气相色谱法直接测量18F-FDG 中Kryptofix 2.2.2的含量

目的对18F-脱氧葡萄糖制备中用作亲核取代反应相转移催化剂，具有强毒性的氨基聚醚Kryptofix 2.2.2的含量进行直接测量，严格控制在50?g/mL的质控范围内。方法 应用气相色谱仪，选用OV-101型毛细管作为分离柱，利用氢火焰检测器(FID)和氮磷检测器(NPD)检测Kryptofix 2.2.2。 结果 氨基聚醚Kryptofix 2.2.2 在分离柱的保留时间为2.4 min,最低检测水平为0.50 ?g/mL。30批次本中心常规制备的18F-FDG中Kryptofix 2.2.2含量检测值为1.10±0.15?g/ml；10批没有应用AG50型树脂吸附的平均含量检测值为106.0±21.0?g/ml。结论 应用气相色谱法对Kryptofix 2.2.2可以进行快速、高灵敏度检测，其检测灵敏度比TLC法高出50倍；同时可直接测量，排除其他杂质的干扰；该方法可推广应用于18F-FDG和其它18F亲核标记正电子药物的日常质量控制检测。     

超声波法合成2-18F-2-脱氧-β-D-葡萄糖的初步研究

采用超声波法合成2-18F-2-脱氧-β-D-葡萄糖(18F-FDG),以提高其合成效率.实验结果表明:F取代前体2位上亲核反应进行的程度与相转移催化剂和温度有关.无相转移催化剂时,84℃超声反应10min,亲核反应进行了70%;而在10mg的K2.2.2存在下,室温(22℃)下超声反应10min,亲核反应进行了85%,在84℃下超声反应2min,亲核反应进行了95%.同经典方法相比,超声波合成法18F-利用率提高了10%,反应管的放射性吸附下降了5%.超声法合成效率(EOS)为60%,校正校率(EOB)为78%,合成时间为40min.仅用一根C-18纯化柱纯化,超声法合成的18F-FDG中18F-含量低于1%.因此,采用超声波法合成18F-FDG可明显提高合成效率.     

分光光度法测定~(18)FDG中的氨基聚醚(2.2.2)

氨基聚醚(2.2.2)在pH 6.4的柠檬酸-氢氧化钠缓冲液介质中与Pb(Ⅱ°)形成稳定的络合物。此络合物在波长253nm有最大吸收,显色后,其吸光度立即达到最大,显色稳定,重现性好,可以用于紫外分光光度法测定PET(Positron Emission Tomography)药物~(18)FDG产品中的微量氨基聚醚(2.2.2)。标准曲线20～100μg氨基聚醚(2.2.2)与吸光度读数的线性相关系数大于0.999,络合物摩尔吸光系数为6.4×10~3L·mol~(-1)·cm~(-1)。5～10μg氨基聚醚(2.2.2)的测定相对标准偏差为±10％～±15％。方法的检出限为1～2μg。方法步骤简单、快速,20分钟之内可以完成~(18)FDG产品三个平行样品的质量控制分析。     

分光光度计法测量氨基聚醚的专属性

氨基聚醚(K_2.2.2)含量是¹⁸F-FDG质控中的关键指标,比较了两种常用测量K_2.2.2方法的专属性。分别采用分光光度计和半定量TLC 碘显色法测量了14个样品,其中9个阴性样品、2个阳性样品和3个供试品,并与LC-MS/MS测量对比。结果显示：9个阴性样品经分光光度计法测量均为阳性,K_2.2.2的测量结果在6.7～470.0 μg/mL;2个阳性样品结果偏高（53,73 μg/mL）,3个供试品的K_2.2.2含量在14.3~19.2 μg/mL;半定量TLC 碘显色法测量9个阴性样品结果为阴性,2个阳性样品半定量结果与实际一致,3个供试品的K_2.2.2含量低于10 μg/mL;LC-MS/MS法测量的14个样品的结果与半定量TLC 碘显色法的结果一致。以上结果表明,半定量TLC 碘显色法测量K_2.2.2的专属性较好,适用于测量¹⁸F-FDG溶液中K_2.2.2含量。     

国产FDG模块半自动合成~(18)F-氟乙基胆碱

18F-氟乙基胆碱(18F-FECH)是18F-FDG的重要补充,在脑瘤转移和前列腺癌及转移的诊断方面有重要的应用价值。利用国产单次PET-FDG-TI-I CPCU型FDG合成模块,未改变硬件,通过更改试剂与耗材,半自动合成18F-FECH,并在产品收集瓶前增加C18纯化柱,减少K2.2.2杂质的含量。合成时间约30min,放化产率42.0%(未时间校正,n=5),放置6h后放化纯度99.0%,体外稳定性良好;合成时间和产率与国内外模块结果相近。结果表明,在国产单次PET-FDG-TI-I CPCU型FDG模块上可半自动合成18F-FECH,合成效率及放化纯度较高。     

