Novel use of an isotope separator to determine the position of fluorine-18 in labelled 1,1,1,2-tetrafluoroethanes

A novel technique is described for measuring the site selectivity of methods for labelling the major CFC-alternative, 1,1,1,2-tetrafluoroethane (HFA 134a), with fluorine-18 (t_1/2 = 109.7 min). The carbon–carbon bond in radiofluorinated HFA 134a is broken in the ion source of an isotope separator. Radioactivity associated with the ion beam of the [CF₂ ¹⁸F]^+. fragment (m/z = 68) is collected, measured and divided by the integrated mass of the simultaneously collected ion beam for the [CF₃]^+. fragment (m/z = 69) to give the ‘specific radioactivity’ (in nCi nmol^–1) of the radiolabel in the 1-position. Similarly, the ‘specific radioactivity’ of the radiolabel in the 2-position is calculated from the measured radioactivity of the ion beam from the [CH₂ ¹⁸F]^+. fragment (m/z = 32) and the integrated mass of the simultaneously collected ion beam from the [CH₂F]^+. fragment (m/z = 33). The selectivity of the labelling procedure for a particular position is then given by the decay-corrected ratio of specific radioactivity at that position to the sum of specific radioactivities. The labelling of HFA 134a by the reaction of [¹⁸F] fluoride with trifluoroethylene was found to have 97% selectivity for the CF₃ group, whereas labelling by the reaction of [¹⁸F] fluoride with 2,2,2-trifluoroethyl p-toluenesulphonate was found to have 91% selectivity for the CH₂F group. This information is of value for tracer studies of the fate of HFA 134a in man following its inhalation as a drug propellant. The described technique is of potentially wider value for determining the position of fluorine-18 in labelled polyfluorinated molecules.     

Capturing aqueous [F]-fluoride with an arylboronic ester for PET: Synthesis and aqueous stability of a fluorescent [F]-labeled aryltrifluoroborate

The aqueous stability of aryltrifluoroborates is of importance to their use in transition metal mediated coupling reactions as well as their potential use in [¹⁸F]-labeled aryltrifluoroborate PET imaging agents. Nevertheless, few studies have fully characterized the solvolysis of fluoride from an aryltrifluoroborate in water. Using [¹⁹F] NMR, fluorescence and [¹⁸F]-labeling techniques, we disclose the composition of an aryltrifluoroborate of exceptional kinetic stability with respect to solvolytic defluoridation. This work not only highlights the potential of using [¹⁸F]-labeled aryltrifluoroborates for PET tracers, but provides a chemical platform and a general approach for evaluating the stability of other aryltrifluoroborates.     

多巴胺受体显像剂 18F-Fethypride的合成、 放射性标记及生物分布

以香草酸甲酯为原料, 经过7步反应合成了前体化合物(S)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯, 采用NMR和HRMS对其进行了表征; 通过¹⁸F标记合成了新型高亲和力的多巴胺受体显像剂¹⁸F-(S)-N-{(1-乙基2-吡咯烷基)甲基}-3-(3-氟丙基)-4,5-二甲氧基苯甲酰胺(¹⁸F-Fethypride). 该显像剂的合成时间为35 min, 放化产率为(36.8±1.4)%(n=6), 放化纯度经HPLC法检测为99%, TLC法检测为100%, 无菌实验、 鲎试剂检测、 K2.2.2含量检测和急性毒性实验均合格. 纹状体/小脑(Str/Cer)比值90 min达到最高(10.68±0.35), 可作为多巴胺受体显像剂用于诊断神经系统疾病.     

