新的五羟色胺转运蛋白二芳基醚类衍生物配体的合成与体外评价

为开发新的配体作为有潜力的五羟色胺转运蛋白（SERT）显像剂,合成了一系列二芳基醚类衍生物,并对这些化合物进行了表征,测定了对SERT的体外亲和性,其中,化合物2-（2-（（dimethylamino）methyl）-4-fluorophenoxy）-5-bromobenzeneamine（15）和2-（2-（（dimethylamino）-methyl）-4-fluorophenoxy）-5-iodobenzeneamine（16）表现出最高的亲和性,K分别为0.28和0．20nmol·L^-1它们可以用碳-11、氟-18、碘-123或者溴-76进一步标记,进而评价作为SERT显像剂的可能性。而且,构效关系的研究为将来设计新的配体提供了一些有用的信息。     

Nafion修饰电极测定5-羟色胺

５－羟色胺（５－ＨＴ）属于吲哚胺类神经递质［１］,当人在病理状态时５－ＨＴ的量将会发生显著变化,如精神分裂症［２］病人血液中的５－ＨＴ比正常人少,因此,５－ＨＴ的测定对于某些疾病的诊断及病理学的研究具有重要意义．５－ＨＴ的测定方法主要为ＨＰＬＣ法．Ｈ...     

细胞膜色谱法定量分析5-羟色胺受体的别构效应

建立了大鼠纹状体细胞膜色谱法研究5-羟色胺(5-hydroxytryptamine)受体1D亚型(5-HT1D)的别构效应。利用大鼠纹状体制备得到细胞膜色谱固定相,特异性地识别混合对照品中的尼群地平、欧前胡素和藁本内酯。以不同浓度(4.62×10-7~4.62×10-5mol/L)的欧前胡素为竞争剂平衡细胞膜色谱柱,考察流动相浓度的变化对样品保留行为的影响。结果表明,欧前胡素的添加可使藁本内酯与受体作用的平衡解离常数(KD)增大2.06倍,说明欧前胡素结合5-HT1D受体后会影响藁本内酯在受体上的结合强度。在流动相中添加藁本内酯(5.26×10-7~5.26×10-5mol/L),考察欧前胡素保留因子的变化,测得藁本内酯的KD为(4.15±0.12)μmol/L,与文献报道值基本一致。该方法为定量研究受体的别构效应提供了一种全新思路。     

多巴胺和5-羟色胺的毛细管电泳测定

建立了高效毛细管电泳结合柱上紫外检测测定单胺类神经递质多巴胺(dopamine,DA)和5_羟色胺(5_hydroxytryptamine,5_HT)的毛细管电泳方法 ,优化了缓冲液 pH值、浓度、电压等实验参数 ;结果表明 ,在优化的实验条件下 ,多巴胺、3,4_二羟苄胺 (3,4_dihydroxybenzylamine)和5_羟色胺在10min内得到很好的分离 ,检出限分别为2.02×10 -5mol/L,1.01×10 -5mol/L,1.20×10 -5mol/L ;该法简便、快速 ,样品用量少 ,结果准确 ,重现性好     

纳米纤维固相萃取-高效液相色谱法测定血浆中的5-羟色胺

基于纳米纤维的富集作用,建立了血浆中5-羟色胺(5-HT)的柱前衍生高效液相色谱-电化学检测(HPLC-ECD)分析方法.用10%(v/v)高氯酸溶液沉淀血浆蛋白,离心后取上清液,用0.1 mol/L 的四苯硼酸钠溶液调节pH值至8.5,加入衍生剂邻苯二甲醛溶液于30 ℃衍生4 min,经纳米纤维固相萃取柱净化富集后,...     

