固相萃取合成PET-CT肿瘤探针2-[18F]-2-脱氧-β-D-葡萄糖及其影响因素初探

目的 探讨常见肿瘤显像剂2-[18F]-2-脱氧-β-D-葡萄糖([18F]-FDG)在西门子Explora One化学合成模块上全自动合成方法、质量控制以及影响因素.方法 西门子Eclipse RD回旋加速器生产出[18F-]与以三氟甘露糖为前体进行亲核取代反应合成乙酰化[18F]-FDG,高纯氮气推动,Sep-Pak@C18萃取柱吸附中间体,氢氧化钠水解C-18柱上中间产物,经纯化,灭菌最终得到[18F]-FDG注射液.通过薄层色谱法对合成的产品进行放射化学纯度(RCP)检测,肿瘤患者行[18F]-FDG PET-CT扫描.结果 最终合成产物[18F]-FDG的RCP＞ 95％,20 mg的三氟甘露糖可获得未校正合成效率约为60％.结论 使用ABX[18F]-FDG套件,Explora One化学合成模块实现固相萃取法合成PET显像剂[18F]-FDG,合成时间短,稳定快捷.     

碳-11标记的6-羟基哒嗪酮衍生物在小鼠体内的生物学分布研究

摘要：目的:研究碳-11标记的6-羟基哒嗪酮衍生物[11C]HCC923在小鼠体内和脑内的分布情况。方法:加速器中产生的[11C]CO2通过TRACERlab FX-MeI模块中的两步反应生成[11C]CH3I,然后与前体化合物反应生成放射性示踪剂[11C]HCC923。在快速纯化和制剂后,用尾静脉注射的方式给正常小鼠注射[11C]HCC923,每只注射100～150μCi。然后经PET/CT成像得到影像数据,并分析各个时间点[11C]HCC923在体内重要脏器以及在脑内亚结构脑区的放射性摄取分布。结果:通过[11C]CH3I的11C-甲基化反应成功制备了[11C]HCC923,从加速器开启到制备完成的合成时间为60～80 min,放射化学产率约为12%（未经时间校正）,放射化学纯度大于95%。小鼠PET/CT的影像数据表明,注射[11C]HCC923后在体内主要脏器都有分布,其在肝脏和肾脏中代谢较快,无明显蓄积。[11C]HCC0923能较快地通过血脑屏障达到脑内,在5～10 min后放射性摄取达到最大,并在脑中持续稳定的的结合;对各个脑内亚结构脑区的放射性摄取分析中可看到,[11C]HCC0923在海马和下丘脑中有相对较高的吸收,其中在海马中%ID/cc为7.65,而在大脑皮质,脑干中则分布较少。结论:[11C]HCC923的放射合成方法可靠有效;[11C]HCC923在体内分布和代谢正常,且能快速通过血脑屏障在脑内特异性的分布,其中主要分布在海马内,并能在扫描时间范围内维持一定的平衡,表明其原型化合物HCC0923具有较高的靶向Sigma-1受体的中枢神经系统小分子药物的研发潜力。     

培美曲塞二钠的合成

对碘苯甲酸甲酯与烯丙醇缩合,与硝基甲烷反应得1-硝基-4-(甲氧基羰基苯基)-1-丁烯,继而与2,6-二氨基-4(3H)-嘧啶酮加成,再经Nef反应脱硝基、闭环、水解得4-[2-(2-氨基-4-氧代-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸,最后与L-谷氨酸二乙酯缩合、水解、中和得培美曲塞二钠,总收率1.8%.     

四氢-1，3-噻嗪-2，6-二酮的制备

四氢-1,3-噻嗪-2,6-二酮(1)在合成肽类化合物时应用广泛,例如在合成L-肌肽时,应用1可以简化反应步骤,减少副产物生成,提高收率等。1属硫代环羧酸酐类,具有环羧酸酐特性,可用于合成硫醇、硫代碳酸酯、烯烃、烷烃、S-活     

(S)-3-羟基-γ-丁内酯的合成

(S)-3-羟基-γ-丁内酯(1)是重要的手性源化合物,也是制备降血脂药物阿托伐他汀[1]、神经介质L肉碱[2]、HIV蛋白酶抑制剂氨普那韦(amprenavir)[3]、饱感剂(2S,4S)-2-羟基-4-羟甲基-4-丁内酯[4]、治疗皮肤病药羟基二十碳四烯酸(12-HETE)[5]和抗癌药aplysistatin[6]等的关键中间体.近年来,国外关于1合成的报道较多,国内主要靠进口产品供应.因此,研究工业化合成1的方法具有重要意义.     

