中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

多巴胺受体显像剂 18F-Fethypride的合成、 放射性标记及生物分布

以香草酸甲酯为原料, 经过7步反应合成了前体化合物(S)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯, 采用NMR和HRMS对其进行了表征; 通过¹⁸F标记合成了新型高亲和力的多巴胺受体显像剂¹⁸F-(S)-N-{(1-乙基2-吡咯烷基)甲基}-3-(3-氟丙基)-4,5-二甲氧基苯甲酰胺(¹⁸F-Fethypride). 该显像剂的合成时间为35 min, 放化产率为(36.8±1.4)%(n=6), 放化纯度经HPLC法检测为99%, TLC法检测为100%, 无菌实验、 鲎试剂检测、 K2.2.2含量检测和急性毒性实验均合格. 纹状体/小脑(Str/Cer)比值90 min达到最高(10.68±0.35), 可作为多巴胺受体显像剂用于诊断神经系统疾病.     

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。     

新型核素~(64)Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究

采用新型核素64Cu标记了含丙烯胺肟[Pn AO(3,3,9,9-Tetramethyl-4,8-diazaundecane-2,10-dione Dioxime)]结构的硝基咪唑类乏氧显像剂Pn AO-1-(2-nitroimidazole)[BMS181321],通过优化反应条件,于室温下反应10 min后即得到高放化纯度和高比活度的标记化合物64Cu-BMS181321.目标产物经放射性高效液相色谱检测验证和体外稳定性实验确认后,通过尾静脉注射到人源胰腺癌(PANC-1细胞系)裸鼠体内,分别于注射显像剂4和8 h后进行小动物正电子发射断层扫描显像(Micro-PET).结果表明,4 h左右肿瘤乏氧区域有良好的放射性浓聚.64Cu-BMS181321的合成及其分子显像研究开创了64Cu标记硝基咪唑类乏氧显像剂进行乏氧显像的先例,经进一步药物临床实验评价后,64Cu-BMS181321有望成为具有良好前景的PET乏氧显像药物.     

多巴胺D3受体显像剂的前体合成及其^19F的标记

自从多巴胺D3受体亚型克隆成功[1]以来,对D3受体功能的研究引起了极大的兴趣.它主要分布于哺乳动物大脑中与认知和情感功能相关的边缘脑区,特别是嗅结节、马列加氏岛和前脑基质的侧坐核隔膜,而且与抗精神病药物具有很高的亲和性,具有特殊的神经药理学意义[2].     

18F标记吲哚苯醌衍生物分子探针的合成及正电子发射型计算机断层显像

基于2-苯基萘型结构,以2-甲基吲哚和四氯苯醌、1-二甲基胺-2-丙炔和碘甲基硼酸频哪醇酯分别作为起始底物,经5步反应合成了一种吲哚苯醌类分子探针的前体。其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)表征。对该前体进行放射性标记,再经高效液相色谱分析纯化,最后将探针注入小鼠体内进行正电子发射型计算机断层显像（PET）。结果表明：探针分子进入小鼠体内后,在膀胱、胆和肠道聚集,随后经肠道和膀胱代谢排出体外。     

正电子发射断层显像剂[18F]FET前体药物的合成

以L-酪氨酸为原料,设计并合成了6个正电子发射断层显像剂[18F]FET前体药物,其中5个未见文献报道,其结构经1H NMR,IR,MS和元素分析表征.     

新型核素~(64)Cu标记D-脱氧葡萄糖及其小动物正电子发射断层扫描显像

为拓展脱氧葡萄糖(DG)在肿瘤代谢显像中的应用,以新型核素64Cu标记葡萄糖胺-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA-DG).通过优化反应条件,于25℃反应30 min后得到高放化纯度和高比活度的标记化合物64Cu-DOTA-DG,标记产物经放射性高效液相色谱(Radio-HPLC)检测.体外稳定性实验结果表明,64Cu-DOTA-DG有良好的稳定性.将64Cu-DOTA-DG通过尾静脉注射入荷瘤肝癌细胞(Hep-G2)裸鼠体内,分别于注射后1和3 h进行小动物正电子发射断层扫描(Micro-PET)显像.结果表明,其在肿瘤部位有所富集.64Cu-DOTA-DG的合成及分子显像研究拓宽了以18F-氟代脱氧葡萄糖为代表的肿瘤代谢类显像剂的应用范围,为新型核素标记肿瘤代谢显像剂提供一种新途径.     

