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PubMed1975

Fluorinated quinazolones III: synthesis and CNS depressant activity of fluorinated quinazolone derivatives.

The synthesis of 2-allylthio-3-(4'-fluorophenyl)-5,6,7,8-tetrafluoro-4-quinazolone, 2-n-propylthio-3-(4'-fluorophenyl)-5,6,7,8-tetrafluoro-4-quinazolone, 3-(4'-bromophenyl)-5,6,7,8-tetrafluoro-2,4-quinazolinedithione, and seven fluorinated 2-alkyl/phenyl-3-aryl-4(3H)-quinazolones is described. The synthesized compounds were screened for CNS depressant activity using pentobarbital sleeping time, pentylenetetrazol convulsions, and condition avoidance test as the parameters. Most of the screened compounds exhibited significant depressant activity.

Animals↗
PubMed2004

Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo.

Fluorine magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI) and proton anatomical magnetic resonance imaging (1H MRI) were performed on brains and lower extremities of six subjects in vivo concurrently with HPLC of serum to investigate tissue and plasma drug localization and withdrawal kinetics in humans treated with fluvoxamine or fluoxetine. 19F MRS signal was unexpectedly detected in the lower extremities months after complete disappearance of signal from plasma and brain. MRSI suggested that the lower extremity fluvoxamine signal originated mainly from bone marrow. Results suggest long-term sequestration of these drugs or their metabolites mainly in bone marrow and possibly in surrounding tissue and demonstrate the usefulness of MRS to reveal drug-trapping compartments in the body.

Adult↗
PubMed2000

Synthesis and experimental study of through-space hydrogen-fluorine and carbon-fluorine spin-spin coupling in 4,5-substituted 1-acetyl-8-fluoronaphthalenes.

The synthesis and NMR study (1H, 13C, and 19F) of a complete series of 4,5-substituted 1-acetyl-8-fluoronaphthalenes are reported. This data revealed a 6J(H,F) and a 5J(C,F) through space coupling between the fluorine and the methyl on the acetyl group (1H and 13C). The magnitude of this coupling constant changes depending on the nature of the substituent at C-4, the internuclear distance, and the solvent.

Carbon↗
PubMed1984

Fluorine-19 nuclear magnetic resonance investigation of fluorine-19-labeled phospholipids. 1. A multiple-pulse study.

A multiple-pulse nuclear magnetic resonance technique has been used to measure the order parameter, SFF, at 40 MHz for dimyristoylphosphatidylcholine labeled with a difluoromethylene group at the 4-, 8-, or 12-position of the sn-2-acyl chain dispersed in water in the liquid-crystalline phase. The Carr-Purcell-Meiboom-Gill multiple-pulse sequence can resolve the homonuclear dipolar coupling between the two fluorine nuclei, thus making a direct determination of the order parameter, SFF, for the F-F internuclear vector possible. Other interactions, such as the 19F chemical shift anisotropy, heteronuclear dipolar couplings, and field inhomogeneity, which normally obscure the dipolar splitting, are effectively canceled. The order parameters obtained in this work compare well with those obtained by 19F nuclear magnetic resonance line-shape analysis of the 19F-labeled phospholipids reported in the following paper [Dowd, S. R., Simplaceanu, V., & Ho, C. (1984) Biochemistry (following paper in this issue)] as well as comparable SCD order parameters, determined for the deuterium-carbon internuclear vector of deuterium-labeled phospholipids [Oldfield, E., Meadows, M., Rice, D., & Jacobs, R. (1978) Biochemistry 17, 2727-2740]. The present results clearly show the usefulness of using nuclear magnetic resonance spectroscopy to investigate lipid-lipid and protein-lipid interactions, especially for those systems containing a difluoromethylene group in the acyl chain of a phospholipid molecule.

Chemical Phenomena↗
PubMed1995

Fluorine for hydroxy substitution in biogenic amines: asymmetric synthesis and biological evaluation of fluorine-18-labeled beta-fluorophenylalkylamines as model systems.

This work explores the biomimetic potential of [18F]fluorine for hydroxy substitution in beta-phenethanolamines as a possible strategy for developing radiotracers for in vivo imaging. Stereospecific syntheses of the two model compounds (1R,2S)-1-[18F]fluoro-1-deoxyephedrine ([18F]FDE) and (1S,2S)-1-[18F]fluoro-1-deoxypseudoephedrine ([18F]FDP) were achieved in high radiochemical yield (62%, decay corrected) and high specific activity (> 2500 Ci/mmol) by reaction of [18F]fluoride ion with the appropriate chiral cyclic sulfamidate precursor. Both tracers exhibited good stability toward metabolic defluorination in vivo. High, homogeneous brain uptake (approximately 8% of injected dose) was observed after intravenous injection in mice similar to that reported for the structurally related analog [11C]methamphetamine. The 1R,2S isomer (FDE) showed a 3-fold higher concentration of radioactivity in whole brain as compared to the 1S,2S isomer (FDP). These results suggest possible employment of this strategy for chiral radiolabeling of biologically important phenethanolamines and catecholamines.

