Fluorine Labeling of Nanoparticles and In Vivo 19F Magnetic Resonance Imaging.

Fluorinated nanoparticles have increasing applications, but they are still challenging to prepare, especially in the case of water-soluble fluorinated nanoparticles. Herein, a fluorine labeling strategy is presented that is based on the conjugation of custom-made small fluorinated building blocks, obtained by simple synthetic transformations, with carboxylated gold nanoparticles through a convenient phase-transfer process. The synthesis of four fluorinated building blocks with different chemical shifts in 19F nuclear magnetic resonance and varied functionalities is reported, along with their conjugation onto nanoparticles. Fluorinated nanoparticles of small core size obtained by this conjugation methodology and by direct synthesis presented high transverse relaxation times (T2) ranging from 518 to 1030 ms, and a large number of equivalent fluorine atoms per nanoparticle (340-1260 fluorine atoms), which made them potential candidates for 19F magnetic resonance related applications. Finally, nontargeted fluorinated nanoparticles were probed by performing in vivo 19F magnetic resonance spectroscopy (19F MRS) in mice. Nanoparticles were detected at both 1 and 2 h after being injected. 19F MRI images were also acquired after either intravenous or subcutaneous injection. Their fate was studied by analyzing the gold content in tissues by ICP-MS. Thus, the present work provides a general fluorination strategy for nanoparticles and shows the potential use of small fluorinated nanoparticles in magnetic-resonance-related applications.

Reproducibility of 19 F-MR ventilation imaging in healthy volunteers.

PURPOSE: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine (19 F)-MRI of inhaled perfluoropropane, implemented at two research sites. METHODS: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018-June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath-hold. Four 19 F-MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1 H images to ventilation images before semi-automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient. RESULTS: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoVobserver1 = 0.43%; CoVobserver2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers. CONCLUSION: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19 F-MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies.

Evaluation of the effect of fluorinated tooth bleaching products using polarized Raman microscopy and particle induced gamma-ray emission.

In this in vitro study, the effect of the application of tooth bleaching products in human enamel was evaluated using polarized Raman microscopy, particle induced gamma-ray emission (PIGE) and Vickers Hardness test. Due to their acidic nature, teeth whitening products are associated with changes in enamel mineralization. Consequently, products have appeared in the market that promote the incorporation of fluorine in order to decrease the solubility of the hydroxyapatite in enamel and prevent demineralization. This way, four commercial products with different active principle concentrations: 16% carbamide peroxide (Opalescence PF® and VivaStyle®) or 6% hydrogen peroxide (Opalescence Go PF® and VivaStyle Paint On®) and presence or not of fluorine were compared. The information on the crystalline state of the enamel was provided by the determination of the depolarization ratio of the symmetric stretching band of phosphate (at 959 cm-1). Furthermore, the content and uptake of F was evaluated using PIGE in the two fluorinated products as well as in one negative control group. In order to evaluate the microhardness of enamel by means of Vickers test, another group of polished samples was prepared (using Opalescence PF®) and evaluated. Conversely to what could be expected, the obtained results determined a statistically significant decrease of depolarization ratio, leading to an increase of mineralization after the application of the bleaching products, except for VivaStyle®. For this group, no significant variation was obtained before-after treatment, most likely due to the acidity of the product (pH = 5.8). Additionally, an increase of concentration of F in the dental tissues was determined for the fluorinated products. On the other hand, enamel polishing, required for the application of the Vickers test, led to increased susceptibility to erosion, resulting in decreased hardness and an increased enamel depolarization ratio.

Study of kinetics of 19F-MRI using a fluorinated imaging agent (19FIT) on a 3T clinical MRI system.