核药物发展小记

简要回顾了20世纪70年代以来核药物领域发展的主要成就,并对目前在临床上应用最为广泛的核药物探针[18F]FDG作了重点介绍。[18F]FDG的发展可追溯至20世纪20年代,历经半个世纪终于成功应用于临床,在肿瘤、神经退行性疾病、心血管疾病的诊断中发挥了巨大作用。除此以外,本文也介绍了多肽类及蛋白类核药物的最新进展。在梳理核药物发展脉络的同时,本文也借此机会向读者介绍了几位为核药物发展做出巨大贡献的科学家,并作为晚辈向其致以崇高的敬意。最终,笔者希望向读者阐明核药物研究立足基础研究、面向临床问题的学科特色,也希望读者能通过对经典核药物发展脉络的了解,对自身的科学研究有所启发。     

稻秆木素侧链13C同位素示踪及固体13CNMR分析

在水稻(Oryza sativa L.)生长过程中,向其茎秆部节间的空腔分别注入在侧链α,β,γ位带有¹³C标记的松柏醇葡萄糖甙,得到¹³C标记的稻秆木素,用高分辨率固体核磁¹³CNMR对其组织进行分析,发现外源性的松柏醇葡萄糖甙并不影响水稻中木素的正常合成.证明了β-O-4,β-β,β-5和β-1结构是稻秆原本木素中的主要结构,另外还有少量的松柏醇和阿魏酸类结构,并证实木素在α位与糖类等组分有共价键形成.     

The synthesis of [2,3,4-C3]glycitein

Glycitein is one of the soy isoflavones which have attracted considerable interest in recent years due to their possible beneficial effects on human health. However, glycitein has been much less studied than other members of this family due to the lack of good methods for its synthesis. Herein we report a short high yielding synthesis of a multiply ¹³C-labelled glycitein derivative, [2,3,4-¹³C₃]glycitein, which has been employed as an internal standard in LC–MS analysis. A key feature is a rapid and efficient synthesis of 2,4-dihydroxy-5-methoxy-[1′,2′-¹³C₂]acetophenone via acetylation of isovanillin with [¹³C₂]acetyl chloride followed by a Baeyer–Villiger reaction, selective hydrolysis and finally a BF₃ catalysed Fries rearrangement. An aldol reaction using 4-benzyloxy-[carbonyl-¹³C]benzaldehyde gave a chalcone and then thallium(III) mediated oxidative rearrangement, deprotection and cyclisation provided the [2,3,4-¹³C₃]glycitein. The overall yield for the 8 step reaction sequence, based on [¹³C₂]acetyl chloride, was 57%.     

Fluorinated tertiary alkoxides of some lanthanides: tris-trifluorotertiarybutoxides of lanthanum, praseodymium and europium

From reactions involving M{N(SiMe₃)₂}₃ (M = La, Pr and Eu) and triflurotertiary butano[(CF₃)Me₂COH; tftb.H], the compounds [La(tftb)₃(thf)_1.5] (1), [Pr(tftb)₃ (2) and [Eu(tftb)₃] (3) have been isolated. From variable temperature ¹H and ¹⁹F NMR studies it is suggested that 1 is a mixture of [La₃(tftb)₉(thf)₂] (1a) and [La₂(tftb)₆(thf)₄] (1b). X-ray crystallography has shown that 2 is the trimer [Pr₃(tftb)₉] and variable temperature ¹H and ¹⁹F NMR suggests that 3 is also a trimer, [Eu₃(tftb)₉].     

Collision of molecular anions of benzenedicarboxylic esters with oxygen in a triple quadrupole mass spectrometer

A series of symmetrical phthalate, isophthalate, and terephthalate ester molecular anions were reacted with oxygen in the collision cell of a triple quadrupole mass spectrometer to produce characteristic [M − R]⁻ fragments that can be used to identify these compounds. The [M − R]⁻/M^−· intensity ratios decreased for homologous esters in the following order: phthalates > isophthalates terephthalates. Based on the [M − R]⁻ ion intensities for different alkyl substituents, on ¹⁸O₂ labeling experiments, and on the reactivity of bis(t-butylcyclohexyl)phthalates, it was concluded that M − R anions are generated through an S_N2 nucleophilic displacement at the alpha carbon of the saturated alkyl substituent. For the phenyl ester, the reaction proceeds through attack at the carbonyl carbon.     

稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

1,4-二氢吡啶结构是许多生物活性物以及药物分子的重要骨架,同时也是非常重要的有机合成中间体。当前并没有一种适用的方法用于¹³C标记1,4-二氢吡啶的合成.提供了一种¹³C标记1,4-二氢吡啶的合成方法以¹³C2-乙酸钠为标记原料,经磷酸酸化得到¹³C2-乙酸,羰基二咪唑酰化¹³C2-乙酸得到¹³C2-N-乙酰咪唑,随后在咪唑钠的作用下进行克莱森缩合反应获得1,2,3,4-¹³C4-乙酰乙酰咪唑的钠盐,经乙酸酸化得到1,2,3,4-¹³C4-乙酰乙酰咪唑,再通过与醇进行酯化得到1,2,3,4-¹³C4-乙酰乙酸酯,1,2,3,4-¹³C4-乙酰乙酸酯经氨基甲酸铵氨化得到1,2,3,4-¹³C4-3-氨基丁烯酸酯。随后采用Hantzsch改进法合成了5,6-位及其取代基碳标记的¹³C4-尼群地平、¹³C4-苯磺酸氨氯地平和¹³C4-马来酸氨氯地平.该方法操作简单,反应条件温和且产率高,为1,4-二氢吡啶的5,6-位及其取代基引入¹³C同位素标记合成提供了新的思路,满足中国仿制药物一致性评价的稳定同位素内标自主合成需求。     

Nuclear motion effects on the C, F and H shielding in methyl fluoride

The ¹⁹F , ¹³C and ¹H shielding in methyl fluoride and its deuterated isotopomers has been calculated from ab initio shielding surfaces for selected temperatures. In each case it is the stretching which contributes most to the nuclear motion corrections which total −9.425 ppm for the ¹⁹F shielding, −4.558 ppm for the ¹³C shielding and −0.601 ppm for the proton shielding. However, some second-order stretching and bending contributions are significant. The deuterium induced isotope shifts are substantial and should be easily measurable. There is a predicted nonadditivity in the ¹⁹F and ¹³C isotope shifts which can be traced to two of the bending contributions.     

Syntheses of dibenzo[b,e][1,4]dioxin derivatives via iron complexes, and further functionalizations via directed metallation

Double nucleophilic aromatic substitution reactions between (cyclopentadienyl)(η⁶-1,2-dichlorobenzene)iron(1 + ) salts and substituted 1,2benzenediols have been carried out under mild conditions to prepare [η⁶-dibenzo[b,e][1,4]dioxin]iron(1 + ) complexes functionalized in the 1- or 2-position with an alkyl, aldehyde, carboxylic acid, methoxycarbonyl, carboxamide, or hydroxy group. 3-Methyl- and 4-methyl-(η⁶-1,2-dichlorobenzene)iron complexes were treated with substituted 1,2-benzenediols to effect functionalization of both aromatic rings of the heterocycle. The dibenzodioxin ligands were liberated routinely by irradiation with ultraviolet light. Directed deprotonation of the free functionalized dibenzodioxins with an alkyllithium reagent followed by quenching with a variety of electrophiles yielded further derivatives, including two new isoindolone systems.     

Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity

Aromatic radiofluorination of the diaryliodonium tosylate precursor with [(18)F]fluoride ions has been applied successfully to access [(18)F]flumazenil in high radiochemical yields of 67.2 ± 2.7% (decay corrected). The stability and reactivity of the diaryliodonium tosylate precursor plays a key role in increasing the production of (18)F-labelled molecules under the fluorine-18 labelling condition. Various conditions were explored for the preparation of [(18)F]flumazenil from different diaryliodonium tosylate precursors. Optimum incorporation of [(18)F]fluoride ions in the 4-methylphenyl-mazenil iodonium tosylate precursor (5f) was achieved at 150 °C for 5 min by utilizing 4 mg of the precursor, K(2.2.2)/K(2)CO(3) complex, and the radical scavenger in N,N-dimethylformamide. This approach was extended to a viable method for use in automated synthesis with a radiochemical yield of 63.5 ± 3.2% (decay corrected, n = 26) within 60.0 ± 1.1 min. [(18)F]Flumazenil was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370-450 GBq μmol(-1), with a radiochemical purity of >99%, which will be suitable for human PET studies.     

