Sulfur [18F]Fluoride Exchange Click Chemistry Enabled Ultrafast Late-Stage Radiosynthesis.

The lack of efficient [18F]fluorination processes and target-specific organofluorine chemotypes remains the major challenge of fluorine-18 positron emission tomography (PET). We report here an ultrafast isotopic exchange method for the radiosynthesis of novel PET agent aryl [18F]fluorosulfate enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully automated 18F-radiolabeling of 25 structurally and functionally diverse aryl fluorosulfates with excellent radiochemical yield (83-100%, median 98%) and high molar activity (280 GBq µmol-1) at room temperature in 30 s. The purification of radiotracers requires no time-consuming HPLC but rather a simple cartridge filtration. We further demonstrate the imaging application of a rationally designed poly(ADP-ribose) polymerase 1 (PARP1)-targeting aryl [18F]fluorosulfate by probing subcutaneous tumors in vivo.

Radiosynthesis of [18F]SiFAlin-TATE for clinical neuroendocrine tumor positron emission tomography.

Here, we describe an extension of our silicon fluoride acceptor (SiFA) protocol for 18F-labeling of peptides that addresses challenges associated with preparing a clinical-grade (Tyr3)-octreotate (TATE) tracer for diagnosis of neuroendocrine tumors (NETs). After several iterations of protocol optimization (e.g., finding the optimal pH at which the isotopic exchange (IE) reaction produces high radiochemical yields (RCYs)), the SiFA technology achieved clinical applicability, as showcased by radiosynthesis of [18F]SiFAlin-TATE ([18F]SiTATE), the first SiFA peptide used in the clinical diagnosis of NETs. The TATE peptide binds to somatostatin receptors associated with NETs. Radiolabeled TATE derivatives are routinely applied in clinical oncological PET imaging. The (SiFA) 18F-labeling technology is based on the IE of a 19F atom for a radioactive 18F atom, a highly efficient labeling reaction under mild conditions. The 19F is part of a biomolecule bearing the SiFA building block, composed of a central silicon (Si) atom, a 19F atom connected to the Si atom, and two Si-bound tert-butyl groups. The IE proceeds through a penta-coordinate bipyramidal intermediate, followed by elimination of non-radioactive 19F, yielding the labeled compound in high RCYs at room temperature (22 °C). The simplicity and lack of side-product formation of this approach enable a one-step, kit-like preparation of structurally complex and unprotected radiopharmaceuticals. Compounds such as peptides used for tumor imaging in nuclear medicine can be 18F-labeled without the need for complex purification protocols. [18F]SiTATE can be synthesized within 30 min in preparative RCYs of 42%, radiochemical purity of >97% and high molar activity of 60 GBq/µmol.

Synthesis of androgen receptor antagonists containing a pentafluorosulfanyl (SF5 ) moiety.

A novel scaffold of pentafluorosulfanyl (SF5 )-containing enzalutamide analogues was discovered for potent androgen receptor (AR) antagonists through rational drug design. Several compounds showed good biological profiles in AR binding. Of the derivatives studied, compound 8a had potent AR antagonist activity (IC50 = 7.1 ± 1.0 µM) and high efficacy (104.5 ± 12.8%). It exhibited an inhibitory effect comparable to that of enzalutamide (inhibition = 66.0 and 77.9%, respectively) in a prostate cancer cell line. The results point to the potential of using this scaffold to develop new AR antagonists.

Aryl fluorosulfate analogues as potent antimicrobial agents: SAR, cytotoxicity and docking studies.