细胞凋亡显像剂~(18)F-ML-10前体合成及放射性标记

~(18)F-2-(5-氟-戊基)-2-甲基丙二酸(~(18)F-ML-10)是一个有潜力的细胞凋亡显像剂。以5-溴-1-戊醇为原料,合成了前体:5-甲基磺酰基戊基-2-甲基丙二酸二乙酯,采用国产MF-2V-IT-1模块,经亲核取代及碱水解,合成了~(18)F-ML-10;粗产品经HPLC纯化及固相萃取,得到~(18)F-ML-10注射液。18 F-ML-10的合成效率为(25.3±4.7)%(n=16,不校正),产品的放射化学纯度大于99%,比活度为740PBq/mol,K2.2.2含量低于10mg/L,有机溶剂乙腈残留量为(0.015±0.01)%(质量分数),无菌、无热原符合要求,产品满足临床研究需求。     

高效液相色谱法测定18F-FDG注射液中氨基聚醚含量

采用高效液相色谱法测定了¹⁸F-FDG注射液中氨基聚醚（K_2.2.2）的含量,并对流动相、流速、检测波长进行了选择,确定检测条件为：V（50 mmol/L乙酸铵）∶V（乙腈）=1∶1为流动相,流速为0.5 mL/min,检测波长210 nm,进样量为10 μL。K_2.2.2在 1～50 mg/L浓度范围内线性良好,线性回归方程：y=265 939.4x+7 490.7,相关系数γ=0.999,回收率为96.0%～100.3%,精密度小于3.5%。本方法回收率较高,精密度较小,样品用量少,可用于¹⁸F-FDG注射液中微量K_2.2.2的测定。     

Synthesis of [^18F]－N－3－fluoropropyl－2β－carbomethoxy－3β－（4－iodophenyl） nortropane（[^18F0－FP－β－CIT

The ligand of N-(3-fluoropropyl)-2β-carbomethoxy-3β(4‘-iodophenyl) nortropane(FP-β-CIT) and mesylate precursor were synthesized by hydrolysis of cocaine,followed by dehydration,esterification,Grignard reaction,N-demethylation,iodination,N-alkylation with 3-bromopropanol and methylsulfonylation,Finally,^18F-FP-β-CIT was prepared by nucleophilic fluorinatioin of the mesylate with K^18F/K2.2.2 (Kryptofix).The labeling yiedl of ^18F-FP-β-CIT is 25%-30%,The total radiochemical yield of this compound ,calculated from the end of bombardment(EOB) with decay correction,is 10%-12% with a synthesis time of 100-110min.The radiochemical purity of ^18F-FP-β-CIT is greater than 90%,and this compound in aqueous solution is also stable for more than 4 hours at room temperature,It is stable enough for for clinical study.     

表皮生长因子受体显像剂~(18)F-FEA-Erlotinib的自动化合成

通过"点击化学"方法尝试埃罗替尼(Erlotinib)的~(18)F标记,探索其全自动放化标记并进行初步评价。使用国产PET-MF-2V-IT-I合成模块,以2-~(18)F-氟叠氮乙烷(~(18)F-FEA)为放射化学反应中间体,通过"点击化学"反应制备~(18)F-FEA-Erlotinib,产物经半制备高效液相色谱(High Performance Liquid Chromatography,HPLC)分离、C-18柱富集,最后经乙醇淋洗即得。~(18)F-FEA-Erlotinib自动化合成时间70 min,总放射化学产率为(54±2)%(n5,衰变校正),放射化学纯度大于99%,放射性比活度高于200 MBq·μmol~(-1),K2.2.2含量低于10 mg·L~(-1),无菌无热原符合要求,体外稳定性好,具有和Erlotinib相似的亲脂性。自动化合成~(18)F-FEA-Erlotinib操作简便,高效可靠,质量控制符合要求,能满足科研及临床用药要求,本工作为进一步研究~(18)F-FEA-Erlotinib靶向表皮生长因子受体(Epithelial Growth Factor Receptor,EGFR)的肿瘤正电子断层扫描(Positron Emission Tomography,PET)显像奠定了良好基础。     