Fluoride ion-mediated nucleophilic fluoroalkylation of alkyl halides with Me3SiCF2SPh: Synthesis of PhSCF2- and CF2H-containing compounds

A facile and highly efficient nucleophilic (phenylthio)difluoromethylation of alkyl halides has been achieved via fluoride ion-mediated substitution reaction using [difluoro(phenylthio)methyl]trimethylsilane (Me₃SiCF₂SPh). The reaction proceeds well with primary alkyl bromides (or alkyl iodides) in DME solvent when CsF/15-crown-5 was used as the fluoride source/additive. The PhSCF₂-containing products can be readily transformed into CF₂H-containing compounds via a free-radical desulfurization method.     

Synthesis, structural and spectroscopic characterisation of three di-μ-fluoro-bis[dioxouranyl] complexes

Three novel uranyl complexes with organic phosphine oxide ligands and bridging fluorides have been synthesised and structurally characterised. In [ UO₂(μ-F)(TPPO)_{3 2}][BF₄]₂ · ⁿC₆H₁₄, 1, and [ UO₂(-μF)(TBPO)_{3 2}][BF₄]₂ 2, (where TPPO and TBPO are triphenylphosphine oxide and tri-n-butylphosphine oxide, respectively) two UO₂ ²⁺ moieties are bridged by two fluorides with three additional terminal PO donor ligands coordinated to each uranium centre. The dicationic complexes are both charge balanced by two uncoordinated tetrafluoroborate anions. In the related structure, [UO₂(μ-F)(F)(DPPMO₂)]₂ · 2MeOH (3), terminal fluoride is also coordinated to both uranyl centres (where DPPMO₂ = bis(diphenylphosphine oxide)methane). All three complexes were prepared during attempted syntheses of complexes with tetrafluoroborate directly coordinated to uranium. It is clear from these results that the fluorophilicity of UO₂ ²⁺ causes the abstraction of fluoride from [BF₄]⁻, with the weakly coordinating anion only present as a counter cation in 1 and 2, and absent completely in 3.     

Monodentate and bidentate trifluoroacetato ligands in bis(trifluoroacetato)-(N-methyl-meso-tetraphenylporphyrinato)thallium(III)—a new dynamic 4:3 piano stool seven-coordinate geometry

The crystal structure of bis(trifluoroacetato)-(N-methyl-meso-tetraphenylporphyrinato) thallium(III), Tl(N---Me---tpp)(CF₃CO₂)₂ (2), was established and the coordination sphere around the Tl³⁺ ion is described as 4:3 tetragonal base–trigonal base piano stool seven-coordinate geometry in which the two cis CF₃CO₂ ⁻ groups occupy two apical sites. The plane of the three pyrrole nitrogen atoms [i.e. N(2), N(3) and N(4)] strongly bonded to Tl³⁺ is adopted as the reference plane 3N. The pyrrole N(1) ring bearing the methyl group [i.e. C(45)H₃] is the most deviated one from the 3N plane making a dihedral angle of 23.3° whereas smaller angles of 9.9, 2.7 and 4.7° occur with pyrroles N(2), N(3), and N(4), respectively. Because of the larger size of the thallium(III) ion, Tl is considerably out of the 3N plane; its displacement of 1.02 Å is in the same direction as that of the two apical CF₃CO₂ ⁻ ligands. The intermolecular trifluoroacetate exchange process for 2 in CD₂Cl₂ solvent is examined through ¹⁹F and ¹³C NMR temperature-dependent measurements. In the slow-exchange region, the CF₃ and carbonyl (CO) carbons of the CF₃CO₂ ⁻ groups in 2 are separately located at δ 114.3 [¹J(C–F)=290 Hz, ³J(Tl–C)=411 Hz] and 155.1 [²J(C–F)=37 Hz, ²J(Tl–C)=204 Hz], respectively, at −106 °C. In the same slow-exchange region, the fluorine atoms of 2, Tl(N---Me---tpp)(CF₃CO₂)⁺ and the free CF₃CO₂ ⁻ are located at δ −73.76 [⁴J(Tl–F)=44 Hz], −73.30 [⁴J(Tl–F)=22 Hz], and −76.15 ppm at −97 °C, respectively.     