A series of aryl fluorosulfate analogues (1-37) were synthesized and tested for in vitro antibacterial and antifungal studies, and validated by docking studies. The compounds 9, 12, 14, 19, 25, 26, 35, 36 and 37 exhibited superior antibacterial potency against tested bacterial strains, while compounds 2, 4, 5, 15, 35, 36 and 37 were found to have better antifungal activity against tested fungal strains, compared to standard antibiotic gentamicin and ketoconazole respectively. Among all the synthesized 37 analogs, compounds 25, 26, 35, 36 and 37 displayed excellent anti-biofilm property against Staphylococcus aureus. The structure-activity relationship (SAR) revealed that the antimicrobial activity depends upon the presence of -OSO2F group and slender effect of different substituent's on the phenyl rings. The electron donating (OCH3) groups in analogs increase the antibacterial activity, and interestingly the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 35, 36 and 37). The mechanism of potent compounds showed membrane damage on bacteria confirmed by SEM. Compounds 35, 36 and 37 exhibited highest glide g-scores in molecular docking studies and validated the biocidal property.

Quantification of 18F-Fluoride Kinetics: Evaluation of Simplified Methods.

UNLABELLED: (18)F-fluoride PET is a promising noninvasive method for measuring bone metabolism and bone blood flow. The purpose of this study was to assess the performance of various clinically useful simplified methods by comparing them with full kinetic analysis. In addition, the validity of deriving bone blood flow from K1 of (18)F-fluoride was investigated using (15)O-H2O as a reference. METHODS: Twenty-two adults (mean age ± SD, 44.8 ± 25.2 y), including 16 patients scheduled for bone surgery and 6 healthy volunteers, were studied. All patients underwent dynamic (15)O-H2O and (18)F-fluoride scans before surgery. Ten of these patients had serial PET measurements before and at 2 time points after local bone surgery. During all PET scans, arterial blood was monitored continuously. (18)F-fluoride data were analyzed using nonlinear regression (NLR) and several simplified methods (Patlak and standardized uptake value [SUV]). SUV was evaluated for different time intervals after injection and after normalizing to body weight, lean body mass, and body surface area, and simplified measurements were compared with NLR results. In addition, changes in SUV and Patlak-derived fluoride influx rate (Ki) after surgery were compared with corresponding changes in NLR-derived Ki. Finally, (18)F-fluoride K1 was compared with bone blood flow derived from (15)O-H2O data, using the standard single-tissue-compartment model. RESULTS: K1 of (18)F-fluoride correlated with measured blood flow, but the correlation coefficient was relatively low (r = 0.35, P < 0.001). NLR resulted in a mean Ki of 0.0160 ± 0.0122, whereas Patlak analysis, for the interval 10-60 min after injection, resulted in an almost-identical mean Ki of 0.0161 ± 0.0117. The Patlak-derived Ki, for 10-60 min after injection, showed a high correlation with the NLR-derived Ki (r = 0.976). The highest correlation between Ki and lean body mass-normalized SUV was found for the interval 50-60 min (r = 0.958). Finally, changes in SUV correlated significantly with those in Ki (r = 0.97). CONCLUSION: The present data support the use of both Patlak and SUV for assessing fluoride kinetics in humans. However, (18)F-fluoride PET has only limited accuracy in monitoring bone blood flow.

One-pot template-free synthesis of NaYF4 upconversion hollow nanospheres for bioimaging and drug delivery.

Hollow-structured nanomaterials with fluorescent properties are extremely attractive for image-guided cancer therapy. In this paper, sub-100 nm and hydrophilic NaYF4 upconversion (UC) hollow nanospheres (HNSs) with multicolor UC luminescence and drug-delivery properties were successfully prepared by a facile one-pot template-free hydrothermal route using polyetherimide (PEI) polymer as the stabilizing agent. XRD, SEM, TEM, and N2-adsorption/desorption were used to characterize the as-obtained products. The growth mechanism of the HNSs has been systematically investigated on the basis of the Ostwald ripening. Under 980 nm excitation, UC emissions of HNSs can be tuned by a simple change of the concentration or combination of various upconverters. As a result, the PEI-coated HNSs could be used as efficient probes for in vitro upconversion luminescence (UCL) cell imaging. Furthermore, a doxorubicin storage/release behavior and cancer-cell-killing ability investigation reveal that the product has the potential to be a drug carrier for cancer therapy.