PURPOSE: To use 19F imaging tracer (19FIT-27) to evaluate kinetics in major organs. INTRODUCTION: Kinetics studies using proton MRI are difficult because of low concentration of 19FIT-27 protons relative to background water protons. Because there is no background source of 19F NMR in a biological body, 19F may be an ideal nucleus to directly trace 19FIT-27. However, there are several challenges for reliable 19F MR imaging and spectroscopy, particularly with clinical whole-body MRI systems, which include low concentrations and long 19F T1. METHODS AND MATERIALS: We performed a dynamic 19F MRI study on mice at a 3T whole-body MRI system using a homemade transmit/receive (Tx/Rx) switch and a Tx/Rx volume RF coil. We used a newly developed fluorine imaging agent, which has 27 identical fluorine atoms with identical chemical shift, a relatively short T1, and high hydrophilicity. Basic kinetics parameters were estimated from the 19F signal-time curve. RESULTS AND DISCUSSIONS: Resultant fluorine images show fairly high spatial (3 × 3 × 3 mm3) and temporal resolutions. Biodistribution and kinetics of 19FIT-27 are obtained via 19F images for major uptake organs. CONCLUSIONS: Whole-body dynamic 19F MRI of newly developed 19FIT-27 in mice was obtained with fairly high spatial and temporal resolutions on a 3T clinical MRI system. The present study demonstrates the feasibility of 19F MRI using our newly developed compound to investigate major organ kinetics.

A mini review of fluoride-induced apoptotic pathways.

Fluorine or fluoride can have toxic effects on bone tissue and soft tissue at high concentrations. These negative effects include but not limited to cytotoxicity, immunotoxicity, blood toxicity, and oxidative damage. Apoptosis plays an important role in fluoride-induced toxicity of kidney, liver, spleen, thymus, bursa of Fabricius, cecal tonsil, and cultured cells. Here, apoptosis activated by high level of fluoride has been systematically reviewed, focusing on three pathways: mitochondrion-mediated, endoplasmic reticulum (ER) stress-mediated, and death receptor-mediated pathways. However, very limited reports are focused on the death receptor-mediated apoptosis pathways in the fluoride-induced apoptosis. Therefore, understanding and discovery of more pathways and molecular mechanisms of fluoride-induced apoptosis may contribute to designing measures for preventing fluoride toxicity.

Tolerance strategies of two Mediterranean native xerophytes under fluoride pollution in Tunisia.

A field study was conducted along a fluorine gradient of soil pollution in Tunisia from Gabes, the most polluted site, to Smara, the reference site. Variations of fluoride (F) concentrations in soils were detected over 1 year in Gabes, Skhira, and Smara. F concentrations in the aerial part of two native plant species, i.e., Erodium glaucophyllum and Rhanterium suaveolens, were above the usual background concentrations. Bioaccumulation factors ranged from 0.08 to 1.3. With F concentrations in aerial parts up to 355 mg kg-1, both species may be described as F accumulators. Both species showed an earlier vegetative growth in Gabes than in Smara. However, some difference between their strategies could be observed, i.e., E. glaucophyllum shortening the period of its vegetative growth with an escape strategy and R. suaveolens decreasing its ratio of alive/dead parts potentially lowering the F toxicity by storage in dead cells. However, at a tissue level, mechanisms of tolerance were similar. Leaf section micrographs of both species showed a higher calcium accumulation in leaf midveins at Gabes than at Smara, confirming the role of calcium in plant F tolerance strategies.

[Electronic probe analysis of enamel remineralization effect of casein phosphopeptide-amorphous calcium phosphate promoted by different concentrations of fluorine].

