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Assessment of lung ventilation by MR imaging: current status and future perspectives.

The aim of this paper is to review the present status of novel MRI techniques as a new important instrument for functional ventilation imaging. The current status and future perspectives in research and clinical applications are summarized. Morphological lung imaging is based on chest radiography and computed tomography, whereas scintigraphy is used for ventilation imaging. During recent years, MRI has emerged as a new means for functional imaging of ventilation. Aerosolized contrast agents and oxygen are used in proton imaging, whereas non-proton imaging relies on fluorine compounds, such as sulfur hexafluoride and perfluorcarbons, or on hyperpolarized noble gases, such as helium-3 or xenon-129. All the gases are administered as inhaled "contrast agents" for imaging of the airways and airspaces. In general, straightforward images demonstrate the homogeneity of ventilation in a breath-hold and allow for determination of ventilated lung. The different properties of the different compounds enable the measurement of additional functional parameters. They comprise airspace size, regional oxygen partial pressure, and analysis of ventilation distribution, ventilation/perfusion ratios, and gas exchange, including oxygen uptake. Novel MRI techniques provide the potential for functional imaging of ventilation. The next steps include definition of the value and the potential of the different contrast mechanisms as well as determination of the significance of the functional information with regard to physiological research and patient management in chronic obstructive pulmonary disease and others.

Contrast Media↗

Quantitative 19F MR spectroscopy at 3 T to detect heterogeneous capecitabine metabolism in human liver.

Chemotherapy in non-responding cancer patients leads to unnecessary toxicity. A marker is therefore required that can predict the sensitivity of a specific tumour to chemotherapy, which would enable individualisation of therapy. 19F MR spectroscopy (19F MRS) can be used to monitor the metabolism of fluorinated drugs. The aim of this study was to develop a method for quantified localised detection of fluorinated compounds in human liver. For this purpose, sensitivity-optimised localised 19F MRS methods at 3 T were used to detect MR signals from capecitabine, 5'DFUR, 5'DFCR and FBAL after oral intake of capecitabine. As the radio-frequency (rf) coil is made tuneable to 19F and 1H, the same localisation method is applied to obtain 1H MR signals of water and of the 19F metabolites. In addition, T1 measurements have been performed to correct for measurement-induced saturation effects. Finally, absolute tissue concentrations of capecitabine metabolites were obtained in vivo, which revealed a substantial spatial heterogeneity of these metabolites in human liver after chemotherapy.

Antimetabolites, Antineoplastic↗

Non-biaryl atropisomers in organocatalysis.

A new class of 6'-hydroxy cinchona alkaloids, with a non-biaryl atropisomeric functionalisation at position 5' of the quinoline core can be prepared by an easy amination procedure. These are the first derivatives for which the principle of atropisomerism is engrafted in the classical core of the cinchona alkaloids. The aminated cinchona alkaloids are effective organocatalysts for the Michael addition of beta-keto esters to acrolein and methyl vinyl ketone, in up to 93 % ee (ee=enantiomeric excess), as well as for the asymmetric Friedel-Crafts amination of a variety of 2-naphthols, permitting the preparation of the latter in up to 98 % ee. The aminated 8-amino-2-naphthol itself is the first chiral organocatalyst based on non-biaryl atropisomerism. The two enantiomers of this chiral primary amine can be used for the direct alpha-fluorination of alpha-branched aldehydes. The fluorinated compounds can thereby be accessed in up to 90 % ee.

Journal Article↗

Toxicology of fluoroacetate: a review, with possible directions for therapy research.

