雌激素受体PET探针~(18)F-FES的放射化学合成

目的自动化合成雌激素受体正电子发射计算机断层成像(PET)显像用的分子探针16(-[18]氟-17(-雌二醇(18F-FES),为实现在体半定量检测雌激素受体(ER)水平提供影像学手段。方法运用正电子药物合成模块TRACERlab FXFN的合成硬件并导入对应18F-FES合成的控制程序,以3-O-(甲氧甲基)-16,17-O-磺酰基-16-表雌三醇(MMSE)为前体,利用亲核氟化取代和酸性水解两步合成。合成的粗产物通过制备型高效液相色谱柱分离,目的产物的紫外吸收峰值设为280 nm。利用标准品19F-FES结合高效液相色谱法(HPLC)对目的产物进行比对鉴定。结果目的产物18F-FES的合成时间小于60 min,放射化学纯度大于98%,衰减校正后放射化学合成产率(36±5)%;在同一分析条件下18F-FES与19F-FES在HPLC柱的平均保留时间TR1=32.52 min和TR2=33.12 min,两者柱留时间基本吻合。结论成功合成18F-FES;合成效率较高,且分离纯化充分,可直接应用于雌激素受体PET显像的临床研究。     

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.     

前列腺癌显像剂~(18)F-8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯的合成

目的制备前列腺癌显像剂~(18)F-8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯的前体8-乙氧基-2-(4-N,N,N-三甲基氨基苯基)-3-硝基-2H-色烯季胺三氟甲磺酸盐;用前体和放射性核素~(18)F合成~(18)F-8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯。方法以2-羟基-1-乙氧基-3-醛基苯为起始原料,经烯化、环化、磺化、成盐反应得到标记前体8-乙氧基-2-(4-N,N,N-三甲基氨基苯基)-3-硝基-2H-色烯季胺三氟甲磺酸盐;然后与放射性核素~(18)F经亲核氟代反应,得到~(18)F-8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯。标记前体8-乙氧基-2-(4-N,N,N-三甲基氨基苯基)-3-硝基-2H-色烯季胺三氟甲磺酸盐及各步反应中间体的结构均经核磁共振谱和质谱确证。结果与结论成功合成前列腺癌诊断显影剂~(18)F-8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯,标记率为(25.8±2.6)%(n=5,未经衰减校正),TLC测定其放化纯度(RCP)为97.5%,为进一步临床研究奠定了基础。     

非放射性氟代乙酸的氟标记合成反应研究

目的用新工艺实现氟代乙酸的氟标记合成。方法以对硝基苯磺酰氯和羟基乙酸乙酯为原料,合成2-（4-硝基）-苯磺酸酯基乙酸乙酯,以此作为中间体,模拟F-18↑F自动化放化合成的氟化反应条件合成氟乙酸乙酯,对产物进行高效液相色谱-质谱、核磁共振谱（NMR）分析。结果中间体2-（4-硝基）-苯磺酸酯基乙酸乙酯产率可达79.38%,以此作为中间体可以实现非放射性F-氟化反应合成18↑F-氟代乙酸乙酯,HPLC-MS及NMR分析表明其就是目标产物。结论以2-（4-硝基）-苯磺酸酯基乙酸乙酯作为前体进行F-18↑F全自动化氟化反应合成18F-氟代乙酸盐可行。     

抗阿尔茨海默病药物2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的合成

目的:合成2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸。方法:以对三氟甲基氯苯和5-氨基水杨酸为起始原料通过5步反应合成了细胞坏死抑制剂2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸。结果与结论:目标产物结构经1H-NMR,13C-NMR和ESI-MS确证,总产率为37.7%。该合成路线具有原料价廉易得、反应条件温和、收率高、操作简便的特点,适合于工业化生产。     