Objective: To evaluate the remineralization effect and mechanism of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) with different concentrations of fluorine on demineralized enamel using electronic probe. Methods: Extracted premolar teeth for orthodontic purpose were immersed into lactic acid gel to prepare artificial white spot lesions (10 teeth in each group). Then the specimens were randomly assigned to three groups: Control group, with 5% of the CPP-ACP+deionized water; Group A with 5% CPP-ACP+500 mg/L F(-) and Group B with 5% CPP-ACP+900 mg/L F(-). The teeth in each group were soaked in different solutions for 4 days and then were measured using electron probe tester. The changes of contents among the three groups were compared. Results: No statistically significant difference in the percentage of fluorine was found in the control group before and after treatment (P=0.06), and the difference in the percentage of fluorine quality in the other two groups was statistically significant (P<0.05). Statistically significant difference was found between calcium oxide and phosphorus peroxide in the three groups before and after mineralization (P<0.05). The percentage change of fluorine mass in group B [(0.107±0.035)%] was significantly greater than that in group A [(0.057±0.038)%] (P<0.05), while fluorine mass in group A was significantly greater than that in control group [(0.013±0.019)%] (P<0.05). In group A and group B, the change in quality of calcium oxide and phosphorus peroxide was significantly greater than that in control group (P<0.05), while no significant difference was found between group A and group B (P>0.05). Conclusions: The addition of fluorine in CPP-ACP increased the transport and penetration of calcium, phosphorus and fluorine on enamel surface.

Fluorine MR Imaging Monitoring of Tumor Inflammation after High-Intensity Focused Ultrasound Ablation.

Purpose To investigate whether high-intensity focused ultrasound (HIFU)-induced macrophage infiltration could be longitudinally monitored with fluorine 19 (19F) magnetic resonance (MR) imaging in a quantitative manner. Materials and Methods BALB/c mice were subcutaneously inoculated with 4T1 cells and were separated into three groups: untreated mice (control, n = 9), HIFU-treated mice (HIFU, n = 9), and HIFU- and clodronate-treated mice (HIFU+Clod, n = 9). Immediately after HIFU treatment, all mice were intravenously given perfluorocarbon (PFC) emulsion. MR imaging examinations were performed 2, 4, 7, 10, and 14 days after HIFU treatment. Two-way repeated measures analysis of variance was used to analyze the changes in 19F signal over time and differences between groups. Histologic examinations were performed to confirm in vivo data. Results Fluorine 19 signals were detected at the rims of tumors and the peripheries of ablated lesions. Mean 19F signal in tumors was significantly higher in HIFU-treated mice than in control mice up to day 4 (0.82 ± 0.26 vs 0.42 ± 0.17, P < .001). Fluorine 19 signals were higher in the HIFU+Clod group than in the control group from day 4 (0.82 ± 0.23, P < .001) to day 14 (0.55 ± 0.16 vs 0.28 ± 0.06, P < .05). Histologic examination revealed macrophage infiltration around ablated lesions. Immunofluorescence staining confirmed PFC labeling of macrophages. Conclusion Fluorine 19 MR imaging can longitudinally capture and quantify HIFU-induced macrophage infiltration in preclinical tumor models. © RSNA, 2018 Online supplemental material is available for this article.

Cargo-influences on the biodistribution of hollow mesoporous silica nanoparticles as studied by quantitative 19F-magnetic resonance imaging.

HYPOTHESIS: Biodistribution is a key issue when it comes to medical applications of nanomaterials. Hollow mesoporous silica nanoparticles (HMSNs) loaded with fluorine compounds can be applied as positive magnetic resonance imaging (MRI) contrast agents (CAs). These CAs exhibit an unusual biodistribution which is influenced by the cargo and which could be linked to their serum protein adsorption behaviour. EXPERIMENTS: HMSNs were post-synthetically loaded with perfluoro-15-crown-5-ether (PFCE). The 19F signal was quantified with MRI in a murine model. Furthermore protein adsorption tests were performed in full serum. FINDINGS: Quantitative analysis of the 19F-signal revealed that the particles were exclusively accumulating in the liver 24h post-injection, and no accumulation in other reticuloendothelial system (RES) organs like spleen or lung was observed. The protein corona around non-loaded and loaded particles was therefore analysed, and more proteins adsorbed on PFCE-loaded particles as compared to the bare particles, and importantly, the amount of apolipoproteins A-1 and A-2, was clearly elevated for the PFCE-loaded particles. The results underline that the type of cargo may have major influences on the biodistribution of mesoporous silica drug vectors.

Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors.

Kappa opioid receptor (KOR) antagonists are potential drug candidates for diseases such as treatment-refractory depression, anxiety, and addictive disorders. PET imaging radiotracers for KOR can be used in occupancy study to facilitate drug development, and to investigate the roles of KOR in health and diseases. We have previously developed two 11C-labeled antagonist radiotracers with high affinity and selectivity toward KOR. What is limiting their wide applications is the short half-life of 11C. Herein, we report the synthesis of a first 18F-labeled KOR antagonist radiotracer and the initial PET imaging study in a nonhuman primate.

(19)F MRSI of capecitabine in the liver at 7 T using broadband transmit-receive antennas and dual-band RF pulses.

Capecitabine (Cap) is an often prescribed chemotherapeutic agent, successfully used to cure some patients from cancer or reduce tumor burden for palliative care. However, the efficacy of the drug is limited, it is not known in advance who will respond to the drug and it can come with severe toxicity. (19)F Magnetic Resonance Spectroscopy (MRS) and Magnetic Resonance Spectroscopic Imaging (MRSI) have been used to non-invasively study Cap metabolism in vivo to find a marker for personalized treatment. In vivo detection, however, is hampered by low concentrations and the use of radiofrequency (RF) surface coils limiting spatial coverage. In this work, the use of a 7T MR system with radiative multi-channel transmit-receive antennas was investigated with the aim of maximizing the sensitivity and spatial coverage of (19)F detection protocols. The antennas were broadband optimized to facilitate both the (1)H (298 MHz) and (19)F (280 MHz) frequencies for accurate shimming, imaging and signal combination. B1(+) simulations, phantom and noise measurements showed that more than 90% of the theoretical maximum sensitivity could be obtained when using B1(+) and B1(-) information provided at the (1)H frequency for the optimization of B1(+) and B1(-) at the (19)F frequency. Furthermore, to overcome the limits in maximum available RF power, whilst ensuring simultaneous excitation of all detectable conversion products of Cap, a dual-band RF pulse was designed and evaluated. Finally, (19)F MRS(I) measurements were performed to detect (19)F metabolites in vitro and in vivo. In two patients, at 10 h (patient 1) and 1 h (patient 2) after Cap intake, (19)F metabolites were detected in the liver and the surrounding organs, illustrating the potential of the set-up for in vivo detection of metabolic rates and drug distribution in the body.

FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.

Applications of Fluorine in Medicinal Chemistry.

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

Fluorine in drug design: a case study with fluoroanisoles.

Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addition to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochemical and pharmacokinetic properties. Analysis of anisole and fluoroanisole matched molecular pairs in the Pfizer corporate database reveals interesting trends: 1) PhOCF3 increases log D by ~1 log unit over PhOCH3 compounds; 2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and 3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3 . Emerging from the investigation, difluoroanisole (PhOCF2 H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3 . Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, our analysis suggests PhOCF2 H may be a more attractive alternative, and greater exploitation of this motif is recommended.

Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions.

BACKGROUND: Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. METHODS AND RESULTS: Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. CONCLUSIONS: Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.

Synthesis and evaluation of fluorine-substituted phenyl acetate derivatives as ultra-short recovery sedative/hypnotic agents.

BACKGROUND: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. METHODOLOGY/PRINCIPAL FINDINGS: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. CONCLUSIONS/SIGNIFICANCE: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.

Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance.

