Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

Following our recently published fluorine‐18 labeling method, “Radio‐fluorination on the Sep‐Pak”, we have successfully synthesized 6‐[¹⁸F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t‐butanol) of its quaternary ammonium salt precursor, 6‐(N,N,N‐trimethylamino)nicotinaldehyde trifluoromethanesulfonate ( 2 ), through a fluorine‐18 containing anion exchange cartridge (PS‐HCO₃). Over 80% radiochemical conversion was observed using 10 mg of precursor within 1 minute. The [¹⁸F]fluoronicotinaldehyde ([¹⁸F] 5 ) was then conjugated with 1‐(6‐(aminooxy)hexyl)‐1H‐pyrrole‐2,5‐dione to prepare the fluorine‐18 labeled maleimide functionalized prosthetic group, 6‐[¹⁸F]fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[¹⁸F]FPyMHO ([¹⁸F] 6 ). The current Sep‐Pak method not only improves the overall radiochemical yield (50 ± 9%, decay‐corrected, n = 9) but also significantly reduces the synthesis time (from 60‐90 minutes to 30 minutes) when compared with literature methods for the synthesis of similar prosthetic groups.     

Synthesis,bioconjugation and stability studies of [18F]ethenesulfonyl fluoride

Fluorine‐18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [¹⁸F]ethenesulfonyl fluoride ([¹⁸F]ESF) and its Michael conjugation with amino acids and proteins. The synthesis of [¹⁸F]ESF was optimised using a microfluidic reactor under both carrier‐added (c.a.) and no‐carrier‐added (n.c.a.) conditions, affording, in a straightforward procedure, 30‐50% radiochemical yield (RCY) for c.a. [¹⁸F]ESF and 60‐70% RCY for n.c.a. [¹⁸F]ESF. The conjugation reactions were performed at room temperature using 10 mg/mL precursor in aqueous/organic solvent mixtures for 15 min. The radiochemical stability of the final conjugates was evaluated in injectable formulation and rat serum, and resulted strongly substrate dependent and generally poor in rat serum. Therefore, in this work we have optimised a straightforward synthesis of [¹⁸F]ESF and its Michael conjugation with model compounds, without requiring chromatographic purification. However, given the general low stability of the final products, further studies will be required for improving conjugate stability, before assessing the use of this PG for PET imaging.     

燃煤型氟暴露相关因素在男性不育中的危险度探讨

[目的]探讨燃煤型氟暴露对男性不育的影响。[方法]对227名病例和对照进行与氟暴露相关的生活居住环境、饮食情况、生育情况等的调查,采用Epidata3．O软件建立数据库,然后进行非条件LogiSticlg／归分析筛选危险因素。[结果]燃煤型氟病区男性不育的危险因素包括年龄（OR=3．52）、吸烟（OR=I．75）、主食炉火烘干（0R=4．25）及食用前少淘洗（OR=2．19）;生育能力低下的危险因素包括年龄（OR=5．64）、主食炉火烘干（OR=4．24）及食用前少淘洗（OR=3．77）、喜欢喝自产烘干茶（OR=3．62）;而文化程度（OR=0．37）及主食密闭储存（OR=0．58）则为其保护因素。[结论]煤烟型氟暴露可致男性人群不育的风险升高,主食少用炉火烘干及食用前多淘洗对降低燃煤型氟中毒地区的男性不育风险具有积极的作用。     

Detection of targeted perfluorocarbon nanoparticle binding using 19F diffusion weighted MR spectroscopy

Real‐time detection of targeted contrast agent binding is challenging due to background signal from unbound agent. ¹⁹F diffusion weighted MR spectroscopy (DWS) could selectively detect binding of angiogenesis‐targeted perfluorocarbon nanoparticles in vivo. Transgenic K14‐HPV16 mice with epidermal squamous carcinomas exhibiting up‐regulated neovasculature were used, with nontransgenic littermates as controls. Mice were treated with α_vβ₃‐integrin targeted perfluorocarbon nanoparticles. ¹⁹F DWS (b‐values from 0 to 16,000 s/mm²) was performed on mouse ears in vivo at 11.74 Tesla. Progressive decay of ¹⁹F signal with increased diffusion weighting at low b‐values (< 1500 s/mm²) was observed in ears of both K14‐HPV16 and control mice, demonstrating suppression of background ¹⁹F signal from unbound nanoparticles in the blood. Much of the ¹⁹F signal from ears of K14‐HPV16 mice persisted at high b‐values, indicating a stationary signal source, reflecting abundant nanoparticle binding to angiogenesis. ¹⁹F signal in controls decayed completely at high b‐values (> 1500 s/mm²), reflecting a moving signal source due to absence of angiogenesis (no binding sites). Estimated ADCs of nanoparticles in K14‐HPV16 and control mice were 33.1 ± 12.9 μm²/s and 19563 ± 5858 μm²/s (p < 0.01). In vivo ¹⁹F DWS can be used for specific detection of bound perfluorocarbon nanoparticles by selectively suppressing background ¹⁹F signal from nanoparticles flowing in blood. Magn Reson Med 60:1232–1236, 2008. © 2008 Wiley‐Liss, Inc.     