Fluoroacetate (FA; CH2FCOOR) is highly toxic towards humans and other mammals through inhibition of the enzyme aconitase in the tricarboxylic acid cycle, caused by 'lethal synthesis' of an isomer of fluorocitrate (FC). FA is found in a range of plant species and their ingestion can cause the death of ruminant animals. Some fluorinated compounds -- used as anticancer agents, narcotic analgesics, pesticides or industrial chemicals -- metabolize to FA as intermediate products. The chemical characteristics of FA and the clinical signs of intoxication warrant the re-evaluation of the toxic danger of FA and renewed efforts in the search for effective therapeutic means. Antidotal therapy for FA intoxication has been aimed at preventing fluorocitrate synthesis and aconitase blockade in mitochondria, and at providing citrate outflow from this organelle. Despite a greatly improved understanding of the biochemical mechanism of FA toxicity, ethanol, if taken immediately after the poisoning, has been the most acceptable antidote for the past six decades. This review deals with the clinical signs and physiological and biochemical mechanisms of FA intoxication to provide an explanation of why, even after decades of investigation, has no effective therapy to FA intoxication been elaborated. An apparent lack of integrated toxicological studies is viewed as a limiter of progress in this regard. Two principal ways of developing effective therapies for FA intoxication are considered. Firstly, competitive inhibition of FA interaction with CoA and of FC interaction with aconitase. Secondly, channeling the alternative metabolic pathways by orienting the fate of citrate via cytosolic aconitase, and by maintaining the flux of reducing equivalents into the TCA cycle via glutamate dehydrogenase.

Aconitate Hydratase↗

Structural properties of perfluorinated linear alkanes: a 19F and 13C NMR study of perfluorononane.

Liquid perfluorocarbons exhibit unique physical-chemical characteristics such as extraordinary stability, combined hydrophobia and lipophobia, low surface tension and a capacity to carry large quantities of gas. They have found widespread use in industry, medicine and biology even though the molecular origin of these properties is not fully understood. The objective of the present work was to elucidate the physical behavior of perfluorinated linear alkanes by investigating their intramolecular electronic environment using 13C and 19F NMR techniques in combination with theoretical calculations of molecular orbitals. Particular advantage was taken of 19F-19F through-space couplings, which led us to propose a molecular model in which delocalized p-electrons of the fluorines cover the entire surface of the molecule in two pairs of intertwined helices. Experimental data are presented for n-perfluorononane and supported by corresponding measurements with shorter and longer perfluorinated alkanes.

Algorithms↗

1H, 13C and 19F NMR spectroscopy of polyfluorinated ureas. Correlations involving NMR chemical shifts and electronic substituent effects.

Seventeen N-(mono-, di-, tri-, tetra- and penta-fluorophenyl)-N'-(3-nitrophenyl)ureas were prepared and characterized. Complete assignment of their (1)H, (13)C and (19)F NMR data was undertaken and the correlation of the chemical shifts of the ureido protons with field-inductive and mesomeric electronic substituent parameters was studied using the Swain-Lupton model. The best correlations were obtained when the study was limited to certain substitution patterns, e.g. non-ortho, mono-ortho- and di-ortho-fluorinated ureas, which reveal probable changes in conformations caused by the degree of ortho fluorination at the phenyl ring. Additionally, there is an excellent linear cross-correlation between the chemical shifts of the fluorine atoms and the ipso carbon atoms for the whole group of fluorinated ureas.

Carbon Isotopes↗

19F magnetic resonance imaging of the reticuloendothelial system.

In this study sequential 1H and 19F magnetic resonance imaging methods were used to map the distribution of fluorinated compounds in vivo. An intravenously administered emulsion of perfluorooctylbromide (PFOB), an agent known to localize in the reticuloendothelial system, was detected in the liver and spleen of all studied hamsters and mice using 19F MRI. Lungs and salivary glands were also affected in some animals. Using a G. E. NMR CSI 2-T spectroscopy/imaging system, projection 19F images were obtained in 4 to 8 min. Subsequent mouse studies using a thick-slice driven equilibrium pulse sequence produced 19F images with an improved signal-to-noise ratio in a shorter acquisition time. With PFOB, 19F MRI has the capability of detecting macrophages in the reticulo-endothelial system and in other sites where macrophages congregate. This is the first report where the reticuloendothelial system was specifically imaged in live animals and where driven equilibrium imaging techniques have been applied to 19F MRI.

Animals↗

Thermodynamic Investigation of the Micellization and the Adsorption of Short Perfluoroalkylated Diols via Fluorescence Spectroscopy and Tensiometry.