BACKGROUND: The goal of this study was to characterize the performance of fluorine-19 ((19)F) cardiac magnetic resonance (CMR) for the specific detection of inflammatory cells in a mouse model of myocarditis. Intravenously administered perfluorocarbons are taken up by infiltrating inflammatory cells and can be detected by (19)F-CMR. (19)F-labeled cells should, therefore, generate an exclusive signal at the inflamed regions within the myocardium. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in BALB/c mice. After intravenous injection of 2×200 µL of a perfluorocarbon on day 19 and 20 (n=9) after immunization, in vivo (19)F-CMR was performed at the peak of myocardial inflammation (day 21). In 5 additional animals, perfluorocarbon combined with FITC (fluorescein isothiocyanate) was administered for postmortem immunofluorescence and flow-cytometry analyses. Control experiments were performed in 9 animals. In vivo (19)F-CMR detected myocardial inflammation in all experimental autoimmune myocarditis-positive animals. Its resolution was sufficient to identify even small inflammatory foci, that is, at the surface of the right ventricle. Postmortem immunohistochemistry and flow cytometry confirmed the presence of perfluorocarbon in macrophages, dendritic cells, and granulocytes, but not in lymphocytes. The myocardial volume of elevated (19)F signal (rs=0.96; P<0.001), the (19)F signal-to-noise ratio (rs=0.92; P<0.001), and the (19)F signal integral (rs=0.96; P<0.001) at day 21 correlated with the histological myocarditis severity score. CONCLUSIONS: In vivo (19)F-CMR was successfully used to visualize the inflammation specifically and robustly in experimental autoimmune myocarditis, and thus allowed for an unprecedented insight into the involvement of inflammatory cells in the disease process.

Fluorine--a current literature review. An NRC and ATSDR based review of safety standards for exposure to fluorine and fluorides.

BACKGROUND: A review of the literature of the element fluorine and its bonded-form, fluoride, was undertaken. Generally regarded as safe, an expanding body of literature reveals that fluoride's toxicity has been unappreciated, un-scrutinized, and hidden for over 70 years. The context for the literature search and review was an environmental climate-change study, which demonstrated widespread fluoride contamination by smokestack emissions from coal-fired electricity-generating plants. The objective of this review is to educate and inform regarding the ubiquitous presence and harmful nature of this now ever-present corrosive and reactive toxin. METHODS: Methods include examination of national health agency reviews, primarily the National Research Council (NRC), Agency for Toxic Substances & Disease Registry (ATSDR), standard medical toxicology references, text books, as well as reports and documents from both private and public research as well as consumer-based NGOs. Study criteria were chosen for relevancy to the subject of the toxicity of fluoride. RESULTS: Fluoride is the extreme electron scavenger, the most corrosive of all elements, as well as the most-reactive. Fluoride appears to attack living tissues, via several mechanisms. Fluoride renders strong evidence that it is a non-biological chemical, demonstrating no observed beneficial function or role in organic chemistry, beyond use as a pesticide or insecticide. Fluorine has a strong role to play in industry, having been utilized extensively in metals, plastics, paints, aluminium, steel, and uranium production. CONCLUSION: Due to its insatiable appetite for calcium, fluorine and fluorides likely represent a form of chemistry that is incompatible with biological tissues and organ system functions. Based on an analysis of the affects of fluoride demonstrated consistently in the literature, safe levels have not been determined nor standardized. Mounting evidence presents conflicting value to its presence in biological settings and applications. Evidence examined in this review of the literature, and specifically the recent report by the National Research Council (NRC), offer strong support for an immediate reconsideration concerning risk vs benefit. Consensus recommendations from several sources are presented.

In vivo 19F MR imaging and spectroscopy for the BNCT optimization.

The aim of this study was to evaluate in vivo the boron biodistribution and pharmacokinetics of 4-borono-2-fluorophenylalanine ((19)F-BPA) using (19)F MR Imaging ((19)F MRI) and Spectroscopy ((19)F MRS). The correlation between the results obtained by both techniques, (19)F MRI on rat brain and (19)F MRS on blood samples, showed the maximum (19)F-BPA uptake in C6 glioma model at 2.5h after infusion determining the optimal irradiation time. Moreover, the effect of L-DOPA as potential enhancer of (19)F-BPA tumour intake was assessed using (19)F MRI.