超声波法合成2—^18F—2—脱氧—β—D—葡萄糖的初步研究

采用超声波法合成2-^18F-2-脱氧-β-D-葡萄糖（^18F-FDG）,以提高其合成效率。实验结果表明：F取代前体2位上亲核反应进行的程度与相转移催化剂和温度有关。无相转移催化剂时,84℃超声反应10min,亲核反应进行了70%;而在10mg的K2.2.2存在下,室温（22℃）下超声反应10min,亲核反应进行了85%,在84℃下超声反应2min,亲核反应进行了95%。同经典方法相比,超声波合成法^18F-利用率提高了10%,反应管的放射性吸附下降了5%。超声法合成效率（EOS）为60%,校正校率(EOB）为78%,合成时间为40min。仅用一根C-18纯化柱纯化,超声法合成的^18F-FDG中^18F^-含量低于1%。因此,采用超声波法合成^18F-FDG可明显提高合成效率。     

HPLC-MS/MS检测[18F]FDG中Kryptofix2.2.2的残留量

应用高效液相色谱-电喷雾串联质谱(HPLC-MS/MS)测定[18F]FDG示踪剂中残留的Kryptofix 2.2.2浓度,并进行方法学确证。以乙腈40 mmol/L NH4Ac水溶液(50:50,V/V)为流动相,采用ultimate XB-C18(4.6×150 mm,3μm)色谱柱进行分离,流速为0.85 mL.min–1,通过电喷雾离子化串联质谱,以多反应监测(MRM)方式对[18F]FDG中的K-222残留量进行检测。结果表明,用HPLC-MS/MS法可以在4 min内完成K-222的检测,其线性范围为0.5–120 ng.mL–1,平均回收率在101.3%–106.6%,批内和批间变异均小于9.4%。HPLC-MS/MS方法简单、快速、灵敏,适合于短半衰期[18F]FDG中K-222残留浓度的检测。     

Specificity of the Spectrophotometry for Detecting Aminopolyether K2.2.2 in 18F-FDG

The residue ofK_2.2.2 was one of the key metric in ¹⁸F-FDG quality control. The specificity of the spectrophotometry forK_2.2.2 was compared with others. Methods: The 14 samples were determined for theK_2.2.2 by the spectrophotometry and iodine vapor TLC stain method, respectively. The results were compared with LC-MS/MS. The spectrophotometry showed that the 9 of negative samples were false positive , 2 of positive samples were higher than its actualK_2.2.2 contents, 3 of ¹⁸F-FDG injections contained 14.3-19.2 μg/mL forK_2.2.2. The iodine-vapor TLC stain method showed that 9 of negative samples were negative, 2 of positive samples were the same with itsK_2.2.2 contents, 3 of ¹⁸F-FDG injections were lower than 10 μg/mL withK_2.2.2. The iodine vapor TLC stain results were confirmed by the LC-MS/MS. Results: The specificity of spectrophotometry was poor forK_2.2.2. The iodine-vapor TLC stain was simple and good specificity method forK_2.2.2 in ¹⁸F-FDG injections.     

铀胁迫凤眼莲根部代谢产物内部萃取电喷雾电离质谱分析

凤眼莲（俗名水葫芦）应答铀胁迫代谢组学研究,是理解其对重金属胁迫耐受性和敏感性复杂生命过程的关键。本研究采用内部萃取电喷雾电离质谱（iEESI-MS）方法,在正离子检测模式下,选择甲醇-水（V∶V=1∶1）作萃取剂,实现了在无需复杂前处理的条件下,对铀胁迫下生长的水葫芦根部代谢物的选择性离子化,获得了组织样品在 m/z 50～400范围内的化学指纹谱,通过碰撞诱导解离（CID）实验,鉴定并分析了甘氨酸、天冬酰胺、组氨酸、胆碱、吲哚乙酸、十一醛等具有代表性的代谢产物的变化情况。研究发现,组氨酸含量随铀浓度的增加呈现明显增大的趋势,且在40 μg/mL铀胁迫第10 d时,水葫芦根部出现发黑、腐烂等症状。本方法具有无需复杂样品预处理、操作较简单、分析速度快等优点,为铀胁迫水葫芦代谢物分析提供了新的质谱方法。本研究为铀胁迫水葫芦次生代谢物分子水平物质变化的研究提供了新的思路。     