Multifunctional core-shell structured nanocarriers for synchronous tumor diagnosis and treatment in vivo.

Multifunctional, mesoporous, silica-coated upconversion luminescent/magnetic NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-PEG (referred to as UCNPS; PEG=polyethylene glycol) nanocomposites were fabricated through a phase-transfer-assisted surfactant-templating coating process, followed by hydrophilic polymer (PEG) functionalization to improve the stability and biocompatibility. The UCNP core imparts the nanomaterials with luminescence and magnetic properties for simultaneous upconversion optical and magnetic resonance (MR) imaging, whereas the mesoporous shell affords the nanomaterials the ability to load the anticancer drug doxorubicin. Proof-of-principle in vitro and in vivo experiments are presented to demonstrate that the resultant composite nanomaterials can serve as nanotheranostics for synchronous upconversion luminescence/MR dual modal imaging and anticancer drug delivery; this finally realizes the integration of diagnostics and the treatment of cancers.

Surfactant-free synthesis, luminescent properties, and drug-release properties of LaF3 and LaCO3F hollow microspheres.

Uniform LaF3 and LaCO3F hollow microspheres were successfully synthesized through a surfactant-free route by employing La(OH)CO3 colloidal microspheres as a sacrificial template and NaBF4 as the fluorine source. The synthetic process consists of two steps: the preparation of a La(OH)CO3 precursor via a facile urea-based precipitation and the following formation of lanthanide fluoride hollow microspheres under aqueous conditions at low temperature (50 °C) and short reaction time (3 h), without using any surfactant and catalyst. The formation of hollow spheres with controlled size can be assigned to the Kirkendall effect. It is found that the phase and structure of the products can be simply tuned by changing the pH values of the solution. Time-dependent experiments were employed to study the possible formation process. N2 adsorption/desorption results indicate the mesoporous nature of LaF3 hollow spheres. Yb(3+)/Er(3+) (Ho(3+)) and Yb(3+)/Tm(3+)-doped LaF3 hollow spheres exhibit characteristic up-conversion (UC) emissions of Er(3+) (Ho(3+)) and Tm(3+) under 980 nm laser-diode excitation, and Ce(3+)/Tb(3+)-doped LaF3 and LaCO3F emit bright yellow-green and near-white light under UV irradiation, respectively. In particular, LaF3:Yb/Er and LaCO3F:Ce/Tb hollow microspheres exhibit obvious sustained and pH-dependent doxorubicin release properties. The luminescent properties of the carriers allow them to be tracked or monitored during the release or therapy process, suggesting their high potential in the biomedical field.

Highly uniform hollow GdF3 spheres: controllable synthesis, tuned luminescence, and drug-release properties.

In this paper, uniform hollow mesoporous GdF3 micro/nanospheres were successfully prepared by a facile two-step synthesis route without using any surfactant, catalyst, and further calcination process. The precursor Gd(OH)CO3 spheres are prepared by a coprecipitation process. After that, uniform and size-tunable GdF3 hollow spheres were easily coprecipitated with NaBF4 at the sacrifice of the precursor with low temperature and short reaction time. X-ray diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution TEM, N2 adsorption/desorption, and up-conversion (UC) photoluminescence spectra were used to characterize the as-obtained products. It is found that the initial pH value and NaBF4/Gd(3+) molar ratios play important roles in the structures, sizes, and phases of the hollow products. The growth mechanism of the hollow spheres has been systematically investigated based on the Kirkendall effect. Under 980 nm IR laser excitation, UC luminescence of the as-prepared Yb(3+)/Er(3+)-codoped GdF3 hollow spheres can be changed by a simple adjustment of the concentration of the Yb(3+) ion. Enhanced red emission is obtained by introducing Li(+) ions in GdF3:Yb(3+)/Er(3+). Furthermore, a doxorubicin release experiment and a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide cytotoxicity assay reveal that the product has potential application in drug delivery and targeted cancer therapy.