The micellization and adsorption of two short chain perfluorodiols 3,3,4,4,5,5,6,6,6-nonafluorohexane-1,2-diol (nFHD) and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctane-1,2-diol (tFOD) are examined from a thermodynamic point of view as a function of temperature and methanol content. The microenvironment of the fluorinated aggregates is evaluated by the fluorescence probe method using pyrene and a molecular rotor 1,1-dicyano-4-p-dimethylaminophenyl)-1,3-butadiene (DMAPhC). The formation of micellar aggregates being evidenced, the results are discussed in terms of the polarity and of the cohesion behavior of the micellar aggregates by taking into account the methanol (MeOH) effect. The critical micellization concentrations thus determined are compared with those given by surface tension measurements. Micellar and adsorption thermodynamic parameters such as Gibbs free energies, enthalpies, and entropies are determined together with the surface areas. The results are compared with literature data and discussed. A model for describing the adsorption process of the fluorinated compounds upon the influence of methanol is finally proposed. Copyright 2001 Academic Press.

Journal Article↗

Synthesis modules and automation in F-18 labeling.

Fast implementation of PET into clinical studies and research has resulted in high demands in the automated modules for the preparation of PET radiopharmaceuticals in a safe and reproducible manner. 18F-labeled radiotracers are of considerable interest due to longer half-life of fluorine-18 allowing remote site application, as demonstrated by [18F]FDG. In this chapter, the state of the art of commercially available modules for [18F]FDG is reviewed with the emphasis on multibatch production of this important radiotracer. Examples are given on the syntheses of other clinically relevant 18F-labeled radiotracers by using existing [18F]FDG synthesizers or with the help of general-purpose [18F]nucleophilic fluorination modules. On-going research and progress in the automation of complex radio labeling procedures followed by development of flexible multipurpose automated apparatus are discussed. The contribution of radiochemists in facilitating automation via introduction of new 18F-labeling techniques and labeling synthons, on-line reactions and purifications etc. is outlined.

Alkylation↗

Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora status exist? A report of two cases using fluorine-19 magnetic resonance spectroscopy.

A relationship between the gut flora level, particularly gram-negative enterobacilli, and the in vivo flucytosine conversion to fluorouracil has been observed in humans from the fluorine-19 magnetic resonance spectroscopy analysis of urine from two patients treated with the flucytosine- (6 to 9 g/day) amphotericin B (1 mg/kg/day) combination. Indeed the percentage of fluorouracil metabolites was extremely low (less than 0.6% of total fluorinated compounds excreted) when the number of enterobacillary colonies was low (less than 10(3] and higher (3.5 to 8.8%) when enterobacillary colonies were under reconstitution or in the normal range (10(5) to 10(8]. The intestinal microflora assessment may therefore be of high interest to predict the risk of an additive flucytosine-induced myelotoxicity suspected to be due to fluorouracil during flucytosine chronic therapy.

Adolescent↗

Structural studies of Bcl-xL/ligand complexes using 19F NMR.

Fluorine atoms are often incorporated into drug molecules as part of the lead optimization process in order to improve affinity or modify undesirable metabolic and pharmacokinetic profiles. From an NMR perspective, the abundance of fluorinated drug leads provides an exploitable niche for structural studies using 19F NMR in the drug discovery process. As 19F has no interfering background signal from biological sources, 19F NMR studies of fluorinated drugs bound to their protein receptors can yield easily interpretable and unambiguous structural constraints. 19F can also be selectively incorporated into proteins to obtain additional constraints for structural studies. Despite these advantages, 19F NMR has rarely been exploited for structural studies due to its broad lines in macromolecules and their ligand complexes, leading to weak signals in 1H/19F heteronuclear NOE experiments. Here we demonstrate several different experimental strategies that use 19F NMR to obtain ligand-protein structural constraints for ligands bound to the anti-apoptotic protein Bcl-xL, a drug target for anti-cancer therapy. These examples indicate the applicability of these methods to typical structural problems encountered in the drug development process.

Fluorine Compounds↗

Functional group contributions to the partitioning of phenols between liposomes and water.