亲核氟源参与的芳环氟-18标记反应研究进展

氟18是用于临床和临床前研究的正电子发射计算机断层扫描(PET)放射性药物中最常用的放射性同位素,至今已发现发展出多种标记方法.亲核性18F氟源由于易于操作且具有高放射性比活度,在氟标记反应中得到广泛应用.同时,引入氟原子可调节药物分子的空间构象和电性,也能影响其极性、亲脂性和解离常数等药物代谢动力学参数.芳香环本身代...     

多巴胺D2受体显像剂125I-DMAIBZM的合成及生物分布实验

为提高苯甲酰胺类衍生物（S）-N-（1-乙基-2-吡咯烷基）甲基-4-氨基-2-甲氧基苯酰胺（ABZM）的入脑量,对其结构进行改造,得到了新的化合物（S）-4-二甲氨基-N-（1-乙基-2-吡咯烷基）甲基-2-甲氧基苯酰胺（DMABZM）.通过Idogen法对DMABZM进行标记得到标记化合物125I-DMAIBZM,标记率为74%,放化纯度达到99%． 体外放射配基结合实验测得DMABZM的IC50为2.9589×10-7 mol?L-1,表明它与能与多巴胺D2受体特异性结合且具有较高的亲和力,在小鼠体内的分布实验中,该标记物纹状体/小脑的比值可达6.5左右,说明了该标记化合物与纹状体的结合有较高的特异性和亲和力．125I-DMAIBZM的脂溶性显著大于125I-AIBZM,入脑量有较大的提高．结论：125I（123I）-DMAIBZM有望用于多巴胺D2受体的显像．     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific binding

Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol-water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand-membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug-lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems.     

Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.     

用于正电子断层扫描成像的68Ga标记PM2.5模拟粒子的制备及其活体示踪

将黑色素纳米颗粒(melanin nanoparticle,MNP)经聚乙二醇(polyethylene glycol,PEG)修饰制备得到PEG-MNP,随后通过与放射性的⁶⁸Ga³⁺离子螯合,高标记产率地制备得到⁶⁸Ga-PEG-MNP,标记产物稳定性良好。进一步将⁶⁸Ga-PEG-MNP通过雾化方式制备得到⁶⁸Ga-PEG-MNP PM_2.5(particulate matter 2.5,size<2.5μm)模拟颗粒,其经雾化小鼠吸入体内后,通过正电子断层扫描(positron emission tomography,PET)成像对小鼠进行全身显影,结果可见雾化的⁶⁸Ga-PEG-MNP PM_2.5模拟颗粒可由气管向肺部双叶区域扩散,并滞留于肺。体内的PET成像结果与离体放射自显影结果高度一致。     

An improved,regioselective synthesis of the radiolabelling precursor for the translocator protein targeting positron emission tomography imaging radiotracer [F]GE-180

[¹⁸F]GE-180 has been demonstrated to be a promising new positron emission tomography radiotracer for targeting translocator protein. PET imaging of TSPO will enable measurement of neuroinflammation and microglia activity in vivo. The synthetic route used in the initial discovery of GE-180, whilst enabling the rapid evaluation of the structure–activity relationships (SAR) in this molecular class, was not high yielding and not suitable for scale-up. Here we present an optimised route towards GE-180 and the radiolabelling precursor of [¹⁸F]GE-180 with significantly improved yields due to a strategy which improves the regioselectivity of the key indole formation step of the synthesis.     

Rapid and efficient purification of positron emission tomography probes by hydrophilic interaction chromatography

A rapid and efficient preparative high-performance liquid chromatographic procedure was established to purify short-lived positron emission tomography radio-probes. This method is based on hydrophilic interaction chromatography utilizing a semi-preparative silica column (10 mm I.D.) and a high volatile organic mobile phase (>90% acetonitrile). In nine different radiopharmaceuticals studied, six compounds could be separated from the unlabeled precursor with good resolution and faster elution than its precursor. These characteristics enabled significant shortening of the separation and evaporation processes in the manufacture of short-lived radiopharmaceuticals. Several ¹¹C-radiopharmaceuticals could be prepared within one half-life of carbon-11 (20.4 min), including radiosynthesis, purification and formulation steps with sufficient radiochemical/chemical purity and high levels of radioactivity/specific radioactivity.