β—CIT、β—FP—CIT及其前体nor—β—CIT的合成

2－β－甲酯基－3－β－（4－碘苯基）降托烷（nor－β－CIT）是多巴胺转运蛋白正电子显像剂[^11C]－2－β甲酯基－3－β－（4－碘苯基）托品烷（[^11C]-β-CIT）和[^18F]－N－3氟丙基－2－β－（4－碘苯基）降托烷([^18F]－β－FP－CIT）的前体。本实验以可卡因为原料,经水解、脱水、酯化、格氏化、碘化、脱甲基等步骤合成了nor-β－CIT,总产率为12．9％,并以nor-β-CIT为原料合成了β－CIT和β－FP－CIT,为进一步放射化学合成[^11C]-β－CIT和[^18F]-β-CIT提供了可靠的技术路线。     

洛美曲索的合成

1,1,3,3-四甲氧基丙烷经水解、溴化后与2,4.二氨基-6-羟基嘧啶反应生成吡啶并[2,3-d]嘧啶环衍牛物,经氨基保护、Heck反应、脱硅后与N-(4-碘代苯甲酰基)一L-谷氨酸二乙酯再经Heck反应、氢化和水解制得抗肿瘤药洛美曲索,总收率约15%.     

3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性

目的初步探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-3位苯环侧链中引入二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶抑制活性。方法以取代的苯甲醛和乙酰甘氨酸为初始原料,经Erlenmeyer-Plchl反应、缩合反应、水解反应、缩合反应,生成6-芳甲基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮反应,得到6-芳甲基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;以芳基乙烯为原料,经温和的氧化反应、缩合反应得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮在乙酸中反应得到6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。两条合成路线得到的3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应制备得到10个3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。结果根据前期已筛选化合物的活性数据和总结出的初步构效关系,设计并合成了10个C-3位苯环侧链中含有二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。体外乙酰胆碱酯酶抑制活性筛选表明,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中7个化合物在10μmol.L-1浓度水平抑制活性超过了50%。结论根据体外重组人源AChE(rhAChE)抑制活性的测试结果,发现C-3位苯环侧链中含有二乙胺基团的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物均具有较好的rh-AChE抑制活性。在这一位置的侧链中引入二乙胺基团,可以增强化合物对rhAChE的抑制活性。     

有机文摘

S37-10亚砜类合成新法Chen Y-J等[Tetrahedron Lett,2005,46:4205]硫化物在过氧化钾与三氟化硼·乙醚(原位生成四氟二硼过氧化物)的乙腈溶液中冰浴反应5min氧化生成亚砜类,几乎没有砜生成,酮、烯、醚、羟等基团不受影响,7例收率91%～98%。[蔡正艳摘]S37-11α-羟基-和α-氨基芳基酮的合成Surendra K等[TetrahedronLett,2005,46:4111]芳基环氧乙烷或芳基N-甲苯磺酰基氮丙啶可用硝酸铈铵和NBS在乙腈/水(9∶1)中室温反应4～10h,分别得到α-羟基芳基酮,6例收率86%～94%,或α-氨基芳基酮,10例收率84%～92%。[蔡正艳摘]S37-12腈合成芳族硫代…     

盐酸头孢替安合成路线图解

头孢替安(cefotiam,1),化学名为(6R,7R)-7-[(2-氨基-4-噻唑基)乙酰胺基]-3-[[1-[2-(二甲胺基)乙基]-1H-四唑-5-基]硫代]甲基]-8-氧代-5-硫代-1-氮杂二环[4.2.0]辛2-烯-2-羧酸,是由日本武田公司研发、1981年首次在日本上市的第二代半合成头孢菌素[1].     

