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Development of ^(18)F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

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Neuroscience Bulletin 2014年第5期30卷 777-811页

作者： peter brust Jrg van den Hoff Jrg Steinbach Helmholtz-Zentrum Dresden-Rossendorf Institute of Radiopharmaceutical Cancer ResearchPermoserstrasse 15Leipzig04318Germany

Positron emission tomography （PET） is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically- engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.

关键词： Alzheimer's disease autoradiography blood-brain barrier brain tumor cholinergic system kinetic modeling metabolism molecular imaging neurodegeneration positron emission tomography precursor psychiatric disorder radiotracer sigma receptor

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand:(S)-(+)-and(R)-(-)-[^(18)F]FBFP

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Chinese Chemical Letters 2022年第7期33卷 3543-3548页

作者： Tao Wang Ying Zhang Xiaojun Zhang Leyuan Chen Mingqiang Zheng Jinming Zhang peter brust Winnie Deuther-Conrad Yiyun Huang Hongmei Jia Key Laboratory of Radiopharmaceuticals(Beijing Normal University) Ministry of EducationCollege of ChemistryBeijing Normal UniversityBeijing 100875China Nuclear Medicine Department The First Medical Center of Chinese PLA General HospitalBeijing 100853China Institute of Radiation Medicine Peking Union Medical College&Chinese Academy of Medical SciencesTianjin 300192China Yale PET Center Department of Radiology and Biomedical ImagingYale University School of MedicineNew HavenCT 06520-8048United States Helmholtz-Zentrum Dresden-Rossendorf Institute of Radiopharmaceutical Cancer ResearchDepartment of NeuroradiopharmaceuticalsLeipzig 04318Germany The Lübeck Institute of Experimental Dermatology University Medical Center Schleswig-HolsteinLubeck 23562.Germany

Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging *** pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors were synthesized and *** two enantiomers(S)-1 and(R)-1 exhibited comparable high affinity forσ_(1) receptors and selectivity overσ_(2) *** Ca^(2+) fluorescence assay indicated that(R)-1 behaved as an antagonist and(S)-1 as an agonist forσ_(1) *** ^(18)F-labeled enantiomers(S)-and(R)-[^(18)F]1 were obtained in>99%enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4%±2.6%and molar activity of 86–214 GBq/μ*** ICR mice both(S)-and(R)-[^(18)F]1displayed comparable high brain uptake,brain-to-blood ratio,in vivo stability and binding specificity in the brain and peripheral *** micro-positron emission tomography(PET)imaging studies in rats,(S)-[^(18)F]1 exhibited faster clearance from the brain than(R)-[^(18)F]1,indicating different brain kinetics of the two ***(S)-and(R)-[^(18)F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging theσ_(1) receptors in humans.

关键词： σ_(1)receptor Enantiomer Radiotracer Positron emission tomography Fluorine-18

Discovery and development of brain-penetrant ^(18)F-labeled radioligands for neuroimaging of the sigma-2 receptors

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1406-1415页

作者： Ying Zhang Tao Wang Xiaojun Zhang Winnie Deuther-Conrad Hualong Fu Mengchao Cui Jinming Zhang peter brust Yiyun Huang Hongmei Jia Key Laboratory of Radiopharmaceuticals(Beijing Normal University) Ministry of EducationCollege of ChemistryBeijing Normal UniversityBeijing 100B75China Nuclear Medicine Department Chinese PLA General HospitalBeijing 100853China Helmholtz-Zentrum Dresden-Rossendorf Institute of Radiopharmaceutical Cancer ResearchDepartment of NeuroradiopharmaceuticalsLeipzig 04318Germany PET Center Department of Radiology and Biomedical ImagingYale University School of MedicineCT 06520-8048USA The Lübeck Institute of Experimental Dermatology University Medical Center Schleswig-HolsteinLubeck 23538Germany

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2(σ_(2))receptor *** ligands with high σ_(2) receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities,and evaluated in *** biodistribution studies in male ICR mice,radioligand[18F]9,or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole,was found to display high brain uptake and high brain-to-blood *** of animals with the selective σ_(2) receptor ligand CM398 led to significant reductions in both brain uptake(29%-54%)and brain-to-blood ratio(60%-88%)of the radioligand in a dose-dependent manner,indicating high and saturable specific binding of[18F]9 to σ_(2) receptors in the ***,ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of[18F]9 in the brain that is consistent with the distribution pattern of σ_(2) *** positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for[18F]9 in the rat brain,along with appropriate tissue *** together,results from our current study indicated the novel radioligand[18F]9 as the first highly specific and promising imaging agent for σ_(2) receptors in the brain.

