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PubMed2004

Effects of peripheral substituents and axial ligands on the electronic structure and properties of iron phthalocyanine.

The effects of peripheral substituents and axial ligands on the electronic structure and properties of iron phthalocyanine, H(16)PcFe, have been investigated using a DFT method. Substitution by electron-withdrawing fluorinated groups alters the ground state of H(16)PcFe and gives rise to large changes in the ionization potentials and electron affinity. For the six-coordinate adducts with acetone, H(2)O, and pyridine, the axial coordination of two weak-field ligands leads to an intermediate-spin ground state, while the strong-field ligands make the system diamagnetic. The electronic configuration of a ligated iron phthalocyanine is determined mainly by the axial ligand-field strength but can also be affected by peripheral substituents. Axial ligands also exert an effect on ionization potentials and electron affinity and can, as observed experimentally, even change the site of oxidation/reduction.

Algorithms↗
PubMed2000

Improved target system for production of high purity [18F]fluorine via the 18O(p,n)18F reaction.

An improved aluminium target system for production of elemental fluorine via the 18O(p,n)18F reaction using a two-step irradiation protocol is described. In the first step highly enriched gaseous oxygen-18 is irradiated with protons to form fluorine-18 which gets deposited on the inner target surface. In the second step, after cryogenic recovery of oxygen-18 target gas, a mixture of elemental 'cold' fluorine and krypton is introduced and a short proton irradiation is done, whereby an isotopic exchange between the gaseous fluorine and the deposited radiofluorine occurs. The second step leads to the recovery of the radiofluorine as [18F]fluorine. Optimisation studies were performed regarding the yield and specific radioactivity of [18F]fluorine. Furthermore, some irradiation parameters relevant to the recovery step were investigated. It was found that a 15 to 20 min irradiation with a beam current of 20 microA is sufficient for the isotopic exchange between the fluorine-carrier and the 18F-radioactivity deposited on the inner wall of the target. The distribution of the 18F-radioactivity deposited on the inner target surface is inhomogeneous, probably due to convection effects. Extensive radioanalytical techniques were applied to characterise the reactivity of [18F]fluorine and to identify undesired nonreactive 18F-compounds, mainly [18F]tetrafluoromethane and [18F]nitrogentrifluoride. The [18F]fluorine produced in the system used has the distinction of having a negligible contamination from those inert 18F-compounds. This is a combined effect of the use of highest purity gases and a welded target construction, which avoids any contact of the gases with organic material during irradiations. The target has proved to be very reliable for production of [18F]fluorine in high yields of up to 34 GBq and specific activities of 350-600 GBq/mmol, both at 30 min after end of activation bombardment.

Aluminum↗
PubMed2001

Monofluorinated polycyclic aromatic hydrocarbons as internal standards to monitor trace enrichment and desorption of their parent compounds during solid-phase extraction.

Solid-phase extraction (SPE) is an established sample-preparation technique for clean-up procedures of polycyclic aromatic hydrocarbons (PAHs). The suitability of monofluorinated polycyclic aromatic hydrocarbons (F-PAHs) as a novel set of internal standards, was tested for two widely used SPE sorbents, octyl-bonded silica and styrene-divinylbenzene copolymer. The elution profiles of eight F-PAHs and their parent PAHs, taken from the priority pollutant list of the US-Environmental Protection Agency, were compared for demineralized water and waste water. In both instances, the match of the elution profiles was exceptionally close. The eight F-PAHs and the corresponding PAHs were determined by reversed-phase liquid chromatography using acetonitrile-water gradient elution with UV detection at 254 nm. The UV spectra of the F-PAHs show a small bathochromic shift compared with the parent PAHs.

Chromatography, Liquid↗
PubMed2006

Synthesis and radiosynthesis of [(18)F]FPhEP, a novel alpha(4)beta(2)-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors.

