Origin of the oxygen in the oxidation of triphenylphosphine by potassium persulfate—application of the 18O isotope effect in 31P NMR

Potassium persulfate oxidizes triphenylphosphine to triphenylphosphine oxide in 60% aqueous acetonitrile. It has been suggested that the oxygen of the product, triphenylphosphine oxide, might originate from solvent water, following nucleophilic attack on an intermediate phosphonium ion. We have investigated the origin of the oxygen in the oxidation of triphenylphosphine by potassium persulfate in 60% aqueous acetonitrile containing 20% [¹⁸O]water. The product was analyzed by using the ¹⁸O isotope effect in ³¹P NMR spectroscopy. The magnitude of the ¹⁸O isotope-induced shift was determined by synthesizing triphenylphosphine [¹⁸O]oxide and was found to be 0.038 ppm upfield. The product of the oxidation reaction in 20% [¹⁸O]water displayed no ¹⁸O isotope effect. The origin of the oxygen in the oxidation reaction is the persulfate ion, consistent with an alternative mechanism involving nucleophilic attack by water at the sulfur atom of a phosphonium peroxysulfate intermediate.     

Electrochemical transfer of [18F]fluoride from [18O]water into organic solvents ready for labeling reactions

For labeling reactions [¹⁸F]fluoride has to be separated from [¹⁸O]water and transferred into an organic solvent suitable for nucleophilic substitutions. An electrolytical method is described for depositing [¹⁸F]fluoride on a vitreous carbon electrode and releasing it directly into CH₃CN or DMSO. In the presence of Et₃N×3HF, [¹⁸F]fluoride is almost quantitatively released into acetonitrile. When using n.c.a conditions, i.e., Et₃N^.HCl, desorption of the ¹⁸F activity is almost 70% and 60% in acetonitrile and DMSO, respectively, already within 5 minutes.     

[F]Fluoromethyl iodide ([F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups

In this study, we report the synthesis and reactivity of [¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F]fluoromethylated compounds. [¹⁸F]FCH₂I was prepared by reacting diiodomethane (CH₂I₂) with [¹⁸F]KF, and purified by distillation in radiochemical yields of 14-31% (n = 25). [¹⁸F]FCH₂I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1-7, but was unstable in basic solutions. [¹⁸F]FCH₂I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [¹⁸F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [¹⁸F]FCH₂I were stable for purification, formulation and storage. In contrast, the [¹⁸F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [¹⁸F]FCH₂I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [¹⁸F]fluoromethyl compounds was a main decomposition route.     

Radiotracers for Bone Marrow Infection Imaging

Introduction: Radiotracers are widely used in medical imaging, using techniques of gamma-camera imaging (scintigraphy and SPECT) or positron emission tomography (PET). In bone marrow infection, there is no single routine test available that can detect infection with sufficiently high diagnostic accuracy. Here, we review radiotracers used for imaging of bone marrow infection, also known as osteomyelitis, with a focus on why these molecules are relevant for the task, based on their physiological uptake mechanisms. The review comprises [⁶⁷Ga]Ga-citrate, radiolabelled leukocytes, radiolabelled nanocolloids (bone marrow) and radiolabelled phosphonates (bone structure), and [¹⁸F]FDG as established radiotracers for bone marrow infection imaging. Tracers that are under development or testing for this purpose include [⁶⁸Ga]Ga-citrate, [¹⁸F]FDG, [¹⁸F]FDS and other non-glucose sugar analogues, [¹⁵O]water, [¹¹C]methionine, [¹¹C]donepezil, [^99mTc]Tc-IL-8, [⁶⁸Ga]Ga-Siglec-9, phage-display selected peptides, and the antimicrobial peptide [^99mTc]Tc-UBI_29-41 or [⁶⁸Ga]Ga-NOTA-UBI_29-41. Conclusion: Molecular radiotracers allow studies of physiological processes such as infection. None of the reviewed molecules are ideal for the imaging of infections, whether bone marrow or otherwise, but each can give information about a separate aspect such as physiology or biochemistry. Knowledge of uptake mechanisms, pitfalls, and challenges is useful in both the use and development of medically relevant radioactive tracers.     