Synthesis and crystal structure of the double barium-titanium methoxide [Ba2Ti4O(OMe)18(MeOH)7]·MeOH

The X-ray diffraction study of crystals isolated from solutions obtained by reaction of Ba(OMe)₂ with Ti(OMe)₄ (molar ratio 1:2) in methyl alcohol was carried out; the crystals of the methanol solvate of the double barium-titanium methoxide, [Ba₂Ti₄O(OMe)₁₈(MeOH)₇]·MeOH (1), contain two Ba²⁺ cations with different environments and two kinds of anionic binuclear titanium complexes with and without oxo-ligand, and thus can be formulated as [Ba(MeOH)₂]²⁺[Ba(MeOH)₅]²⁺[Ti₂O(OMe)₈]²⁻[Ti₂(OMe)₁₀]²⁻·MeOH.     

Synthesis of fluorinated telomers. Part 1. Telomerization of vinylidene fluoride with perfluoroalkyl iodides

Thermal and redox-induced telomerizations of vinylidene fluoride (VDF) with linear (n-C₄F₉I) or branched (i-C₃F₇I) perfluoroalkyl iodides have been performed. In both cases, thermal telomerizations led to telomeric-type distributions of the first five (from linear telogen) or the first three (from branched telogen) adducts produced, with better yields at higher temperatures. The redox-initiated telomerization was more selective since it led to the first two adducts only. For both reactions, mono- and di-adducts were isolated and characterized by ¹H and ¹⁹F NMR spectroscopy. Interestingly, both the diadducts were composed of two isomers (i.e. the expected telomer and R_FCH₂CF₂CF₂CH₂I). Two mechanisms are proposed and it is assumed that the products may be obtained either by chain propagation or by stepwise telomerization. In addition, attack of the electrophilic radical on the nucleophilic side of VDF is discussed.     

A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules

Aprotic solvents are usually preferred for the SN2 reactions, because nucleophilicity and hence SN2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with [18F]fluorine (t1/2 = 110 min) for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [18F]fluoride-radiolabeled molecular imaging probes-[18F]FDG, [18F]FLT, [18F]FP-CIT, and [18F]FMISO-in high yield and purity and in shorter times compared to conventional syntheses.     

Fast production of highly concentrated reactive [F] fluoride for aliphatic and aromatic nucleophilic radiolabelling

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [¹⁸F]F⁻ from [¹⁸O]water to a low water content organic solution compatible with fast nucleophilic labelling of most precursors for PET radiopharmaceuticals in high yield.     

Synthesis, structure and spectral study of two types of novel fluorescent BF2 complexes with heterocyclic 1,3-enaminoketone ligands

Two types of novel BF₂ complexes are readily obtained by the reaction of BF₃OEt with 3-(2-oxo-2-arylethylidene)-3,4-dihydro-1H-quinoxalin-2-ones or 3-(2-oxo-2-arylethylidene)-3,4-dihydrobenzo[1,4]oxazin-2-ones, respectively in refluxing acetic acid/toluene solvent mixture. The complexes are confirmed by elemental analysis, FT-IR, ¹H, ¹³C, ¹¹B, ¹⁹F NMR and one of them is executed its X-ray crystallographic study. The outstanding photophysical properties of these complexes are determined by UV–vis absorption and fluorescence emission spectroscopy.