，将第二步反应的产物与醛基取代的芳香族化合物，加入催化剂溶液中，室温反应，得到目标化合物。
溴取代的芳基乙腈、芳基硼酸、卤代烃、醛基取代的芳香族化合物的用量比为化学计量比，以下各实施例中没有特别说明的，反应物的用量比为化学计量比。
实施例1
(Z)-3-(4-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-磺酸钠盐
在氮气保护下，于碳酸钾的四氢呋喃/水混合液中加入1.1–1.5当量4-吡啶硼酸，1当量4-溴苯乙腈和0.01–0.1当量四三苯基膦钯(0)，85–100℃搅拌回流10–12小时，反应结束后，加入水，二氯甲烷萃取三次，蒸除溶剂，硅胶柱柱层析(石油醚：乙酸乙酯)，得第一步的产物。在氮气保护下，将第一步产物和2–5当量3-溴丙烷磺酸钠在乙腈中回流48–96小时，过滤得到固体，然后分别用乙腈和水洗涤得到第二步产物。在氮气保护下，将第二步产物和0.9–1.2当量4-二甲氨基苯甲醛加入到乙醇中，在0.5–1当量氢氧化钠的催化下，室温搅拌6–12小时，过滤得到固体，最后分别用四氢呋喃和水洗涤得到最终产物。
1H NMR(400MHz,DMSO-d6)δ(ppm)：δ9.11(d,J＝7.0Hz,2H),8.57(d,J＝7.0Hz,2H),8.21(d,J＝8.7Hz,2H),8.07(s,1H),7.95(t,J＝9.0Hz,4H),6.86(d,J＝9.1Hz,2H),4.72(t,J＝6.8Hz,2H),3.05(d,J＝5.5Hz,6H),2.46(t,J＝7.2Hz,2H),2.31–2.22(m,2H).
所制得的产品具体结构如下：
实施例2
(Z)-3-(4-(4-(1-氰基-2-(4'-(二甲基氨基)-[1,1'-联苯]-4-基)乙烯基)苯基)吡啶-1-鎓-1-基)丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量4'-(二甲基氨基)-[1,1'-联苯]-4-甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ9.14(d,J＝6.9Hz,2H),8.60(d,J＝6.9Hz,2H),8.31–8.21(m,3H),8.05(dd,J＝13.3,8.6Hz,4H),7.85(d,J＝8.5Hz,2H),7.69(d,J＝8.9Hz,2H),6.84(d,J＝8.9Hz,2H),4.74(t,J＝6.7Hz,2H),2.98(s,6H),2.46(d,J＝7.0Hz,2H),2.29–2.23(m,2H).
所制得的产品具体结构如下：
实施例3
(Z)-3-(4-(4-(1-氰基-2-(5-(4-(二甲基氨基)苯基)噻吩-2-基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-磺酸钠盐
溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量5-(4-(二甲基氨基)苯基)噻吩-2-甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ9.12(d,J＝6.9Hz,2H),8.58(d,J＝6.9Hz,2H),8.49(s,1H),8.23(d,J＝8.7Hz,2H),7.95(d,J＝8.6Hz,2H),7.77(d,J＝4.2Hz,1H),7.61(d,J＝8.9Hz,2H),7.51(t,J＝5.6Hz,1H),6.80(d,J＝9.0Hz,2H),4.72(t,J＝6.9Hz,2H),2.99(s,6H),2.45(d,J＝7.0Hz,3H),2.29–2.23(m,2H).
所制得的产品具体结构如下：
实施例4
(Z)-3-(4-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-羧酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷羧酸钠)醛基取代的芳香族化合物为(0.9～1.2当量4-二甲氨基苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.82–8.75(d,2H),8.19–8.12(m,2H),7.84–7.76(m,2H),7.73(d,J＝11.4Hz,5H),6.82–6.74(m,2H),4.50–4.43(m,2H),3.01(s,6H),2.33–2.20(m,4H).
所制得的产品具体结构如下：
实施例5
(Z)-3-(2,6-二氰基-4-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量2,6-二氰基-4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量4-二甲氨基苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.09(s,2H),7.82–7.77(m,4H),7.74(s,1H),7.73–7.70(m,2H),6.81–6.74(m,2H),4.53(t,J＝4.2Hz,2H),3.01(s,6H),2.76–2.69(m,2H),2.61–2.52(m,2H).