[F]Fluorophenyl organometallics as intermediates of no-carrier-added F-fluoroarylation reactions

Based on the recent availability of no-carrier-added (n.c.a.) 1-bromo-4-[¹⁸F]fluorobenzene with high radiochemical yield, the 4-[¹⁸F]fluorophenyl compounds of lithium, sodium and magnesium can now also effectively be prepared. Thus, [¹⁸F]fluoroarene reagents with a nucleophilic reaction centre are available and suitable among others for the formation of [¹⁸F]fluorophenyl compounds with electron donating substituents in the radiosynthesis of ¹⁸F-labelled complex organic structures. For these arylation reactions, however, the presence of macroscopic amounts of a haloarene as co-reactant is necessary with all n.c.a. [¹⁸F]fluorophenyl metallics. The ¹⁸F-fluoroarylation was verified for examples of aryl-carbon, -silicon, -sulphur, and -nitrogen bond formation with radiochemical yields of 20-25% related to the starting radioactivity of [¹⁸F]fluoride.     

Sulfonyl Fluoride‐Based Prosthetic Compounds as Potential 18F Labelling Agents

Nucleophilic incorporation of [¹⁸F]F^? under aqueous conditions holds several advantages in radiopharmaceutical development, especially with the advent of complex biological pharmacophores. Sulfonyl fluorides can be prepared in water at room temperature, yet they have not been assayed as a potential means to ¹⁸F‐labelled biomarkers for PET chemistry. We developed a general route to prepare bifunctional 4‐formyl‐, 3‐formyl‐, 4‐maleimido‐ and 4‐oxylalkynl‐arylsulfonyl [¹⁸F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[¹⁸F]F/Cs₂CO_3(aq.) in a reaction time of 15 min at room temperature. With the exception of 4‐N‐maleimide‐benzenesulfonyl fluoride ( 3 ), pyridine could be used to simplify radiotracer purification by selectively degrading the precursor without significantly affecting observed yields. The addition of pyridine at the start of [¹⁸F]fluorination (1:1:0.8 tBuOH/Cs₂CO_3(aq.)/pyridine) did not negatively affect yields of 3‐formyl‐2,4,6‐trimethylbenzenesulfonyl [¹⁸F]fluoride ( 2 ) and dramatically improved the yields of 4‐(prop‐2‐ynyloxy)benzenesulfonyl [¹⁸F]fluoride ( 4 ). The N‐arylsulfonyl‐4‐dimethylaminopyridinium derivative of 4 ( 14 ) can be prepared and incorporates ¹⁸F efficiently in solutions of 100 % aqueous Cs₂CO₃ (10 mg mL^?1). As proof‐of‐principle, [¹⁸F] 2 was synthesised in a preparative fashion [88(±8) % decay corrected (n=6) from start‐of‐synthesis] and used to radioactively label an oxyamino‐modified bombesin(6–14) analogue [35(±6) % decay corrected (n=4) from start‐of‐synthesis]. Total preparation time was 105–109 min from start‐of‐synthesis. Although the ¹⁸F‐peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature ¹⁸F labelling strategy.     

The associations of macrocyclic ethers with cations in 1,4-dioxane/water mixtures; potentiometric Na+ and K+ binding measurements and computational study

This paper deals with the study of different degrees of association constants of Na⁺ and K⁺ ions with macrocycles of [12]crown-4, [15]crown-5, [18]crown-6, and Diaza[18]crown-6 in (1:1)dioxane/water mixture using the sodium and potassium ion selective electrodes (ISE). The gas phase molecular mechanical and quantum chemical calculations of [18]crown-6 and diaza[18]crown-6 were performed at MM+, AM1, MINDO/3, HF/6-31G(d), and B3LYP/6-31G(d) levels with the help of Gaussian03 program. Conformational abilities were compared with the ion binding results of ISE measurements. The results were also discussed in terms of oxygen charges and enthalpy stabilized association mechanism.     