关键词： Indole-based derivatives σ2 receptor Fluorine-18 Positron emission tomography Neuroimaging

^(123)Ⅰ和^(99)Tc^m标记的吲哚类σ_2受体放射性示踪剂的设计、稳定化合物的合成及体外生物评价

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核化学与放射化学 2010年第2期32卷 99-105页

作者：李艳贾红梅 Deuther-Conrad Winnie brust peter Steinbach Joerg 刘伯里放射性药物教育部重点实验室北京师范大学化学学院北京100875 Forschungszentrum Dresden-Rossendorf Institute of Radiopharmacy/Neuroradiopharmaceutical Division04318 LeipzigGermany

设计了123Ⅰ和99Tcm标记的吲哚类σ2受体肿瘤放射性示踪剂,合成了其稳定化合物(Indole-Ⅰ和Indole-MAMA-Re)和标记前体(Indole-MAMA)。体外受体结合分析结果表明,化合物Indole-Ⅰ对σ1和σ2受体的抑制常数Ki值分别为(0.574±0.355)μmo... 详细信息

设计了123Ⅰ和99Tcm标记的吲哚类σ2受体肿瘤放射性示踪剂,合成了其稳定化合物(Indole-Ⅰ和Indole-MAMA-Re)和标记前体(Indole-MAMA)。体外受体结合分析结果表明,化合物Indole-Ⅰ对σ1和σ2受体的抑制常数Ki值分别为(0.574±0.355)μmol/L和(0.162±0.030)μmol/L(n=3),Indole-MAMA-Re对σ1和σ2受体的抑制常数Ki值分别为(3.75±2.22)μmol/L和(7.83±4.87)μmol/L(n=3)。成功制备了99Tcm-Indole-MAMA,纯化后经高效液相色谱法(HPLC)分析其放化纯大于90%。今后可在本文化合物的基础上通过结构优化,设计合成对σ2受体具有高亲和力和选择性的吲哚类SPECT肿瘤显像剂。

关键词：吲哚类配体 σ受体 99Tcm 123Ⅰ

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新的^(99m)Tc标记σ受体肿瘤显像剂

中国科学（B辑） 2005年第6期35卷 499-505页

作者：樊彩云贾红梅 Deuther-Conrad Winnie brust peter Steinbach Jrg 刘伯里北京师范大学化学系放射性药物教育部重点实验室 Institute of Interdisciplinary Isotope Research Permoserstr.1504318 LeipzigGermany

采用整体法设计合成了新的99mTc标记的配合物[N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl)(2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]technetium(Ⅴ)oxide(PPPE-MAMA′-99mTcO)([99mTc]-2)及其相应的铼配合物(PPPE-MAMA′-ReO)(Re-2).竞争结合实验表明Re-2对σ1和σ2受体有中等亲和力,Ki值分别为8.67±0.07和5.71±1.88μmol/L;荷MCF-7人乳癌裸鼠尾静脉注射[99mTc]-2后0.5h,4h,20h采集平面图像,20h时可以看到肿瘤部位有放射性浓集,共同注射[99mTc]-2和抑制剂氟哌啶醇(1mg/kg)后显像,20h时肿瘤部位无明显放射性浓集;体内生物分布结果显示,注射后24h肿瘤中的放射性摄取为0.14%±0.01%ID/g,肿瘤/肌肉比为6.02±0.87.上述结果表明:虽然用整体设计法对前体化合物的结构进行了较大修饰,但得到的99mTc-配合物([99mTc]-2)在肿瘤内仍有一定的浓集,与σ1和σ2受体仍保持一定的亲和力.在此配合物的基础上,对其进行进一步的结构修饰有可能得到对σ受体亲和力更高的肿瘤显像剂.