^18F-FDG放射化纯度的快速测定

用HPLC和TLC两种方法测量了CTI双管法生产的^18F FDG的放射化学纯度。用TLC方法测未水解的酯含量，HPLC测游离的氟离子。采用糖柱作为分离柱，新的流动相：85%的乙睛，流速为2.5ml/min，^18F离子的保留时间为2.6min，^18F FCG为3.5min,^18F-FDG中游离^18F测量可在5min内完成。     

芳基硼酸频哪醇酯的氟19标记方法的研究

目的开发一种高效合成氟标记放射性药物的方法。方法使用4-硝基苯硼酸频哪醇酯为反应底物,探索化合物氟标记的有效方法。考察反应配体、反应溶剂、反应温度和反应时间对4-氟硝基苯收率的影响,并通过1H-NMR、13C-NMR、19F-NMR方法对目标产物的结构进行表征,采用HPLC法对反应条件进行定量评价。结果确定了芳基硼酸频哪醇酯类化合物的氟-19标记的最佳反应条件:以3-溴咪唑并[1,2-b]哒嗪为最优配体,在100℃反应10 min即可得到目标化合物。在自动合成仪上重现了最优条件,并用此方法成功合成了11β-羟化酶显像剂美托咪酯。结论本方法为氟-18标记芳基硼酸频哪醇酯类放射性药物前体提供重要合成依据。     

2-三氟甲基噻吨-9-酮合成工艺的改进

目的 改进2-三氟甲基噻吨-9-酮的合成工艺.方法 以邻氨基苯甲酸为原料,经重氮化、还原、偶合和环合四步反应制备2-三氟甲基噻吨-9-酮.结果 与结论通过改进合成2-三氟甲基噻吨-9-酮的投料方法和后处理方法,使反应产率由36.8%提高到48%.     

7,8-二氟-6,11-二苯并[b,e]硫杂艹卓-11-醇的合成工艺研究

目的优化巴洛沙韦酯的关键中间体7,8-二氟-6,11-二苯并[b,e]硫杂艹卓-11-醇的合成工艺。方法以3,4-二氟-2-甲基苯甲酸为原料,经酯化、溴代、取代、水解、环合、还原反应得到7,8-二氟-6,11-二苯并[b,e]硫杂艹卓-11-醇。结果与结论目标产物的结构经质谱、核磁共振氢谱确证,总收率为60.93%(以3,4-二氟-2-甲基苯甲酸计),纯度为99.52%(HPLC法)。该工艺具备原料易得、操作简便、反应条件温和、生产成本低等优点,更具应用价值。     

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。     

A concisely automated synthesis of TSPO radiotracer [18F]FDPA based on spirocyclic iodonium ylide method and validation for human use

Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([¹⁸F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [¹⁸F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [¹⁸F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [¹⁸F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [¹⁸F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.     

Fine‐tuning of the automated [18F]PSMA‐1007 radiosynthesis

Radiolabeled prostate‐specific membrane antigen (PSMA) targeting PET‐tracers have become desirable radiopharmaceuticals for the imaging of prostate cancer (PC). Recently, the PET radiotracer [¹⁸F]PSMA‐1007 was introduced as an alternative to [⁶⁸Ga]Ga‐PSMA‐11, for staging and diagnosing biochemically recurrent PC. We incorporated a one‐step procedure for [¹⁸F]PSMA‐1007 radiosynthesis, using both Synthra RNplus and GE TRACERlab FxFN automated modules, in accordance with the recently described radiolabeling procedure. Although the adapted [¹⁸F]PSMA‐1007 synthesis resulted in repeatable radiochemical yields (55 ± 5%, NDC), suboptimal radiochemical purities of 87 ± 8% were obtained using both modules. As described here, modifications made to the radiolabeling and the solid‐phase extraction purification steps reduced synthesis time to 32 minutes and improved radiochemical purity to 96.10%, using both modules, without shearing the radiochemical yield.     