Ion-molecule reactions in the gas phase. part XXII. Reactivity of the cis- and trans-indanediols with dimethyl ether ions

Specific reactivity of cis- and trans-indanediols has been investigated under dimethyl ether (DME) chemical ionization conditions. Several unusual species, such as [M + 29]⁺ and [M + 27]⁺ ions, are produced in high yield. From DME pressure variations and tandem mass spectrometry experiments (low-energy collisions with Ar and NH₃) including some labeled compounds, it appears that [M + 29]⁺ ions are generated by nucleophilic substitution according to a S_Ni pathway from the proton bound[M + DMEH]⁺ adduct ion. On the other hand, [M + 27]⁺ ions are produced from the covalent [M + DME ? H]⁺ adduct ions via a stepwise process inducing a water loss. This latter dehydration occurs from the adducts prepared by [DME ? H]⁺ attachment to the homobenzylic hydroxy site, which allows internal proton transfer from the charged position to the benzylic hydroxy group, promotingthe loss of water. In addition, trans indanediol labeled with ¹⁸O has been used to obtain evidence for the regioselectivity of both water-loss mechanisms from the benzylic site.     

A General Copper‐Mediated Nucleophilic 18F Fluorination of Arenes

Molecules labeled with fluorine‐18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (S_NAr) with [¹⁸F]F^?. In the ideal case, the ¹⁸F fluorination of these substrates would be performed through reaction of [¹⁸F]KF with shelf‐stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of ¹⁸F arenes from pinacol‐derived aryl boronic esters (arylBPin) upon treatment with [¹⁸F]KF/K₂₂₂ and [Cu(OTf)₂(py)₄] (OTf=trifluoromethanesulfonate, py=pyridine). This method tolerates electron‐poor and electron‐rich arenes and various functional groups, and allows access to 6‐[¹⁸F]fluoro‐L ‐DOPA, 6‐[¹⁸F]fluoro‐m‐tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.     

Automated synthesis of symmetric integrin αvβ3-targeted radiotracer [18F]FP-PEG3-β-Glu-RGD2

A automated synthesis of symmetric integrin α_vβ₃-targeted radiotracer [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was carried out by multi-step procedure on the modified PET-MF-2V-IT-I synthesizer. Firstly, the prosthetic group of 4-nitrophenyl 2-[¹⁸F]fluoropropionate ([¹⁸F]NFP) was automated synthesized by a convenient three-step, one-pot procedure. Secondly, [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was synthesized by coupling [¹⁸F]NFP with the symmetric RGD-peptide (PEG₃-β-Glu-RGD₂) and purified by a solid-phase extraction cartridge. The radiochemical yields of [¹⁸F]NFP were 35 ± 5 % (n = 10, decay-corrected) based on [¹⁸F]fluoride in 80 min. [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was obtained with yield 40 ± 10 % (n = 5, decay-corrected) from [¹⁸F]NFP within 20 min. The radiochemical purity of [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was greater than 98 %.     

[18F]CuCF3: A [18F]Trifluoromethylating Agent for Arylboronic Acids and Aryl Iodides

Positron emission tomography has emerged as the leading method for medical imaging with fluorine‐18 as the most widely used radioactive isotope. Here we report a semi‐automated method for the preparation of valuable [¹⁸F]trifluoromethylcopper, as well as its use for the radiosynthesis of [¹⁸F]trifluoromethylarenes and heteroarenes. Mild conditions of [¹⁸F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [¹⁸F]trifluoromethylarenes and heteroarenes.     