“In-loop” carbonylation—A simplified method for carbon-11 labelling of drugs and radioligands

Transition-metal mediated carbonylation with ¹¹C-labelled carbon monoxide ([¹¹C]CO) is a versatile method for introducing ¹¹C (t_1/2 = 20.3 min) into drugs and radioligands for subsequent use in positron emission tomography (PET). The aim of the current study was to perform the ¹¹C-carbonylation reaction on the interior surface of a stainless-steel loop used for high performance liquid chromatography (HPLC). In the experimental setup, cyclotron produced ¹¹C-labelled carbon dioxide ([¹¹C]CO₂) was converted to [¹¹C]CO by reduction over heated Molybdenum and swept into an HPLC loop pre-charged with the appropriate reaction mixture. Following a 5 min reaction, the radiochemical purity (RCP) and the trapping efficiency (TE) of the reaction mixture was determined. After optimization, [¹¹C]N-Benzylbenzamide was obtained in quantitative radiochemical yield (RCY) following a 5 min reaction at room temperature. The methodology was further applied to label [¹¹C]benzoic acid (RCP≥99%, TE>91%), [¹¹C]methyl benzoate (RCP≥99%, TE>93%) and [¹¹C]phthalide (RCP≥99%, TE>88%). A set of pharmaceuticals was finally radiolabelled using non-optimized conditions. Excellent yields were obtained for the histamine-3 receptor radioligand [¹¹C]AZ13198083, the oncology drug [¹¹C]olaparib and the dopamine D2 receptor radioligand [¹¹C]raclopride, whereas a moderate yield was observed for the high-affinity dopamine D2 receptor radioligand [¹¹C]FLB457. The presented “in-loop” process proved efficient for diverse ¹¹C-carbonylations, providing [¹¹C]amides, [¹¹C]esters and [¹¹C]carboxylic acids in moderate to excellent RCYs. Based on the advantages associated with performing the radiolabelling step as an integrated part of the purification system, this methodology may become a valuable addition to the toolbox of methodologies used for ¹¹C-carbonylation of drugs and radioligands for PET.     

表皮生长因子受体正电子显像剂-[~(11)C]PD153035的自动化合成

目的建立全自动化生产正电子放射性示踪药物-[11C]PD153035(表皮生长因子受体酪氨酸激酶抑制剂)的方法,为临床肿瘤检测提供新的手段。方法首先采用全新的气相反应法制备出[11C]CH3I,合成的[11C]CH3I先被吸附浓集,然后由氦气流推动进入反应器与前体在70℃发生反应,反应混合液经半制备HPLC分离纯化后用无菌生理盐水稀释得到[11C]PD153035注射液。结果合成时间从加速器轰击结束开始共28min,放化产率经过衰减校正后为20%,化学纯度大于95%,放化纯度大于99%。产品的无菌及无热原要求均符合规定。结论通过计算机远程控制实现[11C]PD153035注射液的全自动合成,简化了操作步骤,而且保证了生产的可靠性和重现性,可完全满足临床需要。     

Synthesis of the phytohormone [11C]methyl jasmonate via methylation on a C18 Sep Pak™ cartridge

[¹¹C]labeled (±)‐methyl jasmonate was synthesized using a C₁₈ Sep Pak? at ～100°C to sustain a solid‐supported ¹¹C‐methylation reaction of sodium (±)‐jasmonate using [¹¹C]methyl iodide. After reaction, the Sep Pak was rinsed with acetone to elute the labeled product, and the solvent evaporated rendering [¹¹C]‐(±)‐methyl jasmonate at 96% radiochemical purity. The substrate, (±)‐jasmonic acid, was retained on the Sep Pak so further chromatography was unnecessary. Total synthesis time was 25 min from the end of bombardment (EOB) which included 15 min to generate [¹¹C]methyl iodide using the GE Medical Systems PET Trace MeI system, 5 min for reaction and extraction from the cartridge, and 5 min to reformulate the product for plant administration. An overall radiochemical yield (at EOB) of 17±4.3% was obtained by this process, typically producing 10 mCi of purified radiotracer. A specific activity of 0.5 Ci/µmol was achieved using a short 3 min cyclotron beam to produce the starting ¹¹C. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of C‐11 labeled auxin (3‐indolyl[1‐11C]acetic acid) and its derivatives from gramine