Automated radiosynthesis of the adenosine A2A receptor-targeting radiotracer [18F]FLUDA

[¹⁸F] FLUDA is a selective radiotracer for in vivo imaging of the adenosine A_2A receptor (A_2AR) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [¹⁸F] FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [¹⁸F] FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69–333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [¹⁸F] FLUDA.     

Automated one‐step radiosynthesis of the CB1 receptor imaging agent [18F]MK‐9470

The fluorine‐18‐labeled positron emission tomography (PET) radiotracer [¹⁸F]MK‐9470 is a selective, high affinity inverse agonist that has been used to image the cannabinoid receptor type 1 in human brain in healthy and disease states. This report describes a simplified, one‐step [¹⁸F]radiofluorination approach using a GE TRACERlab FX_FN module for the routine production of this tracer. The one‐step synthesis, by [¹⁸F]fluoride displacement of a primary tosylate precursor, gives a six‐fold increase in yield over the previous two‐step method employing O‐alkylation of a phenol precursor with 1,2‐[¹⁸F]fluorobromoethane. The average radiochemical yield of [¹⁸F]MK‐9470 using the one‐step method was 30.3 ± 11.7% (n = 12), with specific activity in excess of 6 Ci/µmol and radiochemical purity of 97.2 ± 1.5% (n = 12), in less than 60 min. This simplified, high yielding, automated process was validated for routine GMP production of [¹⁸F]MK‐9470 for clinical studies.     

心脏神经受体显像剂11C标记羟基麻黄素合成方法优化

目的：建立简便实用的正电子放射性示踪药物11C标记的羟基麻黄素（11C-mHED）自动化生产的方法,满足临床诊断需要.方法：首先使用加速器通过14N（p,α）11C核反应来生产11C-CO2,然后使用TRACERlab FXc合成模块将11C-CO2还原为11C-CH4,进一步反应生成11C-CH3I,以此作为甲基化试剂,与间羟胺前体反应得到11C-mHED的混合液,经HPLC进行纯化并用0.9%氯化钠溶液稀释,通过0.22 μm的微孔无菌滤膜过滤得到所需的注射液.结果：合成时间从加速器轰击结束开始共33 min,放化产率经过衰减校正后为12%±1%（n=5）,化学纯度大于97%,放射化学纯度大于99%.产品的无菌及无热原要求均符合规定.结论：通过对比不同文献的方法和修改多个反应参数,简化了生产流程,节省了合成时间,实现了11C-mHED注射液的计算机远程控制全自动生产,保证了生产的可行性和重现性,可完全满足临床需要.     

A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [18F]‐THK‐5351

The radiotracer, [¹⁸F]‐THK‐5351, is a highly selective and high‐binding affinity PET imaging agent for aggregates of hyper‐phosphorylated tau protein. Our report is a simplified 1‐pot, 2‐step radiosynthesis of [¹⁸F]‐THK‐5351. This report is broadly applicable for routine clinical production and multi‐center trials on account of favorable half‐life of flourine‐18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FX_FN. First, the O‐THP protected tosyl precursor underwent nucleophilic fluorinating reaction with potassium cryptand fluoride ([¹⁸F] fluoride (K[¹⁸F]/K₂₂₂)) in Dimethyl sulfoxide at 110°C for 10 minutes followed by O‐THP removal by using diluted hydrochloric acid (HCl) at same temperature. [¹⁸F]‐THK‐5351 was purified via semi‐preparative high‐performance liquid chromatography and formulated by using 10% EtOH, United States Pharmacopeia (USP) in 0.9% sodium chloride for injection, USP and an uncorrected radiochemical yield of 21 ± 3.5%, with a specific activity of 153.11 ± 25.9 GBq/μmol (4138 ± 700 mCi/μmol) at the end of synthesis (63 minutes; n  = 3).     