Fluorine‐18 labelling of small interfering RNAs (siRNAs) for PET imaging

Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two single‐stranded ribonucleic acids of short sequences, have been labelled with the positron‐emitter fluorine‐18 (T_1/2: 109.8 min). The strategy involves (1) prosthetic conjugation of a single‐stranded oligonucleotide with [¹⁸F]FPyBrA (N‐[3‐(2‐[¹⁸F]fluoropyridin‐3‐yloxy)‐propyl]‐2‐bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [¹⁸F]siRNAs. Pure fluorine‐18‐labelled siRNAs (0.55–1.11 GBq, specific activity: 74–148 GBq/µmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [¹⁸F]fluoride (1.5–3.0%, non‐decay‐corrected isolated yields). Copyright © 2007 John Wiley & Sons, Ltd.     

One‐step radiosynthesis of [18F]LBT‐999: a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3‐beta‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2‐beta‐carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (K_D : 9 nM for the DAT and IC₅₀ > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine‐18‐labelling of LBT‐999 was based on the robust and reliable two‐step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene followed by a N‐alkylation reaction with the appropriate nor‐tropane moiety. In the present work, a simple one‐step fluorine‐18‐labelling of LBT‐999 is reported, based on a chlorine‐for‐fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high‐performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[¹⁸F]F–Kryptofix^®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C‐18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Typically, 3.70–5.92 GBq of [¹⁸F]LBT‐999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep‐Pak‐based formulation included), starting from a 37.0 GBq [¹⁸F]fluoride batch (overall radiochemical yields: 10–16%, non‐decay‐corrected). Copyright © 2007 John Wiley & Sons, Ltd.     

加味关节康联合来氟米特治疗类风湿性关节炎临床观察

目的：观察自拟方加味关节康联合来氟米特治疗类风湿性关节炎疗效.方法：65例类风湿性关节炎患者,随机分为治疗组和对照组.治疗组35例,服用加味关节康联合来氟米特;对照组30例,服用甲氨喋呤联合来氟米特,疗程均24周.观察临床症状改善情况,检验指标血、尿常规,肝、肾功能,血沉（ESR）、类风湿因子（RF）等的变化.结果：加味关节康联合来氟米特治疗类风湿性关节炎疗效肯定,总有效率达85.7%,副作用发生率则明显低于对照组（P＜0.05）.结论：加味关节康联合来氟米特治疗类风湿性关节炎,效果显著,减少副作用,安全性较好.     

左氧氟沙星治疗肺结核近期疗效观察

目的：观察左氧氟沙星联合其他一线抗结核药物治疗肺结核患者的疗效和安全性.方法：采用患者随机配对分组.将68例肺结核患者分为治疗组和对照组.方案两组都用一线抗结核药,治疗组加用左氧氟沙星.定期观察痰菌阴转、X线好转情况及药物副反应.结果：治疗2个月末、六个月末,治疗组和对照组痰菌阴转率、病灶吸收、症状改善,均明显高于对照组.结论：左氧氟沙星具有良好的抗结核作用,是一种使用安全、副反应小的新一代抗结核药物,可应用于各种类型肺结核的治疗,但最好用于复治肺结核病人.     

19F NMR in vivo spectroscopy reflects the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy.

Nuclear magnetic resonance spectroscopy of fluorine-19 ((19)F NMR) has proven useful for evaluating kinetics of fluorinated chemotherapy drugs in tumors in vivo. This work investigated how three perfusion-enhancing vascular modifiers (BQ123, thalidomide, and Botulinum neurotoxin type A [BoNT-A]) would affect the chemotherapeutic efficacy of gemcitabine, a fluorinated drug widely used in human cancer treatment. Murine tumor growth experiments demonstrated that only BoNT-A showed a strong trend to enhance tumor growth inhibition by gemcitabine (1.7 days growth delay, P = 0.052, Student t-test). In accord with these results, (19)F NMR experiments showed that only BoNT-A increased significantly the uptake of gemcitabine in tumors (50% increase, P = 0.0008, Student t-test). Further experiments on gemcitabine kinetics (NMR vs time) and distribution ((19)F MRI) confirmed the uptake-enhancing properties of BoNT-A. The results of this study demonstrate that (19)F NMR can monitor modulation of the pharmacokinetics of fluorinated chemotherapy drugs in tumors. The results also show that (19)F NMR data can give a strong indication of the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy in murine tumors. (19)F NMR is a promising tool for preclinical evaluation of such vascular modifiers and may ultimately be used in the clinic to monitor how these modifiers affect chemotherapy.     

Teflon radiolysis as the major source of carrier in fluorine‐18

The practical upper limit of fluorine‐18 specific activity has remained constant for many years among cyclotron facilities internationally. Although there have been isolated reports of very high specific activity and hints concerning the sources of carrier, experiments designed to identify carrier sources have been inconclusive and largely ineffective. This report describes experiments to test the hypothesis that radiolysis of fluorinated components is a source of carrier fluoride. Controlled experiments were performed in which contributions of irradiated fluorinated components to the mass of synthesized [¹⁸F]fluorobenzaldehyde (FBA) were measured. There was clear correlation between irradiation of Teflon and carrier mass. There was an additive effect of carrier due to different fluoropolymer components. It was concluded that in typical target and radiosynthesis systems it is radiolysis of fluorinated material and not the material itself that generates a large majority of the carrier typically reported. All Teflon and other fluorinated materials in contact with the [¹⁸F]fluoride solution were removed. With no further efforts to reduce carrier fluoride, FBA produced from a modest irradiation attained a reduction in mass from over 500 nmol to 30 nmol, and an increase in specific activity from 0.1 TBq (3 Ci) to 1.9 TBq (51 Ci) per micromole. Copyright © 2009 John Wiley & Sons, Ltd.