细胞膜色谱法研究5-羟色胺受体与藁本内酯的亲和作用

建立了大鼠纹状体细胞膜色谱前沿分析法,研究5-羟色胺(5-HT)受体5-HT_1D与藁本内酯的亲和作用。通过大鼠纹状体组织制备得到色谱固定相,利用酶联免疫吸附剂测定法(ELISA)分别测定硅胶吸附前后细胞膜悬液中5-HT的量,求得细胞膜固定相上5-HT受体含量为每克硅胶(40.5±2.3) pg。利用细胞膜色谱与液相色谱的离线联用,特异性地识别混合对照品中的舒马普坦和藁本内酯;以不同浓度(24.2~242 nmol/L)的5-HT_1D受体激动剂舒马普坦为模型药物,连续通过细胞膜色谱柱,记录舒马普坦的突破曲线,测得舒马普坦与受体作用的平衡解离常数(K_D)为389 nmol/L;并将舒马普坦通过不同浓度(37.0~370 nmol/L)的藁本内酯饱和后的细胞膜色谱柱,记录色谱柱饱和前后舒马普坦突破曲线的变化,测得藁本内酯与受体作用的K_D值为4.21 μmol/L。该方法快速、有效,适用于求解存在竞争结合时药物与受体作用的平衡解离常数。     

基于硫化钼及金属有机骨架材料Co-MOF的5-羟色胺电化学传感器的研制

5-羟色胺(5-HT)是人体中枢神经系统的重要神经递质,其含量及功能异常与重度抑郁和自杀行为等多种疾病的发病有关.本文采用AuNPs@MoS2@金属有机骨架材料(Co-MOF)复合材料修饰电极,构建高灵敏、特异性强的电化学传感器检测5-羟色胺(5-HT).实验考察了测试底液、pH、富集电压及时间对传感器响应电流的影响,...     

5-羟色胺在碳纤维微电极上的电化学测定及伏安行为研究

本文研究了5 羟色胺在Na2HPO4 KH2PO4(pH6.0)缓冲溶液中,于自制的碳纤维微电极上的伏安行为。在此缓冲溶液中5 羟色胺有一对氧化还原峰,峰电位分别为0.2V和0.4V。峰电流与5 羟色胺的浓度分别在4.0×10-6～4.0×10-5mol/L和5.0×10-6～5.0×10-5mol/L范围内呈良好的线性关系,检出限分别为4.70×10-6mol/L和1.76×10-6mol/L。同时利用多种电化学方法求出了动力学参数。     

高效液相色谱/电化学检测法测定大鼠下丘脑的组胺和5-羟色胺

采用高效液相电化学检测的方法测定了大鼠下丘脑内组胺和5_羟色胺。色谱柱为NUCLEOSILRC18(250mm×4mm ,10μm) ,流动相 :磷酸二氢钠溶液 (25mmol/L ,内含乙二胺四乙酸二钠0.5mmol/L ,辛烷磺酸钠3mmol/L,pH4.8) -乙腈=100∶14(体积比 ) ,流速0.8mL/min,检测电位0.6V。大鼠下丘脑匀浆液经低温高速离心 ,上清液直接进样测定5_羟色胺 ,另取上清液衍生后进样测定组胺。组胺在0.075～1.8μg/mL ,5_羟色胺在0.0625～1.25μg/mL浓度范围内 ,线性关系良好。组胺测定的日内和日间相对标准偏差分别小于1.0%和11.4 %,5_羟色胺测定的日内和日间相对标准偏差分别小于3.4 %和6.3 %,两者回收率分别为94.1 %～102.3%和72.8 %～89.1 %。正常雄性SD大鼠下丘脑内组胺和5_羟色胺的平均含量分别为0.280±0.029μg/mL和0.224±0.068μg/mL。本法简便、准确、快捷 ,可用于大鼠下丘脑内组胺和5_羟色胺的测定     

Multimodality Imaging Agents with PET as the Fundamental Pillar

Positron emission tomography (PET) provides quantitative information in vivo with ultra‐high sensitivity but is limited by its relatively low spatial resolution. Therefore, PET has been combined with other imaging modalities, and commercial systems such as PET/computed tomography (CT) and PET/magnetic resonance (MR) have become available. Inspired by the emerging field of nanomedicine, many PET‐based multimodality nanoparticle imaging agents have been developed in recent years. This Minireview highlights recent progress in the design of PET‐based multimodality imaging nanoprobes with an aim to overview the major advances and key challenges in this field and substantially improve our knowledge of this fertile research area.     