硅胶表面季铵功能化接枝过程的29SiCP/MSNMR和XPS法研究

本工作采用29SiCP/MSNMR和XPS测试方法对硅胶表面接枝季铵功能基团的过程和机理进行了分析。XPS光谱分析结果表明，硅基季铵化产品的XPS谱中含有Si、O、C、N元素，并出现了以R4N+形式存在的401.26eV结合能峰，表明硅胶表面已被季铵化。TGA-DTA分析其接枝率为 0.46mmol/g，同时，本工作采用29SiCP/MSNMR法对接枝机理进行探索研究，得出了接枝的可能反应途径和产品分子结构。     

电喷雾串联质谱模拟天然单质铀的形成

采用三重四级杆质谱模拟并分析微观含铀分子化学键断裂形成新的物质的过程以探讨单质铀的产生机理。结果表明,含铀分子在质谱中离子化后经碰撞诱导解离可生成U⁺。研究还发现,硝酸铀酰溶液通过电喷雾可形成UO⁺₂(m/z 270)、UO₂OH⁺(m/z 287)、UO₂H₂OOH⁺(m/z 305)、UO₂NO⁺₃(m/z 332)、UO₂(H₂O)₃NO⁺₃(m/z 386)及双聚铀酰离子［(UO₂NO₃H₂O)₂NO₃］⁺(m/z 762),在具有一定动能N₂的碰撞下它们均可产生游离的U⁺。通过模拟实验推测,天然单质铀形成的微观机理为：在漫长地质年代中放射性核素持续衰变产生的能量粒子撞击含铀分子使其化学键断裂生成游离铀离子,在封闭或强还原性等特殊地质条件下形成单质铀并被保存下来。     

Full Automated Synthesis of18F-FDOPA and Preliminary PET/CT Imaging

¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸F-FDOPA) as a dopamine neurotransmitter imaging agent has been widely used for diagnosis and therapy evaluation of Parkinson's disease, brain tumors and neuroendocrine diseases with positron emission tomography (PET) imaging in clinical setting and research. To meet the increasing clinical demand in oncology and neurology, a routine protocol for the automated synthesis of¹⁸F-FDOPA with a disposable cassette system on an imported multifunctional synthesizer was studied and discussed.¹⁸F-FDOPA was automatically synthesized via a multiple-step reaction, including fluorination, reduction, iodization alkylation and hydrolysis, following purification by using a semi-preparative high-performance liquid chromatography (HPLC) system which was built in the multifunctional synthesizer. After HPLC purification, the purified¹⁸F-FDOPA solution was collected and passed through a sterilizing filter into a collection bottle. The final¹⁸F-FDOPA injection was obtained for quality control (QC) determination. The QC indexes of the final products were detected： the injection was colorless and transparent, pH value was at 4 to 5.5, radiochemical purity >98%, radionuclide purity >99%, specific activity >1.9 GBq/μmol, K_2.2.2 content <50 mg/L, methanol content <0.01%, alcohol content <0.01%, dichloromethane content <0.01 mg/L, dimethylformamide content <15 mg/L, bacterial endotoxin test <0.100 EU/mL, sterility test 0 cfu/mL,and abnormal toxicity test was negative. PET/CT imaging of rats was performed by intravenous injection of¹⁸F-FDOPA half an hour after the intraperitoneal injection of carbidopa, PET/CT scan was performed after 100 min post-injection. The imaging of¹⁸F-FDOPA showed symmetry high uptake in the bilateral striatum of normal rats. The decay-corrected radiochemical yield of¹⁸F-FDOPA from the¹⁸F-fluoride was (63.1±3.8)% (n=10) at the end of synthesis (EOS), the radiochemical purity was no less than 98%, and the total radiosynthesis time was within 80 min. The quality control results demonstrated that the quality indexes of the final injection solution met the relevant requirements of radiopharmaceutlcals, which were well-suited for clinical application. An efficient and high reproducible automatic method for the radiosynthesis of¹⁸F-FDOPA with high radiochemical yields and good radiochemical purity is obtained and performed via a multi-step reaction on the multifunctional synthesizer.¹⁸F-FDOPA can be used for animal and human PET imaging.     

Research into keV N irradiated glycine

A set of experimental results obtained concerning glycine irradiated with N⁺ at an energy of 30 keV is obtained. The techniques used to get insight into the induced products are mass spectrometry, infrared spectrometry and ultraviolet visible spectrometry. The main non-volatile stable products obtained have been identified by combined gas chromatography mass spectrometry (GC/MS) and other modern instrumental analysis. The results were compared with those obtained with γ rays and show that more kinds of products are formed in keV ion irradiation. The combination of the implanted ion with glycine and nuclear collisions were thought to be probable processes to form the products. Some possible implications of the results are also suggested.