Animals↗
PubMed1981

Influence of fluorine substitution on the site of enzymatic O-methylation of fluorinated norepinephrines.

The extent of meta- and para-O-methylation by catechol O-methyltransferase of 2-fluoro-, 5-fluoro-, and 6-fluoronorepinephrine (FNE) at pH 7 and 9 was determined. The rank order of preference for para-O-methylation is 5FNE much greater than NE greater than 6FNE greater than 2FNE. In all cases, increasing the pH to 9 results in an increase in para-O-methylation. Results with 2F- and 5FNE demonstrate the importance of ionization in the methyltransferase reaction when fluorine is situated ortho to one of the phenolic groups. To establish unequivocally the identities of the products, the isomeric, monofluorinated vanillins and isovanillins were synthesized and directly related to the products formed enzymatically from the monofluorinated norepinephrines.

Catechol O-Methyltransferase↗
PubMed2005

Fluorinated diaryl sulfides as serotonin transporter ligands: synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents.

A series of new, fluorine-containing substituted diphenyl sulfides was synthesized to serve as candidate ligands for positron emission tomography (PET) imaging of the serotonin transporter (SERT) and to further probe the structure-activity relationship (SAR) of this class of compounds. Candidate compounds were assayed for their affinities to the monoamine transporters (SERT, norepinephrine transporter (NET), and dopamine transporter (DAT)) in competitive binding experiments in vitro using cloned human transporters. From these in vitro assays, four compounds (7c-f) were chosen for further evaluation. All four compounds have nanomolar affinity for SERT (K(i) 1.46 nM, 1.04 nM,1.83 nM, and 3.58 nM for 7c, 7d, 7e, and 7f, respectively). The F-18-labeled compounds, 16 and 18a-c, were prepared via a two-step radiosynthesis. Biodistribution studies in rats indicated that the F-18-labeled compounds localized in brain regions with high concentrations of SERT. Furthermore, competition experiments demonstrated that the binding of these radioligands in the rat brain was saturable, specific, and selective to SERT. Specific binding in the rat hypothalamus peaked at 5.6 for ligand 16 and 4.4 for 18b at 90 min after radioactivity administration. For ligand 18a, this same ratio was 8.4 at 120 min postinjection, while compound 18c displayed a lower specific binding ratio of 2.4. In summary, four F-18-labeled ligands were prepared and evaluated as candidate PET imaging agents for SERT. Among these four ligands, three appear to be promising radioligands suitable for the labeling of SERT in vivo, with 18a providing a higher specific binding in vivo than 16 or 18b.

Animals↗
PubMed2003

4-Fluorinated L-lysine analogs as selective i-NOS inhibitors: methodology for introducing fluorine into the lysine side chain.

In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.

Animals↗
PubMed1992

Fluorinated blood substitute retention in the rat measured by fluorine-19 magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Emulsions of perfluorocarbons (PFCs) have been tested as blood substitutes. However, evidence exists that there is long-term retention of some PFCs by the organs of the reticuloendothelial system (RES). The authors investigate organ retention of the blood substitute component, perfluorotripropylamine (FTPA), using fluorine-19 (19F) magnetic resonance imaging (MRI). METHODS: Various dosages of an emulsion of FTPA were administered to five rats. At intervals up to 86 weeks after infusion, 19F MRI was used to measure the amount of FTPA in liver and spleen. The data were fit to both linear and exponential elimination models, and organ retention half-lives were calculated. RESULTS: The exponential half-lives for combined liver and spleen FTPA ranged from 110 to 190 days. Linear half-lives ranged from 175 to 300 days. CONCLUSIONS: FTPA retained by the liver and spleen may be quantified by 19F MRI: The half-lives that were measured are longer than those reported previously for FTPA.

Animals↗
PubMed2004

Symmetric fluoro-substituted diol-based HIV protease inhibitors. Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy.

HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 A resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluoro-substitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

Amino Acids↗
PubMed1991

Tracer feasibility for monitoring tumor radiotherapy: a quadruple tracer study with fluorine-18-fluorodeoxyglucose or fluorine-18-fluorodeoxyuridine, L-[methyl-14C]methionine, [6-3H]thymidine, and gallium-67.