3‐Indolylacetic acid (IAA) is the major auxin in higher plants and plays a key role in plant growth and development. We report the rapid radiolabeling of the important plant hormone using carbon‐11 (half life: 20.4 min) enabling in vivo imaging of its distribution and movement in whole plants. 3‐Indolyl[1‐¹¹C]acetic acid was synthesized in 2‐steps: (1) reaction of gramine with [¹¹C]cyanide to give 3‐indolyl[1‐¹¹C]acetonitrile in >99% radiochemical purity; (2) hydrolysis of the intermediate in aqueous sodium hydroxide solution to give 3‐indolyl[1‐¹¹C]acetic acid in >98% radiochemical purity after HPLC purification. The overall nondecay corrected radiochemical yield was 28%, synthesis time was 68 min and specific activity was (0.7 mCi/nmol). Hydrolysis proceeded through the formation of 3‐indolyl[1‐¹¹C]acetamide and by varying the temperature of this step, either C‐11 labeled acid or amide were obtained. This procedure provides unexpectedly high C‐11 incorporation in a short time and using a simple and selective hydrolysis without the need of an indole‐nitrogen protecting group or a typical leaving group. Since 3‐indolylacetonitrile and 3‐indolylacetamide are also intermediates in the biosynthesis of IAA, and also function as auxins, this versatile reaction makes all three of these labeled compounds available for imaging studies in whole plants in vivo. Copyright © 2011 John Wiley & Sons, Ltd.     

正电子放射性示踪剂—[~(11)C]氟马西尼注射剂的质量控制研究

目的研究电子放射性示踪药物—[11C]氟马西尼([11C]Flumazenil)的质量控制方法,保证临床用药安全。方法应用高效液相色谱法(HPLC)对[11C]Flumazenil注射剂的化学纯度和放射化学纯度进行检测,并按药典规定对无菌及细菌内毒素等项检查进行测定。结果[11C]Flumazenil注射剂的化学纯度和放射化学纯度分别大于97%和99%,其它各项检测指标也全部合格。结论[11C]Flumazenil注射液的质量符合药用要求,可满足临床安全使用的要求。     

Corticotropin releasing factor stimulation of protein carboxylmethylation in mouse pituitary tumor cells

A putative role for the protein carboxylmethylase (PCM) enzyme has been suggested in exocytotic secretion. The involvement of 3H-methyl incorporation into protein carboxylmethyl esters during corticotropin releasing factor (CRF)-induced ACTH secretion from AtT-20/D16-16 mouse pituitary cells was investigated. Protein carboxylmethylation and ACTH secretion both increased as a function of extracellular CRF concentration, and both processes were temporally parallel up to 60 min incubation. The less potent [Met(O)21]-CRF also stimulated increases in protein carboxylmethylation and ACTH secretion. The free acid analogue of CRF did not alter either process. A combination of the PCM inhibitors, 3-deazaadenosine and L-homocysteine thiolactone, reduced both CRF-stimulated protein carboxylmethylation and ACTH release. Dexamethasone, known to inhibit ACTH secretion and synthesis, inhibited both CRF-stimulated protein carboxylmethylation and ACTH secretion.     

Radiosynthesis of the diastereomerically pure (E)‐[11C]ABP688

We report an efficient protocol for the radiosynthesis of diastereomerically pure (E)‐[¹¹C]ABP688, a positron emission tomography (PET) tracer for metabotropic glutamate type 5 (mGlu5) receptor imaging. The protocol reliably provides sterile and pyrogen‐free formulation of (E)‐[¹¹C]ABP688 suitable for preclinical and clinical PET imaging with >99% diastereomeric excess (d.e.), >99% overall radiochemical purity (RCP), 14.9 ± 4.3% decay‐corrected radiochemical yield (RCY), and 148.86 ± 79.8 GBq/μmol molar activity in 40 minutes from the end of bombardment.     