FPhEP (1, (+/-)-2-exo-(2'-fluoro-3'-phenyl-pyridin-5'-yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3'-phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice). FPhEP (1, K(i) of 0.24 nM against [(3)H]epibatidine) as reference as well as the corresponding N-Boc-protected chloro- and bromo derivatives (3a,b) as precursors for labelling with fluorine-18 were synthesized in eight and nine steps, respectively, from commercially available N-Boc-pyrrole (overall yields=17% for 1, 9% for 3a and 8% for 3b). FPhEP (1) was labelled with fluorine-18 using the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho-radiofluorination from the corresponding N-Boc-protected chloro- or bromo derivatives (3 a,b-1mg) and the activated K[(18)F]F-Kryptofix(222) complex in DMSO using microwave activation at 250 W for 1.5 min, followed by (2) quantitative TFA-induced removal of the N-Boc-protective group. Radiochemically pure (>99%) [(18)F]FPhEP ([(18)F]-1, 2.22-3.33 GBq, 66-137 GBq/micromol) was obtained after semi-preparative HPLC (Symmetry C18, eluent aq 0.05 M NaH(2)PO(4)/CH(3)CN, 80:20 (v:v)) in 75-80 min starting from a 18.5 GBq aliquot of a cyclotron-produced [(18)F]fluoride production batch (10-20% nondecay-corrected overall yield). In vitro binding studies on rat whole-brain membranes demonstrated a subnanomolar affinity (K(D) 660 pM) of [(18)F]FPhEP ([(18)F]-1) for nAChRs. In vitro autoradiographic studies also showed a good contrast between nAChR-rich and -poor regions with a low non-specific binding. Comparison of in vivo Positron Emission Tomography (PET) kinetics of [(18)F]FPhEP ([(18)F]-1) and [(18)F]F-A-85380 in baboons demonstrated faster brain kinetics of the former compound (with a peak uptake at 20 min post injection only). Taken together, the preliminary data obtained confirm that [(18)F]FPhEP ([(18)F]-1) has potential for in vivo imaging nAChRs in the brain with PET.

Animals↗
PubMed1992

Liposomes containing fluorinated steroids: an analysis based on photon correlation and fluorine-19 nuclear magnetic resonance spectroscopy.

Small unilamellar liposomes containing fluorinated steroids (flumethasone and dexamethasone) were obtained. A physicochemical evaluation was conducted based on photon correlation spectroscopy (PCS) and fluorine-19 (19F) nuclear magnetic resonance (NMR) spectroscopy compared with standard biochemical methods (HPLC). The PCS method provides a fast and adequate evaluation of some critical features of liposomes (size, physical stability). In addition, 19F NMR spectroscopy gives substantial information, in a nondestructive manner, on steroid behavior in the membrane upon encapsulation and also when the temperature of liposomes is increased. The combined spectroscopic approach proposed here might prove useful in (1) the management of liposomal formulation, especially in the documentation of physicochemical properties, (2) pharmaceutical control in the industrial production line, and (3) control preceding injection at the clinical site. Spectroscopic techniques might offer a complementary approach to classical biochemical methods in the evaluation of the properties of a liposomal formulation and could be usefully integrated into quality control procedures.

Chemical Phenomena↗
PubMed1999

Syntheses and beta-adrenergic binding affinities of (R)- and (S)-fluoronaphthyloxypropanolamines.

The beta-adrenergic receptors mediate several physiological processes including heart rate (beta 1), bronchodilation (beta 2), and lipolysis (beta 3). Therefore, selectivity is important for a possible therapeutic agent acting via these receptors. Aryloxypropanolamines are beta-receptor agonists or antagonists, depending on the aryl group and its substituents. We therefore hypothesized that fluorine substitution on the aromatic ring in this class could lead to significant biological effects because of the unique chemical characteristics of fluorine. Because the target compound has a chiral center, we set out to synthesize the two enantiomers so that effects of stereochemistry on biological activity could be evaluated. Syntheses of the enantiomers were performed starting with commercially available fluoronaphthalene and subsequent use of the chiral synthon (2R)- or (2S)-glycidyl 3-nitrobenzenesulfonate, depending on the desired enantiomer. High-pressure liquid chromatography (HPLC) methods were used to characterize %ee. Each enantiomer was synthesized. They exhibited nanomolar binding activities on beta-adrenergic receptors. The (S)-enantiomer was found to be up to 310 times more potent than the (R). It was also found to be about five-fold more selective for beta 2- than for beta 1-receptors. The current report demonstrates the importance of stereochemistry for the fluoroaromatic beta-receptor ligands.

Adrenergic beta-Antagonists↗
PubMed2004

Fluorine interactions at the thrombin active site: protein backbone fragments H-C(alpha)-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles.

In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure analysis of the protein-ligand complex revealed favorable C-F...H-C(alpha)-C=O and C-F...C=O interactions of the 4-F substituent of the inhibitor with the backbone H-C(alpha)-C=O unit of Asn98. The importance of these interactions was further corroborated by the analysis of small-molecule X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C--F...C=O interactions that are observed for both aromatic and aliphatic C-F units and a variety of carbonyl and carboxyl derivatives, the F atom approaches the C=O C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions C--F.C[triple chemical bond]N, C-F.C-F, and C-F...NO(2), in which the F atoms interact at sub-van der Waals distances with the electrophilic centers.

Animals↗
PubMed2003

Macrocycles from perhalogenated heterocycles.