A Universal Procedure for the [18F]Trifluoromethylation of Aryl Iodides and Aryl Boronic Acids with Highly Improved Specific Activity

Herein, we describe a valuable method for the introduction of the [¹⁸F]CF₃ group into arenes with highly improved specific activity by the reaction of [¹⁸F]trifluoromethane with aryl iodides or aryl boronic acids. This [¹⁸F]trifluoromethylation reaction is the first to be described in which the [¹⁸F]CF₃ products are generated in actual trace amounts and can therefore effectively be used as PET tracers. The method shows broad scope with respect to possible aryl iodide and aryl boronic acid substrates, as well as good to excellent conversion. In particular, the [¹⁸F]trifluoromethylation of boronic acids was found to outperform [¹⁸F]trifluoromethylation reactions of halogenated aryl precursors with regard to conversion, reaction conditions, and kinetics.     

Hexanuclear Niobium Cluster Compounds with Protonated N-Base Cations

Octahedral clusters of the [M₆X₁₂] type offer numerous possibilities to form structural arrangements through different choices of bonding situations. In this paper a series of new cluster compounds of the transition metal niobium is described, which consist of the [Nb₆Cl₁₈]^2–, and in one case [Nb₆Cl₁₈]^3–, anion and protonated N-base cations ([MIm-H]⁺, [nPr₃N-H]⁺, [TMGu-H]⁺, and [Tzn-H]⁺). They all are prepared using water scavenger compounds [SOCl₂ or (Ac)₂O] under oxidising conditions, resulting in two-electron (or one-electron, respectively) oxidized cluster units with respect to the starting material [Nb₆Cl₁₄(H₂O)₄] · 4H₂O. Of five members of this group single-crystal X-ray structures were determined. The cluster anions exist in all structures as discrete units. The acidic H atoms of all N-bases are hydrogen bonded to H acceptors, in 4 cases to outer, exo bonded Cl atoms of the cluster unit and in one case to the O atom of a co-crystallized THF molecule. In [TMGu-H]₂[Nb₆Cl₁₈] chains of cluster anions exist hydrogen-bonded through bridging [TMGu-H]⁺ cations. ESI mass spectra of [MIm-H]₂[Nb₆Cl₁₈] · 2SOCl₂ and [TMGu-H]₂[Nb₆Cl₁₈] show the expected isotopic distribution patterns for the anions together with other peaks associated to chloride mass losses and/or reduction processes.     

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia

PET of β-Amyloid plaques (Aβ) using [¹⁸F]florbetaben ([¹⁸F]FBB) and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer’s disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [¹⁸F]FBB, [¹⁸F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological assessment battery (CERAD-NAB); (3) [¹⁸F]FBB and [¹⁸F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [¹⁸F]FDG and [¹⁸F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [¹⁸F]FBB combined with [¹⁸F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [¹⁸F]FBB combined with [¹⁸F]FDG PET is a helpful tool for differential diagnosis, and supports the patients’ management as well as treatment.     

A practical route for synthesizing a PET ligand containing [F]fluorobenzene using reaction of diphenyliodonium salt with [F]F

The aim of this study was to develop a practical route for preparing a fluorine-18 ([¹⁸F]) labelled ligand ([¹⁸F]1) containing [¹⁸F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [¹⁸F]F⁻. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [¹⁸F]DAA1106 ([¹⁸F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared.     

Efficient alkali iodide promoted F-fluoroethylations with 2-[F]fluoroethyl tosylate and 1-bromo-2-[F]fluoroethane

Radiochemical ¹⁸F-fluorination yields of several compounds using the secondary labelling precursors 2-[¹⁸F]fluoroethyl tosylate ([¹⁸F]FETos) and 1-bromo-2-[¹⁸F]fluoroethane ([¹⁸F]BFE) could be considerably enhanced by the addition of an alkali iodide. The radiochemical yield of [¹⁸F]fluoroethyl choline for example could be doubled with [¹⁸F]BFE and increased from 13% to ≈80% with [¹⁸F]FETos. By addition of alkali iodide to the precursor, the ¹⁸F-fluoroethylation yields of established radiopharmaceuticals, especially in the case of automated syntheses, could be significantly increased without major changes of the reaction conditions.     