关键词：肿瘤 σ受体 SPECT ^99mTc

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

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中国科学（B辑） 2008年第2期38卷 143-149页

作者：郭运行陈祥纪贾红梅 DEUTHER-CONRAD Winnie brust peter STEINBACH Jorg VERCOUILLIE Johnny 刘伯里北京师范大学化学系放射性药物教育部重点实验室北京100875 Institute of Interdisciplinary Isotope Research Permoserstr. 15 04318 Leipzig Germany

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-((dimethyl-amino)-methyl)-4-fluorophenoxy)-5-iodobenzeneamine(16)表现出最高的亲和性,Ki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.

关键词：五羟色胺转运蛋白二芳基醚显像剂体外评价

18F标记的苄基哌嗪类σ1受体PET显像剂的合成及其生物评价

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18F标记的苄基哌嗪类σ1受体PET显像剂的合成及其生物评价

99mTc标记的三羰基环戊二烯类σ2受体肿瘤分子探针的合成及生物评价

第十二届全国放射性药物与标记化合物学术交流会

作者：王霞 Deuther-Conrad Winnie brust peter 刘伯里贾红梅放射性药物教育部重点实验室北京师范大学化学学院

σ受体通过其"分子伴侣"性质调节其他受体或离子通道的活性,与精神分裂症、抑郁症、早老性痴呆等中枢神经系统疾病以及药物成瘾、学习记忆等密切相关。此外,σ受体在肿瘤中高度表达。研制对σ受体具有高亲和性和选择性的示踪剂可以为中... 详细信息

σ受体通过其"分子伴侣"性质调节其他受体或离子通道的活性,与精神分裂症、抑郁症、早老性痴呆等中枢神经系统疾病以及药物成瘾、学习记忆等密切相关。此外,σ受体在肿瘤中高度表达。研制对σ受体具有高亲和性和选择性的示踪剂可以为中枢神经系统疾病及脑肿瘤的早期诊断提供灵敏的分子探针。本课题组前期研究工作发现用于F标记的苄基哌嗪类化合物1对σ受体具有高亲和性、高脑摄取值和较好的脑滞留。为了提高化合物在体内的特异性结合,提高其在脑内的清除速率,本文设计合成了类似物6、9a和9b,进行了体外受体配体竞争结合分析,选择性质优良的化合物9a,合成其标记前体,并对其进行F标记及其一系列体内外评价。结果与结论:化合物6、9a和9b的合成路线示于图2,中间体和目标化合物均通过了核磁和质谱的确认。受体配体竞争结合实验结果显示,化合物6和9a对σ受体均具有高亲和性和选择性(6:Kσ=2.84±0.03 nM,Kσ/Kσ=116;9a:Kσ=3.85±1.14 nM,Kσ/Kσ=49.1)。化合物9b对σ受体的亲和性为Kσ=17.7±7.28 nM,Kσ=168±19.1 nM。选择对σ受体具有高亲和性和高选择性的化合物9a,合成了其相应的标记前体,并进行了F标记。HPLC分离后,得到放射化学纯度大于99%的示踪剂[F]9a,标记率为45-55%。其log D=2.62±0.01,说明该示踪剂具有合适的脂溶性,有利于穿过血脑屏障。生物分布实验结果表明,[SF]9a在小鼠脑内初始摄取值较高,为5.94±0.47%ID/g,15 min时脑摄取达最大值(6.39±0.36%ID/g),且在脑内清除相对较快,达到了预期目的。提前5 min注射氟哌啶醇和SA4503,示踪剂在小鼠脑内的摄取值分别降低了60%和72%,表明[[F]9a在小鼠脑内与σ受体特异结合。以上结果表明,示踪剂[[F]9a值得进行进一步的研究。

关键词： σ1受体 18F 苄基哌嗪 PET

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99mTc标记的三羰基环戊二烯类σ2受体肿瘤分子探针的合成及生物评...

第十二届全国放射性药物与标记化合物学术交流会

作者：陈媛媛 Deuther-Conrad Winnie brust peter 刘伯里贾红梅放射性药物教育部重点实验室北京师范大学化学学院

研究表明,σ

关键词： σ2受体肿瘤 CpTc(CO)3

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苄基哌啶类σ受体配体的研究

苄基哌啶类σ受体配体的研究