Synthesis and in vitro evaluation of new diphenyl ether derivatives as serotonin transporter ligands

For the development of new ligands as potential imaging agents for the serotonin transporter (SERT),a series of diphenyl ether derivatives have been synthesized,characterized,and evaluated for their in vitro binding affinities to the SERT. Among the above compounds,2-(2-((dimethylamino)methyl)-4-fluoro-phenoxy)-5-bromobenzenamine (15) and 2-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5-iodobenzene amine (16) show high binding affinities for the SERT with Ki values of 0.28 and 0.20 nmol·L-1,respectively. They can be further labeled with carbon-11,fluorine-18,iodine-123 or bromine-76,and evaluated as useful imaging agents for the SERT. Moreover,the study of the structure-activity relationship (SAR) provides some useful information for the future design of new ligands.     

Cyclodextrin‐Based Bimodal Fluorescence/MRI Contrast Agents: An Efficient Approach to Cellular Imaging

A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the Gd^III complex of a macrocyclic DOTA‐based ligand (GdL) having one aminobenzyl‐phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)_6.9‐F_0.1‐β‐CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of ～22 s^?1 mM ^?1 per Gd^III or ～150 s^?1 mM ^?1 per molecule of the final conjugate (20 MHz, 25 °C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time.     

Redox Properties and in Vivo Magnetic Resonance Imaging of Cyclodextrin-Polynitroxides Contrast Agents

This paper reports the synthesis, characterization and in vivo application of water-soluble supramolecular contrast agents (Mw: 5–5.6 kDa) for MRI obtained from β-cyclodextrin functionalized with different kinds of nitroxide radicals, both with piperidine structure ( CD2 and CD3 ) and with pyrrolidine structure ( CD4 and CD5 ). As to the stability of the radicals in presence of ascorbic acid, CD4 and CD5 have low second order kinetic constants (≤0.05 M⁻¹ s⁻¹) compared to CD2 (3.5 M⁻¹ s⁻¹) and CD3 (0.73 M⁻¹ s⁻¹). Relaxivity (r₁) measurements on compounds CD3 - CD5 were carried out at different magnetic field strength (0.7, 3, 7 and 9.4 T). At 0.7 T, r₁ values comprised between 1.5 mM⁻¹ s⁻¹ and 1.9 mM⁻¹ s⁻¹ were found while a significant reduction was observed at higher fields (r₁≈0.6-0.9 mM⁻¹ s⁻¹ at 9.4 T). Tests in vitro on HEK293 human embryonic kidney cells, L929 mouse fibroblasts and U87 glioblastoma cells indicated that all compounds were non-cytotoxic at concentrations below 1 μmol mL⁻¹. MRI in vivo was carried out at 9.4 T on glioma-bearing rats using the compounds CD3 - CD5 . The experiments showed a good lowering of T₁ relaxation in tumor with a retention of the contrast for at least 60 mins confirming improved stability also in vivo conditions.     

Amphiphilic Lipopeptide Microparticles as Contrast Agents for Medical Ultrasound Imaging

In this study we investigated the utility of complementary amphiphilic lipopeptides as a new membrane formulation suitable for the preparation of gas‐filled microbubbles. Through primarily ion pairing and hydrophobic interactions we rationalized that the stacking of synthetic lipopeptides into the surface of microbubbles would make bubble suspensions useful as ultrasound contrast agents. By mixing charged lipopeptides in propylene glycol/glycerol solutions in the presence of a perfluorocarbon gas followed by vigorous shaking, microbubble suspensions were formed in good yield with a size distribution spanning the range 1–7 × 10^?6 m. The microbubbles were studied in an in vivo model and provided imaging efficacy comparable with conventional ultrasound contrast agents.