In a rat AH109A tumor model, metabolic tracers for glucose, amino acid, and nucleic acid metabolisms (2-deoxy-2-[18F]fluoro-D-glucose (18FDG), L-[methyl-14C]methionine (14C-Met), [6-3H]thymidine (3H-Thd), and 2'-deoxy-5-[18F]fluorouridine (18FdUrd], and the conventional radionuclide 67Ga-citrate were used to assess the feasibility of monitoring tumor radiotherapy using a quadruple tracer technique. Two combinations of four tracers (18FDG or 18FdUrd, 14C-Met, 3H-Thd and 67Ga) were compared in a time-course study after single-dose irradiation (20 Gy) and were also used in a dose-dependency study performed 6 days after 5, 10, 15, or 20 Gy of irradiation. Fluorine-18-FDG showed a large change in uptake and a steady response to radiotherapy. Fluorodeoxyuridine showed a rapid decrease after radiotherapy, but the range of change in uptake was narrow. Gallium-67 could not detect tumor response early after treatment, but showed a marked change in uptake later. [6-3H]Thd and 14C-Met showed a rapid response to irradiation and a high sensitivity for monitoring radiotherapy, suggesting that they may be feasible for PET studies.

Animals↗
PubMed1985

New synthesis of fluorine-18-labeled 6-fluoro-L-dopa by cleaving the carbon-silicon bond with fluorine.

A new synthesis of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine using 6-trimethylsilyl-3,4-dimethoxy-L-dopa-ethylester as a fluorination substrate is described. The silane is prepared from the corresponding bromo compound by reacting the latter with magnesium and trimethylsilyl chloride. Reaction of the silane with [18F]F2 (0.5% F2 in neon) in a mixture of freon-11/CCl4 (1:1) kept in a dry ice bath, subsequent hydrolysis with concentrated HBr in a bath at 140 degrees C, and simple chromatographic purification yielded 18F-labeled 6-fluoro-L-dopa. A radiochemical yield of about 8% was achieved at the end of the 1-hr synthesis. The specific activity at the end of the synthesis was about 680 mCi/mmol after a 30-min irradiation.

Chemical Phenomena↗
PubMed1980

Effect of fluorine content of drinking water on fluorine concentration of foods.

Foods originating from areas where the drinking water contains 1 mg F per litre since at least 30 years were examined for their fluorine content. In the F content, no difference was found between raw vegetables, cereals, and dishes of cooked meat whether they originated from areas where the drinking water was F-poor or containing 1 mg F per litre, despite the fact that in the latter areas the vegetable gardens were watered regularly with this F-rich water for 3 decades. The mean F content of the foods originating from the F-rich water for 3 decades. The mean F content of the foods originating from the F-rich areas were 0.28 mg per kg, 0.27 mg per kg, and 0.27 mg per kg, respectively. The mean F content of soups from F-rich places was 1.5 mg per kg, and that of the dishes of cooked vegetables, though lower, was still high enough: 0.40 mg per kg. It is pointed out that watering with water containing 1 mg F per litre does not increase the F content of the foods. The higher F content found in the foods and cooked vegetables came from the drinking water used for cooking.

Fluoridation↗
PubMed1994

Enantioselective synthesis of 6-[fluorine-18]-fluoro-L-dopa from no-carrier-added fluorine-18-fluoride.

METHODS: A trimethylammonium veratraldehyde triflate was synthesized and used as a precursor for the asymmetric synthesis of 6-[18F]fluoro-L-dopa. RESULTS: Its nucleophilic fluorination with 18F-fluoride produced by the 18O(p,n)18F nuclear reaction on enriched 18O-water led to the corresponding no-carrier-added [18F]fluoroveratraldehyde (45 +/- 5% EOB). Diiodosilane was used to prepare the corresponding [18F]fluorobenzyl iodide (36.5 +/- 5.3% EOB). Akylation of (S)-1-tert-boc-2-tert-butyl-3-methyl-4-imidazolidinone with this electrophilic agent, hydrolysis and purification by preparative high-pressure liquid chromatography made 6-[18F]fluoro-L-dopa ready for human injection, in a 23% +/- 6% decay-corrected radiochemical yield. The enantiomeric purity and the specific activity were above 96% and 1 Ci/mumole respectively. CONCLUSION: Through this procedure, starting from 250 mCi of 18F-fluoride, multimillicurie amounts (32 +/- 8.5 mCi) of no-carrier-added 6-[18F]fluoro-L-dopa are now available at the end of synthesis (90 min) with a good radiochemical purity (more than 98%).

Chromatography, High Pressure Liquid↗
PubMed1981

Studies in potential organo-fluorine antibacterial agents. Part 6: Synthesis and antibacterial activity of some new fluorine containing 1,3,4,5,7-pentasubstituted dipyrazolo[3,4-b,; 4,3-3]pyridines.

Ten new fluorine containing dipyrazolo [3,4-b;4,3-3]pyridines have been synthesized as possible antibacterial agents. The synthesis involves the condensation of 5-amino-1,3-disubstituted pyrazoles with an appropriate arylaldehyde at 220-240 degrees C. The synthesized compounds have been characterized by their m. p.'s elemental analysis, TLC, IR, 1H-NMR and 19F-NMR. A representative number of compounds have also been screened for their antibacterial activity and most of them were found to inhibit the growth of different bacteria.

Anti-Bacterial Agents↗