The temperature dependency of the partitioning of p-alkylphenols and p-halophenols has been determined between dimyristoyl phosphatidylcholine liposomes and 0.15 M NaCl. Partition coefficients increased as a function of temperature below the endothermic phase transition temperature (Tc) of the phospholipid but decreased above this temperature. The transfer process was found to be entropy-dominated below and enthalpy-dominated above the Tc, although large negative entropy changes were observed. Regular changes in the thermodynamic functions, partition coefficients and functional group free energies occurred as a function of the alkyl chain length or size of the halogen substituent below but not above the Tc. This has tentatively been attributed to increased phenol-phospholipid interaction at the higher temperatures. The partitioning of p-fluorophenol behaved in a manner expected of fluorinated compounds, yielding relatively low partition coefficients, but it produced an additional effect of markedly lowering the Tc of dimyristoyl phosphatidylcholine. Good correlations of the partition coefficients in liposomes with those in bulk organic solvents and with molecular size of the solute have been obtained.

Dimyristoylphosphatidylcholine↗

Direct observation of 6-fluorodopamine in guinea pig nerve microsacs by 19F NMR.

19F nuclear magnetic resonance (NMR) has been used to examine the disposition of ring-fluorinated dopamine and norepinephrine in microsacs prepared from striata of guinea pig brains. Following incubation with a 10(-4)M initial concentration of 6-fluorodopamine (6F-DA), intact micmicrosacs at 4 degrees C gave a 19F NMR spectrum in which the 6F-DA present was sufficiently mobile to be visible. Intra-vesicular 6F-DA in striatal nerve terminals thus appears to exist in an environment resembling that in chromaffin vesicles but different from that prevailing inside the amine storage vesicles of platelets. Our data also suggest that the study of fluorinated compounds by 19F NMR can be used to expand our understanding of processes related to amine uptake, metabolism, and storage in nerves.

Animals↗

Metabolic fate of injected radiolabelled dopamine and 2-fluorodopamine in rats.

In evaluating positron-emitting analogs of dopamine (DA) as possible imaging agents for visualizing tissue sympathetic innervation and function, the metabolic fate of systemically injected [3H]-DA or [14C]-DA was compared with that of [3H]-2-fluoroDA in plasma and in sympathetically innervated tissues (left ventricle, spleen and salivary glands) of rats. By 60 min after the injection of [3H]-DA or [3H]-2-fluoroDA, concentrations of [3H]-DA. [3H]-2-fluoroDA, [3H]-norepinephrine ([3H]-NE) and [3H]-2-fluoroNE in tissue exceeded concentrations in plasma by up to several thousand-fold. Whereas most of the radioactivity in tissue was in catechols, radioactivity in plasma was due to O-methylated metabolites of DA, including homovanillic acid (HVA) and of NE, including normetanephrine (NMN) and methoxyhydroxphenylglycol (MHPG). Estimated ratios of tissue: blood radioactivity at 60 min after injection of [3H]-2-fluoroDA were 4.10 for the heart, 1.91 for the spleen and 2.10 for the salivary glands. The patterns of levels of catechol metabolites and analogs of HVA in plasma and effects of blockade of neuronal uptake with desipramine suggested that [3H]-2-fluoroDA was not as efficiently removed by neuronal uptake and not as efficiently beta-hydroxylated as the non-fluorinated compound. Concurrent administration of [3H]-DA and large amounts of non-radioactive 2-fluoroDA did not substantially alter the pattern of metabolites of [3H]-DA in plasma. After injection of [18F]-fluoroDA, visualization of sympathetic innervation of tissue should be feasible by position emission tomography.

Animals↗

Fluorine-19 NMR spectroscopic studies of the metabolism of 5-fluorouracil in the liver of patients undergoing chemotherapy.

Fluorine-19 nuclear magnetic resonance allows direct observation of fluorinated drugs and their metabolites in the human body without background signal from the tissue. A well-known fluorinated chemotherapeutic drug, 5-fluorouracil, and its metabolites were observed noninvasively in the liver of three patients undergoing cancer chemotherapy. Spectra were obtained at 1.5 T with a surface coil centered over the right lobe of the patient's liver. Administration of 1.5 gm of 5-fluorouracil was done after positioning in the magnet. Serial spectra, collected over a 2-h period, revealed both the nature of the metabolites present in the liver, and the time course of each patient's metabolism. These observations represent the first noninvasive NMR study of drugs in human patients and show the feasibility of using in vivo F-19 NMR spectroscopy for human studies of fluorinated compounds.