Efficient in‐loop synthesis of high specific radioactivity [11C]carfentanil

The synthesis of the precursor for [¹¹C]carfentanil and the precursor labelling with ¹¹C have both been improved. The problem ‘bottleneck’ step in the carfentanil precursor synthesis, due to low chemical yield (14%) of intermediates nitrile into amide conversion, has been solved. Application of a H₂O₂/K₂CO₃/DMSO reaction method significantly increased the yield of this chemical transformation (up to 84%). A simple and straight‐forward synthesis of [¹¹C]carfentanil was achieved by combining in‐loop methylation of the ammonia salt of the precursor by [¹¹C]CH₃I, using tetrabutylammonium hydroxide as a base, with a previously developed product purification procedure using a C2 extraction disc. A decay corrected yield with respect to [¹¹C]CH₃I of [¹¹C]carfentanil was 64±12% (n=6) with the synthesis time of 21 min. The radiochemical purity was >98%. Comparatively high specific radioactivity of [¹¹C]carfentanil [11.2±4.8 Ci/μmol (EOS, n=5)] was partially attributed to the use of [¹¹C]methane target gas for production of carbon‐11 methyl iodide. Copyright © 2003 John Wiley & Sons, Ltd.     

N‐heterocyclic carbenes as ligands in palladium‐mediated [11C]radiolabelling of [11C]amides for positron emission tomography

A model palladium‐mediated carbonylation reaction synthesizing N‐benzylbenzamide from iodobenzene and benzylamine was used to investigate the potential of four N‐heterocyclic carbenes (N,N′‐bis(diisopropylphenyl)‐4,5‐dihydroimidazolinium chloride ( I ), N,N′‐bis(1‐mesityl)‐4,5‐dihydroimidazolinium chloride ( II ), N,N′‐bis(1‐mesityl)imidazolium chloride ( III ) and N,N′‐bis(1‐adamantyl)imidazolium chloride ( IV )) to act as supporting ligands in combination with Pd₂(dba)₃. Their activities were compared with other Pd‐diphosphine complexes after reaction times of 10 and 120 min. Pd₂(dba)₃ and III were the best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [¹¹C]N‐benzylbenzamide in good radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically unreactive and insoluble [¹¹C]CO which was then released and reacted via the Pd‐mediated carbonylation process. Potentially useful side products [¹¹C]N,N′‐dibenzylurea and [¹¹C]benzoic acid were also observed. Increased amounts of [¹¹C]N,N′‐dibenzylurea were yielded when PdCl₂ was the Pd precursor. Reduced yields of [¹¹C]benzoic acid and therefore improved RCP were seen for III /Pd₂(dba)₃ over commonly used dppp/Pd₂(dba)₃ making it more favourable in this case. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 11C‐labeled ubiquinone and ubiquinol via Pd0‐mediated rapid C‐[11C]methylation using [11C]methyl iodide and 39‐demethyl‐39‐(pinacolboryl)ubiquinone

To enable positron emission tomography (PET) imaging of the in vivo kinetics of ubiquinone and ubiquinol, which is referred to as coenzyme Q₁₀, their ¹¹C‐radiolabeled counterparts were synthesized herein. ¹¹C‐Labeled ubiquinone [¹¹C]‐ 1 was realized by Pd‐mediated rapid C‐[¹¹C]methylation of [¹¹C]CH₃I with 39‐demethyl‐39‐(pinacolboryl)ubiquinone, prepared by Ru‐catalyzed olefin metathesis of unradiolabeled ubiquinone with 2‐(pinacolboryl)propene. Subsequent reduction of [¹¹C]‐ 1 using Na₂S₂O₄ yielded ¹¹C‐labeled ubiquinol [¹¹C]‐ 2 . The synthesis time and [¹¹C]CH₃I‐based radiochemical yield of [¹¹C]‐ 1 were within 36 minutes and up to 53%, while those of [¹¹C]‐ 2 were within 38 minutes and up to 39%, respectively. After radiopharmaceutical formulation, the qualities of [¹¹C]‐ 1 and [¹¹C]‐ 2 were confirmed to be applicable for animal PET studies. The analytical values of [¹¹C]‐ 1 and [¹¹C]‐ 2 are as follows: radioactivity of up to 3.5 and 1.4 GBq, molar activity of 21 to 78 and 48 to 76 GBq/μmol, radiochemical purity of greater than 99% and greater than 95%, and chemical purity of greater than 99% and 77%, respectively. The concept behind this radiolabeling procedure is that unradiolabeled natural ubiquinone can be converted to ¹¹C‐radiolabeled ubiquinone and ubiquinol via a pinacolborane‐substituted ubiquinone derivative. Each PET probe was used for molecular imaging using rats to investigate the in vivo kinetics and biodistribution of the coenzyme Q₁₀.