Direct visualization of gastrointestinal tract with lanthanide-doped BaYbF5 upconversion nanoprobes.

Nanoparticulate contrast agents have attracted a great deal of attention along with the rapid development of modern medicine. Here, a binary contrast agent based on PAA modified BaYbF5:Tm nanoparticles for direct visualization of gastrointestinal (GI) tract has been designed and developed via a one-pot solvothermal route. By taking advantages of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of these well-designed nanoparticles, their feasibility as a multi-modal contrast agent for GI tract was intensively investigated. Significant enhancement of contrast efficacy relative to clinical barium meal and iodine-based contrast agent was evaluated via X-ray imaging and CT imaging in vivo. By doping Tm(3+) ions into these nanoprobes, in vivo NIR-NIR imaging was then demonstrated. Unlike some invasive imaging modalities, non-invasive imaging strategy including X-ray imaging, CT imaging, and UCL imaging for GI tract could extremely reduce the painlessness to patients, effectively facilitate imaging procedure, as well as rationality economize diagnostic time. Critical to clinical applications, long-term toxicity of our contrast agent was additionally investigated in detail, indicating their overall safety. Based on our results, PAA-BaYbF5:Tm nanoparticles were the excellent multi-modal contrast agent to integrate X-ray imaging, CT imaging, and UCL imaging for direct visualization of GI tract with low systemic toxicity.

Attitude towards personal protective equipment in the French nuclear fuel industry.

This descriptive cross-sectional study examines the compliance of workers from the European Gaseous Diffusion Uranium Enrichment Consortium (EURODIF) with personal protection equipment (PPE) in view of the various hazards in the nuclear fuel industry. The PPE inventory was drawn up by an industrial hygienist in charge of the PPE at EURODIF. Two hundred and twenty seven (10%) randomly selected, active and retired, EURODIF workers filled in a questionnaire on their attitudes towards PPE. Exposure data from the EURODIF job exposure matrix were used to examine whether PPE usage varies according to exposure level. The study suggests a PPE usage profile that varies depending on the hazards present and PPE available. Anti-uranium PPE and gloves were among the best rated, while anti-spray goggles were the least used. We found that, for most hazards known to cause cancer or irreversible health damage, PPE usage varied according to exposure (homogeneity test, p<0.05; trend test, p<0.05). The continuous use of PPE among workers should be encouraged through improvements to the PPE management system. A precise model of individual exposure can only be designed if the use and efficiency of PPE are taken into consideration.

Phase and size controllable synthesis of NaYbF4 nanocrystals in oleic acid/ionic liquid two-phase system for targeted fluorescent imaging of gastric cancer.

Upconversion nanocrystals with small size and strong fluorescent signals own great potential in applications such as biomolecule-labeling, in vivo tracking and molecular imaging. Herein we reported that NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with small size and strong fluorescent signals were controllably synthesized by oleic acid (OA)/ ionic liquid (IL) two-phase system for targeted fluorescent imaging of gastric cancer in vivo. The optimal synthesis condition of NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals by OA/IL two-phase system was established, adding more metal ion such as Na(+) ion could facilitate the size control and crystal-phase transition, more importantly, markedly enhancing fluorescent intensity of beta-phase nanocrystals compared with traditional methods. Alpha-phase NaYbF4, 2%Tm upconversion nanocrystals with less than 10nm in diameter and beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with 30 nm or so in diameter and strong fluorescent signals were obtained, these synthesized nanocrystals exhibited very low cytotoxicity. Folic acid-conjugated silica-modified beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals were prepared, could actively target gastric cancer tissues implanted into nude mice in vivo, and realized targeted fluorescent imaging. Folic acid-conjugated silica-modified NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals show great potential in applications such as targeted near infared radiation fluorescent imaging, magnetic resonance imaging and targeted therapy of gastric cancer in the near future.