Perhalogenated heteroaromatic systems, such as trichloro-s-triazine and pentafluoropyridine, are multifunctional "building blocks" that react with a number of appropriate difunctional nucleophiles to provide access to a variety of macrocyclic and even cage-like molecular architectures. Unusual structural and complexation characteristics of the systems reported so far, such as the recognition of anions, provide a further stimulus for the development of this area.

Bridged-Ring Compounds↗
PubMed2005

Analysis and calculation of the 31P and 19F NMR spectra of hexafluorocyclotriphosphazene.

The higher order high-resolution (31)P and (19)F NMR spectra of hexafluorocyclotriphosphazene (F(2)PN)(3) were measured at 183 K and interpreted using subspectral analysis and iterative fitting computation. (F(2)PN)(3) forms a rigid nine-spin system [A[X](2)](3) with D(3h) symmetry. Two complete and very similar sets of six experimental spin-spin coupling constants, (1)J(P,F), (2)J(P,P), (2)J(F,F), (3)J(P,F), (4)J(F,F)(cis) and (4)J(F,F)(trans), were determined for the first time. Theoretical DFT calculations of chemical shifts and coupling constants were performed to assess their predictive value. The PP/aug-cc-pVDZ treatment rendered the best agreement with experimental data.

Fluorine↗
PubMed1984

Discovery and development of flecainide.

The flecainide discovery and development process started in 1966 with the broad goal of investigating the effects of fluorine substitution in potential drug molecules. The overall process evolved slowly. The original goals of the project were translated into the 3 major phases: (1) the synthesis and evaluation of 2 major chemical series through the efforts of chemists who incorporated fluorine atoms into new compounds; (2) a change in focus from local anesthetic programs to the antiarrhythmic project through the efforts and advisement of pharmacologists; and (3) commitment to a flecainide development plan culminating in the new drug application for approval of flecainide in the suppression and prevention of ventricular arrhythmias.

Anesthetics, Local↗
PubMed1984

6-Fluoro-vitamin D3: a new antagonist of the biological actions of vitamin D3 and its metabolites which interacts with the intestinal receptor for 1 alpha,25(OH)2-vitamin D3.

The biological activity and the binding affinity for the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] intestinal receptor of a new fluorine-containing vitamin D compound, namely 6-fluoro-vitamin D3 (6-F-D3), is reported. A significant interaction of 6-F-D3 with the 1,25(OH)2D3 receptor was found, with a relative competitive index (RCI) of 0.26 +/- 0.04, which is intermediate between 25-hydroxyvitamin D3 (0.14 +/- 0.01) and 1 alpha-hydroxyvitamin D3 (0.46 +/- 0.08), where the RCI of 1,25(OH)2D3 is defined to be 100. In contrast, vitamin D3 was unable to interact with the 1,25(OH)2D3 receptor. Also, the biological activity of 6-F-D3 was assessed in vivo in the vitamin D-deficient chick. 6-F-D3 at doses up to 130 nmol displayed no biological action on either intestinal calcium absorption (ICA) or bone calcium mobilization (BCM) over the time interval of 14-48 h after dosing. However, when 130 nmol 6-F-D3 was given 2 h before and 6 h after vitamin D3 (1.62 nmol), a significant inhibition of vitamin D-mediated ICA was noted. Also, a dose of 130 nmol 6-F-D3 given 2 h before and 6 h after 1,25(OH)2D3 (0.26 nmol) significantly inhibited ICA, as measured at 12 h. 6-F-D3 is the first vitamin D analog found which has an ability to both bind to the 1,25(OH)2D3 receptor and to antagonize the production of biological responses by 1,25(OH)2D3.

Animals↗
PubMed1989

Chronic effects of tranylcypromine and 4-fluorotranylcypromine on regional brain monoamine metabolism in rats: a comparison with clorgyline.

A regional analysis of brain amine and acid metabolite levels was conducted after chronic administration of the antidepressant tranylcypromine (0.5 mg/kg/day), of a novel fluorinated analog of this compound, and of clorgyline (1.0 mg/kg/day). These compounds were administered to male Sprague-Dawley rats for 28 days by subcutaneous infusion using osmotic minipumps (Alzet 2002). Levels of noradrenaline, 5-hydroxytryptamine, dopamine, and of the acid metabolites 5-hydroxyindole-3-acetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in the frontal cortex, nucleus accumbens, caudate nucleus, hippocampus, and hypothalamus. After 28 days of drug administration, sustained increases in amines and decreases in their acid metabolites were observed. Regional differences in these effects were minimal. These results are consistent with reports of sustained increases in brain amine concentrations following prolonged administration of other monoamine oxidase inhibitors.

3,4-Dihydroxyphenylacetic Acid↗