实施例6
(Z)-3-(2,6-三氟甲基-4-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量2,6-二三氟甲基-4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量4-二甲氨基苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.18(s,2H),7.85–7.82(m,2H),7.82–7.78(m,2H),7.74(s,1H),7.73–7.70(m,2H),6.81–6.74(m,2H),4.53(t,J＝4.3Hz,2H),3.01(s,6H),2.73(t,J＝6.1Hz,2H),2.50(tt,J＝6.1,4.2Hz,2H).
实施例7
(Z)-3-(4-(4-(1-氰基-2-(4-(甲基羟乙基氨基)苯基)乙烯基)苯基)吡啶-1-基-1-基)丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量N-甲基羟乙氨基-4-苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.82–8.76(m,2H),8.26–8.20(m,2H),7.75(d,J＝8.3Hz,3H),7.71(s,4H),6.81–6.74(m,2H),4.51(t,J＝4.3Hz,2H),4.18(t,J＝7.2Hz,1H),3.70–3.64(m,2H),3.64–3.55(m,2H),3.05(s,3H),2.71(t,J＝6.1Hz,2H),2.47(tt,J＝6.1,4.2Hz,2H).
实施例8
(Z)-3-(4-(4-(2-(4-(双(4-(二甲基氨基)苯基)氨基)苯基)-1-氰基乙烯基)苯基)吡啶-1-1-基-1-丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈为(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-吡啶硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)醛基取代的芳香族化合物为(0.9～1.2当量4-(二(4-(二甲基氨基)苯基)氨基)苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.82–8.76(m,2H),8.38–8.32(m,2H),7.75(d,J＝8.6Hz,2H),7.74(s,1H),7.74–7.71(m,4H),7.31–7.25(m,2H),7.03–6.96(m,4H),6.84–6.77(m,4H),4.51(t,J＝4.3Hz,2H),3.01(s,12H),2.71(t,J＝6.1Hz,2H),2.47(tt,J＝6.1,4.2Hz,2H).
实施例9
(Z)-3-(6-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)-2-氧代喹喔啉-1(2H)-基)丙烷-1-磺酸钠
原料分别为：溴取代的芳基乙腈(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量喹喔啉酮硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)，醛基取代的芳香族化合物为(0.9～1.2当量4-二甲氨基苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ8.25(s,1H),7.92–7.88(m,2H),7.85(t,J＝1.2Hz,1H),7.82–7.78(m,2H),7.74(s,1H),7.74–7.71(m,2H),7.71(d,J＝1.2Hz,2H),6.81–6.74(m,2H),4.23(t,J＝6.4Hz,2H),3.01(s,6H),2.70(t,J＝6.1Hz,2H),2.07(p,J＝6.2Hz,2H).
实施例10
(Z)-3-(4-(4-(1-氰基-2-(4-(二甲基氨基)苯基)乙烯基)苯基)噻唑-1-基-1-基)丙烷-1-磺酸钠盐
原料分别为：溴取代的芳基乙腈(1当量4-溴苯乙腈)芳基硼酸为(1.1～1.5当量4-异噻唑硼酸)，直链卤代化合物为(2～5当量3-溴丙烷磺酸钠)，醛基取代的芳香族化合物为(0.9～1.2当量4-二甲氨基苯甲醛)
制备方法同实施例1，1H NMR(400MHz,DMSO-d6)δ(ppm)：δ9.30(d,J＝1.5Hz,1H),7.89–7.83(m,2H),7.83–7.77(m,2H),7.74(s,1H),7.72–7.68(m,2H),6.81–6.74(m,2H),4.39(t,J＝4.2Hz,2H),3.01(s,6H),2.71(dd,J＝6.4,5.8Hz,2H),2.59–2.50(m,2H).