A simple and rapid automated radiosynthesis of [18F]fluoroacetate

Two fully automated synthetic procedures of [¹⁸F]fluoroacetate ([¹⁸F]FAC) have been developed using a modified commercial TRACERlab FX_FN synthesizer. One was a two‐step one‐pot procedure, consisting of nucleophilic [¹⁸F]fluorination of benzyl‐2‐bromoacetate as a precursor with no‐carrier‐added [¹⁸F]fluoride, hydrolysis within the same [¹⁸F]fluorination reaction vessel, and purification with/without high‐performance liquid chromatography (HPLC). The second procedure consisted of nucleophilic [¹⁸F]fluorination, hydrolysis on the column, and purification with SEP‐PAK cartridges instead of HPLC. The radiochemical purity of [¹⁸F]FAC was >95% by the two procedures. The second procedure was a simple, rapid, and fully automated synthesis of [¹⁸F]FAC with a high and reproducible radiochemical yield exceeding 60% (decay uncorrected) within the total synthesis time less than 20 min. The new, simple, and rapid on‐column hydrolysis procedure should be adaptable to the fully automated synthesis of [¹⁸F]FAC at a commercial fluoro‐deoxyglucose synthesis module. Copyright © 2008 John Wiley & Sons, Ltd.     

Automated synthesis and purification of [18F]fluoro‐[di‐deutero]methyl tosylate

Automated synthetic procedures of [¹⁸F]fluoro‐[di‐deutero]methyl tosylate on a GE TRACERlab FX F‐N module and a non‐commercial synthesis module have been developed. The syntheses included azeotropic drying of the [¹⁸F]fluoride, nucleophilic ¹⁸F‐fluorination of bis(tosyloxy)‐[di‐deutero]methane, HPLC purification and subsequent formulation of the synthesized [¹⁸F]fluoro‐[di‐deutero]methyl tosylate (d₂‐[¹⁸F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated ¹⁸F‐fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.     

cGMP production of the radiopharmaceutical [18F]MK‐6240 for PET imaging of human neurofibrillary tangles

Fluorine‐18–labelled 6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine ([¹⁸F]MK‐6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2‐step radiosynthesis of [¹⁸F]MK‐6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FX_FN. Nucleophilic fluorination of the 5‐diBoc‐6‐nitro precursor with potassium cryptand [¹⁸F]fluoride (K[¹⁸F]/K₂₂₂) was performed by conventional heating, followed by acid deprotection and semipreparative high‐performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170‐250 mCi) of [¹⁸F]MK‐6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [¹⁸F]fluoride) with a specific activity of 222 ± 67 GBq/μmol (6.0 ± 1.8 Ci/μmol) at the end of synthesis (90 minutes; n = 3). [¹⁸F]MK‐6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.     

Automated radiosynthesis of no‐carrier‐added 4‐[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry

4‐[¹⁸F]Fluoroiodobenzene ([¹⁸F]FIB) is a versatile building block in ¹⁸F radiochemistry used in various transition metal‐mediated C–C and C–N cross‐coupling reactions and [¹⁸F]fluoroarylation reactions. Various synthesis routes have been described for the preparation of [¹⁸F]FIB. However, to date, no automated synthesis of [¹⁸F]FIB has been reported to allow access to larger amounts of [¹⁸F]FIB in high radiochemical and chemical purity. Herein, we describe an automated synthesis of no‐carrier‐added [¹⁸F]FIB on a GE TRACERlab? FX automated synthesis unit starting from commercially available (4‐iodophenyl)diphenylsulfonium triflate as the labelling precursor. [¹⁸F]FIB was prepared in high radiochemical yields of 89 ± 10% (decay‐corrected, n = 7) within 60 min, including HPLC purification. The radiochemical purity exceeded 95%, and specific activity was greater than 40 GBq/µmol. Typically, from an experiment, 6.4 GBq of [¹⁸F]FIB could be obtained starting from 10.4 GBq of [¹⁸F]fluoride. Copyright © 2013 John Wiley & Sons, Ltd.