Female↗

Vapor pressure determinations of 8-2 fluorortelomer alcohol and 1-H perfluorooctane by capillary gas chromatography Relative retention time versus headspace methods.

Two distinctly different capillary gas chromatographic methods were used to determine the vapor pressure of 8-2 fluorotelomer alcohol (8-2 FTOH) and 1-H perfluoroheptane at several temperatures. For measurements employing the relative retention-time method, a short polymethylsiloxane column was used from 25 to 65 degrees C. For the 8-2 FTOH, hydrocarbon alcohols and perfluoroalcohols were used as reference standards. For 1-H perfluoroheptane, hydrocarbons were used as reference standards. Vapor pressure estimates could differ by as much as an order of magnitude compared to published results determined by other (nonchromatographic) methods. This variance may be a function of solvent-solute interactions within the gas chromatographic column and the infinite dilution assumption, both used in the relative retention method. For comparison, data were also gathered using headspace gas chromatography (GC) with atomic emission detection (AED). The results from this novel GC/AED method were consistent with prior nonchromatographic results. A discussion of why headspace is the preferred technique for the determination of vapor pressure for fluorinated compounds is presented.

Chromatography, Gas↗

A research synthesis of humans, animals, and environmental compartments exposed to PFAS: A systematic evidence map and bibliometric analysis of secondary literature.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a class of widely used anthropogenic chemicals. Concerns regarding their persistence and potential adverse effects have led to multiple secondary research publications. Here, we aim to assess the resulting evidence base in the systematic secondary literature by examining research gaps, evaluating the quality of reviews, and exploring interdisciplinary connections. METHODS: This study employed a systematic evidence-mapping approach to assess the secondary literature on the biological, environmental, and medical aspects of exposure to 35 fluorinated compounds. The inclusion criteria encompassed systematic reviews published in peer-reviewed journals, pre-prints, and theses. Comprehensive searches across electronic databases and grey literature identified relevant reviews. Data extraction and synthesis involved mapping literature content and narrative descriptions. We employed a modified version of the AMSTAR2 checklist to evaluate the methodological rigour of the reviews. A bibliometric data analysis uncovered patterns and trends in the academic literature. A research protocol for this study was previously pre-registered (osf.io/2tpn8) and published (Vendl et al., Environment International 158 (2022) 106973). The database is freely accessible through the interactive and user-friendly web application of this systematic evidence map at https://hi-this-is-lorenzo.shinyapps.io/PFAS_SEM_Shiny_App/. RESULTS: Our map includes a total of 175 systematic reviews. Over the years, there has been a steady increase in the annual number of publications, with a notable surge in 2021. Most reviews focused on human exposure, whereas environmental and animal-related reviews were fewer and often lacked a rigorous systematic approach to literature search and screening. Review outcomes were predominantly associated with human health, particularly with reproductive and children's developmental health. Animal reviews primarily focused on studies conducted in controlled laboratory settings, and wildlife reviews were characterised by an over-representation of birds and fish species. Recent reviews increasingly incorporated quantitative synthesis methodologies. The methodological strengths of the reviews included detailed descriptions of study selection processes and disclosure of potential conflicts of interest. However, weaknesses were observed in the critical lack of detail in reporting methods. A bibliometric analysis revealed that the most productive authors collaborate within their own country, leading to limited and clustered international collaborations. CONCLUSIONS: In this overview of the available systematic secondary literature, we map literature content, assess reviews' methodological quality, highlight data gaps, and draw research network clusters. We aim to facilitate literature reviews, guide future research initiatives, and enhance opportunities for cross-country collaboration. Furthermore, we discuss how this systematic evidence map and its publicly available database benefit scientists, regulatory agencies, and other stakeholders by providing access to current systematic secondary literature on PFAS exposure.

Bibliometrics↗