实施例11
(1)光物理性能表征(以实施例1制备的探针为例，下同)
用二甲亚砜将探针配制成10–3M的母液，稀释成10–5M的溶液测试紫外吸收光谱，得到探针的最大吸收波长455nm。再将母液稀释成10–5M的溶液测试荧光光谱(激发波长455nm)，得到探针的最大荧光发射波长为720nm，斯托克斯(Stokes)位移达到265nm(见图1)。
取一定量的10–3M的母液，在不断震荡下逐渐加入不同体积比例的四氢呋喃配成10–5M的二甲亚砜/四氢呋喃溶液，再进行荧光光谱测试。荧光强度随着不良溶剂四氢呋喃的比例增大，荧光逐渐加强(见图2)。
(2)pH稳定性测试
取少量的10–3M的母液，用不同pH的PBS溶液配置成10–5M的溶液测试荧光光谱。荧光强度在pH 3–10之间保持稳定，尤其是在人体正常pH范围内(见图3)。
(3)Aβ42纤维的制备
称取0.25mg Aβ42单体溶解于六氟异丙醇中，室温孵育1小时，氮气流干燥除去六氟异丙醇，进一步真空干燥，完成后加入55.4μL二甲亚砜配制成1mM的溶液，再加入221.6μL(pH＝7.4)PBS缓冲液配制成0.2mM的溶液，将溶液在37℃下孵育并持续震荡7天。制得的Aβ42纤维进行透射电镜照相(见图4)。
(4)探针对Aβ42纤维的响应测试
取少量的10–3M的母液，加入PBS缓冲液，再加入Aβ42纤维储备液，保持每次探针浓度为5μM，最后进行荧光光谱测试。在未加入Aβ42纤维时，溶液荧光很弱，当加入Aβ42纤维后，荧光强度显著增强。最高荧光强度是探针本体荧光强度的60倍，很明显，探针的信噪比极高(见图5)。
(6)市售探针ThT与AIE探针的响应对比测试
参照探针检测Aβ42纤维的测试方法，同浓度的市售探针ThT对同浓度的Aβ42纤维的信噪比只有6倍，远小于探针的60倍信噪比(见图6)。
(7)探针不同生物物种的选择性测试
参照探针检测Aβ42纤维的测试方法，同浓度的探针对同浓度不同的底物响应测试结果(见图7)，可以看出探针对Aβ42纤维的选择性非常优秀，尤其是对Aβ42单体的响应是很低的。
(8)市售探针ThT与AIE探针和Aβ42纤维的亲和力测试
先准备ThT(λex＝420nm，c＝5μM)/Aβ42纤维(c＝15μM)复合溶液，再逐渐向复合液中滴加的荧光探针(λex＝455nm，c＝5μM)，随着复合液中ThT的荧光强度逐渐减小，探针的荧光强度逐渐增大，说明探针对Aβ42纤维的亲和力要比ThT强许多(见图8)。
(9)细胞毒性测试
采用标准的CCK-8方法测试探针的细胞毒性。具体实验步骤如下：首先将人乳腺癌细胞系MCF-7铺到96孔板中，细胞密度为5000个细胞/孔，并在细胞培养箱中培养过夜。不同浓度的探针溶液(0–32μM，探针最大浓度的样品含1％的DMSO，200μL/孔)分别加入到不同的孔中，无血清1640培养基(200μL/孔)作为阴性对照组。细胞在细胞培养箱中培养24小时，除去探针溶液，然后在每孔中加入含10μL的CCK-8试剂的新鲜培养基(200μL/孔)。在5％CO2气氛中于孵育3小时后，用酶标仪(Flexstation 3，Molecular Devices)测定450nm处的吸光度(见图9)。细胞毒性数据所示，当探针的浓度增大到32μM时，细胞存活率超过95％，表明探针具有良好的生物相容性。
(10)5*FAD小鼠与野生小鼠活体成像对比
1)分别对2.5月龄的5*FAD小鼠(同月龄野生小鼠的处理方法相同)进行麻醉，头部剃毛之后，温水清洗。
2)对5*FAD转基因小鼠和野生型小鼠进行一次剂量给药400μL的尾静脉注射，给药剂量为2mg/kg。
3)用living image系统进行活体成像，七氟烷麻醉后，拍摄，激发波长和接收波长分别为500nm和620nm，结果见图10A。
(11)APP/PS1小鼠与野生小鼠活体成像对比
1)分别对2月龄，3月龄和4月龄APP/PS1小鼠(同月龄野生小鼠的处理方法相同)进行麻醉，头部剃毛之后，温水清洗。