Estimation of Li+, K+ and Ca2+ Complexation with [12] crown-4, [15] crown-5 and [18] crown-6 Using a Na+ ISE in Dioxane-Water, Part IV*

 The (1:1) Na⁺ equilibrium constants, Ke1, of macrocyclic ethers of [12]crown-4, [12]crown-5 and [18]crown-6 were determined with a Na⁺ ISE in the presence of a second cation e.g. Li⁺, K⁺ and Ca²⁺ in dioxane/water (50/50). We estimated the (1:1) equilibrium constants, K e2 of the macrocyclic ethers with Li⁺, K⁺ and Ca²⁺ by this way. The binding selectivity of a macrocyclic ether between two cations was estimated in the same binary solvent mixture where the water hydration role is diminished. Results showed clearly the effect of macrocyclic size and cation radii in a solution. Received October 27, 1998. Revision March 22, 1999.     

Reactivity of Hydroxy‐ and Aquo(hydroxy)‐λ3‐iodane–Crown Ether Complexes

We have designed a series of hydroxy(aryl)‐λ³‐iodane–[18]crown‐6 complexes, prepared from the corresponding iodosylbenzene derivatives and superacids in the presence of [18]crown‐6, and have investigated their reactivities in aqueous media. These activated iodosylbenzene monomers are all non‐hygroscopic shelf‐storable reagents, but they maintain high oxidizing ability in water. The complexes are effective for the oxidation of phenols, sulfides, olefins, silyl enol ethers, and alkyl(trifluoro)borates under mild conditions. Furthermore, hydroxy‐λ³‐iodane–[18]crown‐6 complexes serve as efficient progenitors for the synthesis of diaryl‐, vinyl‐, and alkynyl‐λ³‐iodanes in water. Other less polar organic solvents, such as methanol, acetonitrile, and dichloromethane, are also usable in some cases.     

[F]Fluoroamines via ring-opening of N-Cbz-2-methylaziridine with [F]-fluoride

A highly regioselective method was developed for ring-opening benzyloxycarbonyl (Cbz)-protected 2-methylaziridine with [¹⁸F]-labelled fluoride. Following catalytic hydrogenation, 1-[¹⁸F]fluoro-2-propanamine ([¹⁸F]1) and 2-[¹⁸F]fluoro-1-propanamine ([¹⁸F]2) were prepared as the major and minor products, respectively (85:15), and were characterized following acylation with benzyl chloride. This methodology is applicable towards the generation of new [¹⁸F]-labelled amines for incorporation into radiopharmaceuticals.     

Thermodynamics of formation for the 18-crown-6-triglycine molecular complex in water-dimethylsulfoxide solvents

The effect of a water-dimethylsulfoxide (DMSO) solvent on the formation of a molecular complex of 18-crown-6 (18C6) with triglycine (diglycylglycine, 3Gly) is studied via calorimetric titration. It is found that switching from water to an H₂O-DMSO mixture with DMSO mole fraction of 0.30 is accompanied by a monotonic increase in the stability of [3Gly18C6] complex, from logK ^° = 1.10 to logK ^° = 2.44, and an increase in the exothermicity of the reaction of its formation, from ?5.9 to ?16.9 kJ/mol. It is shown that the [3Gly18C6] complex exhibits enthalpy stabilization with negative values of enthalpy and entropy over the investigated range of H₂O-DMSO solvents. Analysis of the reagents’ solvation characteristics reveals that the increase in the reaction’s exothermicity of transfer is due to differences in the solvation of [3Gly18C6] and 18C6 with a small solvation contribution from 3Gly. It is concluded that the change in the Gibbs energy of the reaction 3Gly_solv + 18C6_solv ? [3Gly18C6]_solv is due to differences in the change in the solvation state of the complex and the peptide (Δ_tr G ^°([3Gly18C6])-Δ_tr G ^°(3Gly)).