Crude sample (before flotation) of Formulation A analyzed at ×40 magnification. The solid bar indicates 10 × 10^?6 m.     

苯酰胺类D2受体显像剂的共平面效应

苯酰胺类化合物是多巴胺Ｄ2受体的拮抗剂,它不仅与Ｄ2受体的亲和力高,而且产生的锥体外副反应极轻,是一类很有应用潜力的抗精神病药物.放射性同位素(123Ｉ等)标记的苯酰胺类化合物可作为多巴胺Ｄ2受体显像剂用于临床诊断疾病.近年来,相继报导了一系列高亲和力的该类化合物,其中,123ＩＩＢＺＭ等已用于临床诊断疾病[1].本文在前文[2]苯酰胺类Ｄ2受体显像剂结构效应的研究基础上,利用ＳＹＢＹＬ6.4软件,研究了该类化合物分子的不同构象以及空间结构与结合活性之间的关系,证实了前文提出的由于分子内氢键形成六元共平面假想Ａ环、Ｂ环等是影响…     

PET心肌灌注显像剂

由于PET在心肌灌注显像方面具有高分辨率、高灵敏度、低组织衰减和心肌血流定量等优势而使得PET心肌灌注显像剂的研究日益受到关注。本文介绍了目前已经应用于临床的PET心肌灌注显像剂的情况,分别综述了 ¹⁸F 标记和其他正电子核素标记的PET心肌灌注显像剂的研究进展,重点讨论了几种亲脂性阳离子类和线粒体复合物Ⅰ(MC-Ⅰ)抑制剂类 ¹⁸F 标记心肌灌注显像剂,特别是近年取得突破性进展的MC-Ⅰ抑制剂类心肌灌注显像剂(如BMS-747158-02和[¹⁸F]FP1OP),介绍了各类PET心肌灌注显像剂的生物性能、心肌摄取机制,对其优缺点进行比较,并对PET心肌灌注显像剂的应用前景进行了展望。     

Nanopharmacological Force Sensing to Reveal Allosteric Coupling in Transporter Binding Sites

Controversy regarding the number and function of ligand binding sites in neurotransmitter/sodium symporters arose from conflicting data in crystal structures and molecular pharmacology. Here, we have designed novel tools for atomic force microscopy that directly measure the interaction forces between the serotonin transporter (SERT) and the S‐ and R‐enantiomers of citalopram on the single molecule level. This approach is based on force spectroscopy, which allows for the extraction of dynamic information under physiological conditions thus inaccessible via X‐ray crystallography. Two distinct populations of characteristic binding strengths of citalopram to SERT were revealed in Na⁺‐containing buffer. In contrast, in Li⁺‐containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT‐G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT when accessed in a physiological context. Competition experiments revealed that these two sites are allosterically coupled and exert reciprocal modulation.     

铀促排化合物的研究进展

本文简要介绍了铀中毒的毒理机制和铀促排化合物的解毒机制,综述了自20世纪70年代以来用于铀促排的化合物,并对其中主要的几大类,如邻苯二酚类、羟基吡啶酮类、膦酸类等进行了分析,展望了铀促排化合物的发展前景.     

纳米级造影剂在肿瘤影像学诊疗中的基础应用进展

肿瘤的早期诊断对其生存率及预后有极大的意义,医学成像造影剂的应用可极大地提高肿瘤的早期诊断水平。通过新兴纳米技术开发无毒、成像能力更强、循环时间更长的纳米级造影剂是目前研究的热点。本文综述了纳米级造影剂在MRI、CT、US、PET和SPECT等生物医学成像技术中,对于肿瘤诊疗的基础应用,并列举了部分研究实例。纳米级造影剂具有广阔的临床应用前景,未来的研究重点将会是开发集诊断、治疗于一体的多功能的纳米平台。