2)对APP/PS1转基因小鼠和野生型小鼠进行一次剂量给药400μL的尾静脉注射，给药剂量为2mg/kg，结果见图10B。
3)用living image系统进行活体成像，七氟烷麻醉后，拍摄，激发波长和接收波长分别为500nm和620nm。
市售探针ThS对APP/PS1小鼠与野生小鼠活体成像的操作同上，激发波长和接收波长分别为430nm和500nm，结果见图10C。
可以看出，尾静脉注射探针后，4月龄APP/PS1转基因小鼠的大脑区域出现明显的荧光信号，而野生小鼠的信号不明显。同时市售探针ThS的成像效果明显劣于我们的探针。表明我们的探针具有良好穿透血脑屏障能力和活体成像特性，另外探针能对更低龄的APP/PS1小鼠进行较为有效的成像检测，证明本发明的探针能够投入到对AD的早期诊断的应用中。
Claims (10)
1.一种红/近红外AIE探针，其特征在于，该探针具有以下通式：
X，Y均为杂原子，包括C、N、O或S；
m、n、k为自然数，且不同时为0；
R1，R2为氢，直链烷基，环烷基，羟基取代烷基，苯基或各类取代芳环；
Ar为芳香环或其相应的取代芳环，包括苯环，吡咯，吡啶，喹啉，咪唑，吡唑，噻唑，噁唑，喹喔啉；
R3为离子基团，包括SO3H、SO3 –Na+、COOH、COONa+、PO(OH)2、PO2Na+、PO3 2Na2 +、P+Ph3Br。
2.根据权利要求1所述的一种红/近红外AIE探针，其特征在于，所述的m为1～3，n为0～5，k为0～5；
R1，R2可为CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、CH2OH、CH2CH2OH、CH2CH2CH2OH、4-CH3OPh或4-NH2Ph；
Ar为
R3为SO3 –Na+，COO–Na+，PO3 2–Na2 +。
3.一种如权利要求1所述红/近红外AIE探针的制备方法，其特征在于，包括以下步骤：
第一步，将溴取代的芳基乙腈与芳基硼酸进行Suzuki反应，
第二步，再与直链卤代化合物发生取代或成盐反应，
第三步，最后与醛基取代的芳香族化合物进行Knoevenagel缩合反应，得到目标化合物。
4.根据权利要求3所述红/近红外AIE探针的制备方法，其特征在于，第一步Suzuki反应是在惰性气体保护下，将溴取代的芳基乙腈与芳基硼酸加入钯催化剂的碱性溶液中，于80–120℃回流反应；
所述的钯催化剂的碱性溶液中钯催化剂的用量为0.01–0.1当量；惰性气体为氮气。
5.根据权利要求4所述红/近红外AIE探针的制备方法，其特征在于，所述的钯催化剂为四三苯基膦钯(0)，所述的碱性溶液为以1–2M碳酸钾或碳酸钠水溶液为母液，与有机溶剂按照水溶液：有机溶剂的体积比为1:3～1:5配置的混合溶液；回流温度为85–100℃。
6.根据权利要求5所述红/近红外AIE探针的制备方法，其特征在于，所述的有机溶剂为四氢呋喃、乙醇、甲苯中的至少一种。
7.根据权利要求4所述红/近红外AIE探针的制备方法，其特征在于，第二步反应是在惰性气体保护下，反应物在纯溶剂中以90–150℃回流反应；
惰性气体为氮气，纯溶剂为乙腈，N,N′-二甲基甲酰胺，二甲亚砜中的一种。
8.根据权利要求4所述红/近红外AIE探针的制备方法，其特征在于，第三步Knoevenagel缩合反应是在惰性气体保护下，加入碱作为催化剂的溶液中室温反应；
催化剂用量为0.5–1当量；
惰性气体为氮气，催化剂为氢氧化钾或氢氧化钠，配置催化剂的溶液采用的溶剂为二氧六环，乙醇，N,N′-二甲基甲酰胺，二甲亚砜中的一种，室温为20–25℃。
9.一种如权利要求1所述的红/近红外AIE探针在检测Aβ聚集体中的应用。
10.一种如权利要求1所述的红/近红外AIE探针在小鼠体内检测Aβ聚集体和纤维化斑块并成像的应用。
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