Surface modification of upconverting NaYF4 nanoparticles with PEG-phosphate ligands for NIR (800 nm) biolabeling within the biological window.

We present a technique for the replacement of oleate with a PEG-phosphate ligand [PEG = poly(ethylene glycol)] as an efficient method for the generation of water-dispersible NaYF(4) nanoparticles (NPs). The PEG-phosphate ligands are shown to exchange with the original oleate ligands on the surface of the NPs, resulting in water-dispersible NPs. The upconversion intensity of the NPs in aqueous environments was found to be severely quenched when compared to the original NPs in organic solvents. This is attributed to an increase in the multiphonon relaxations of the lanthanide excited state in aqueous environments due to high energy vibrational modes of water molecules. This problem could be overcome partially by the synthesis of core/shell NPs which demonstrated improved photophysical properties in water over the original core NPs. The PEG-phosphate coated upconverting NPs were then used to image a line of ovarian cancer cells (CaOV3) to demonstrate their promise in biological application.

Synthesis and biocompatibility of an experimental glass ionomer cement prepared by a non-hydrolytic sol-gel method

The aims of this study were to demonstrate the synthesis of an experimental glass ionomer cement (GIC) by the non-hydrolytic sol-gel method and to evaluate its biocompatibility in comparison to a conventional glass ionomer cement (Vidrion R). Four polyethylene tubes containing the tested cements were implanted in the dorsal region of 15 rats, as follows: GI - experimental GIC and GII - conventional GIC. The external tube walls was considered the control group (CG). The rats were sacrificed 7, 21 and 42 days after implant placement for histopathological analysis. A four-point (I-IV) scoring system was used to graduate the inflammatory reaction. Regarding the experimental GIC sintherization, thermogravimetric and x-ray diffraction analysis demonstrated vitreous material formation at 110oC by the sol-gel method. For biocompatibility test, results showed a moderate chronic inflammatory reaction for GI (III), severe for GII (IV) and mild for CG (II) at 7 days. After 21 days, GI presented a mild reaction (II); GII, moderate (III) and CG, mild (II). At 42 days, GI showed a mild/absent inflammatory reaction (II to I), similar to GII (II to I). CG presented absence of chronic inflammatory reaction (I). It was concluded that the experimental GIC presented mild/absent tissue reaction after 42 days, being biocompatible when tested in the connective tissue of rats.

O objetivo deste estudo foi demonstrar a sinterização pelo método sol-gel não-hidrolítico de um cimento de ionômero de vidro experimental (CIV) e avaliar sua biocompatibilidade em relação a um cimento de ionômero de vidro convencional (Vidrion R). Quatro tubos de polietileno contendo os cimentos testados foram implantados no dorso de 15 ratos, da seguinte maneira: GI - CIV Experimental e GII - CIV Convencional. A lateral do tubo foi considerada Grupo Controle. Os ratos foram sacrificados em 7, 21 e 42 dias pós-implantação para análise histopatológica. Uma escala de I a IV foi utilizada como sistema de score para graduar a reação inflamatória. Em relação à sinterização do CIV experimental, as análises termogravométrica e por difração de raio-x demonstraram a formação de material vítreo aos 110oC pelo método sol-gel. Para o teste de biocompatibilidade, os resultados mostraram uma reação inflamatória moderada para o GI (III), severa para o GII (IV) e branda para o Grupo Controle (II) aos 7 dias. Após 21 dias, GI apresentou uma reação branda (II); GII, moderada (III) e Grupo Controle, branda (II). Aos 42 dias, GI apresentou uma reação inflamatória branda/ausente (II a I), similar ao GII (II a I). O Grupo Controle demonstrou ausência de reação inflamatória (I). Concluiu-se que o CIV Experimental apresentou reação tecidual branda/ausente após 42 dias, sendo biocompatível quando testado em tecido conjuntivo de ratos.

Monodisperse upconverting nanocrystals by microwave-assisted synthesis.

Upconverting nanocrystals have a tremendous potential for applications in fields such as bioanalysis, medical therapy, or display technologies. However, a prerequisite for many applications is the availability of small, monodisperse, and highly luminescent nanocrystals. Here we show, that a microwave-assisted synthesis approach allows for the synthesis of such monodisperse and luminescent upconverting nanocrystals within 5 min in a closed reaction vessel. Even though the same reactants and solvents as with classical conductive heating reactions were used, microwave-assisted synthesis resulted in differently sized and shaped particles and provided superior reaction control. The nucleation and growth mechanism follows a La Mer scheme and can be controlled extremely accurately. It is expected that the fundamental principles of this synthesis approach can be applied to many other types of nanocrystals as well.

Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors.

HIV-1 integrase (IN) has emerged as an important therapeutic target for anti-HIV drug development. Its uniqueness to the virus and its critical role in the viral life cycle makes IN suitable for selective inhibition. The recent approval of Raltegravir (MK-0518) has created a surge in interest and great optimism in the field. In our ongoing IN drug design research, we herein report the discovery of substituted analogs of 3-acetyl-4-hydroxy-2-pyranones and their difluoridoborate complexes as novel IN inhibitors. In many of these compounds, complexation with boron difluoride increased the potency and selectivity of IN inhibition. Compound 9 was most active with an IC(50) value of 9 microM and 3 microM for 3'-processing and strand transfer inhibition, respectively.

The gas-phase on-line production of phosphorus thiotrihalides, SPX3 and their identification by infrared spectroscopy.

A new route has been devised, leading to the production of phosphorus thiotrihalides, SPX3 where X = F, Br and I by an on-line process using phosphorus thiotrichloride, SPCl3 as starting compound gassed over the following heated salts NaF, KBr and KI at 530, 800 and 440 degrees C, respectively. The products have been characterized by their IR spectra, showing bands with PQR type structure, centered at 985, 762, 744 and 715 cm(-1). These bands are assigned to v1(a1), the S=P stretching fundamental modes of SPF3, SPCl3, SPBr3 and SPI3, respectively.

Electroytic partial fluorination of organic compounds. 52. Regio- and diastereoselective anodic fluorination of thiazolidines.

Anodic fluorination of N-benzoyl, N-acethyl-, and N-formylthiazolidine derived from L-cysteine was carried out in dimethoxyethane (DME) and acetonitrile containing various supporting fluoride salts using an undivided cell. Highly regioselective fluorination proceeded to provide the corresponding 5-monofluorinated thiazolidine derivatives in good yields in DME, and the diastereoselectivitiy was moderate to high regardless of the supporting fluoride salts. The diastereoselectivitiy of the fluorination was greatly affected by the bulkyness of the subsitituent on the nitrogen atom, and N-benzoylthiazolidine gave much higher diastereoselectivity compared with N-formyl derivative. The fluorination of the thiazolidines was not achieved by commercially available fluorinating reagents such as N-fluoropyridinium salts.

[Fluorinated organic compounds: synthesis and biological applications]. / Les composés organiques fluorés: synthèses et applications biologiques.

Since the discovery of molecular fluorine by Henri Moissan, fluorinated products have found numerous biological applications. Fluorine substitution can have profound effects on the properties of organic compounds. The very high electronegativity of this small substituent can modify electron distribution in the molecule, affecting its absorption, distribution and metabolism. Fluorination and 18F labeling methods are briefly described. Some examples of enzymatic inhibition by fluorinated products are examined. Nowadays, fluorine-containing medicinals are featuring significantly in such diverse areas as the provision of anti-cancer and anti-inflammatory agents, antibiotics and general anesthetics, anti-parasitic and central nervous system agents, and in cardiac therapy. Fluorocarbon emulsions show promise as blood substitutes. Several medical diagnostic techniques, such as positron emission tomography and the use of X-ray contrast agents, have profited from the use of fluorinated substances.