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Review 19
F applications in drug development and imaging – a review
Dorota Bartusik a,*, David Aebisher b a b
Southern Polytechnic State University, Department of Biology and Chemistry, 1100 South Marietta Parkway, Marietta, GA 30060, USA Shorter University, Natural Sciences Department, 315 Shorter Ave, Rome, GA 30165, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 June 2014 Accepted 8 July 2014
To control drugs in vivo, new approaches are needed. Considerable progress has been made towards the applications of fluorine (19F) in pharmacotherapy in this regard. To date, many authors have showed that by using 19F labelled drugs and non-invasive magnetic resonance imaging (MRI) techniques together, drug biodistribution can be tracked. This review presents methods for 19F incorporation into pharmaceuticals by forming C–F bonds and drug fluorine oil-water emulsions. Inadequate drug delivery is a major cause of drug resistance, which can be improved using approaches discussed herein aided by 19F MRI. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: 19 F drugs 19 F MRI
1. Introduction Fluorine-19 (19F) was discovered by Professor Henri Moissan of the University of Paris in 1886. For the discovery and successful isolation of 19F, he was awarded the Nobel Prize for chemistry in 1906. Subsequent research in organofluorine chemistry has demonstrated that the presence of the 19F nucleus in an organic molecule can dramatically change the properties of compounds, including stability, lipophilicity and bioavailability [1,2]. It is known that the carbon–fluorine C–F bond is the strongest single bond in organic chemistry [3,4]. This can be explained by the high electronegativity of the fluorine atom causing the C–F bond to be highly polarized with electron density displaced towards 19F. The number of fluorinated drugs released on the pharmaceutical market is rapidly increasing annually [5]. The first widely used fluorinated drug, 5-fluorouracil, was introduced in 1957 before which there were no drugs containing 19F in the pharmacy market [6]. Over the past few decades, magnetic resonance imaging (MRI) has proven to be extremely successful in medical applications. More recently, the biomedical applications of MRI have been gaining more use in the field of clinical pharmacy. Only four years after the invention of proton (1H) MRI by Lauterbur in 1973 [7], 19F MRI images were performed for the first time [8]. In 1977, perfluorocarbon compounds (PFC), which form emulsions that can carry drugs, were analyzed by 19F MRI [8]. Emulsified PFC compounds have been investigated as potential blood substitutes
* Corresponding author. Tel.: +1 678 915 3265. E-mail address: [email protected] (D. Bartusik).
since the early 1960s [9] and now a wide variety of PFC compounds are currently available as 19F MRI biomarkers [10,11]. In 2005, it was shown for the first time by Ahrens et al. that cells can be labelled with PFC emulsions and tracked in vivo by 19F MRI [12]. Molecules with 19F substituents are attractive for use in drug tracking by 19F MRI due to 100% 19F abundance, high 19F MR sensitivity (0.83 relative to 1H MR) and an impressively large chemical shift range ( 300 ppm). The high 19F gyromagnetic ratio, 40.05 MHz/T (approximately 6% lower than 1H), allows for the use of 1H MR hardware and software instrumentation with minimal adjustment for the 19F resonance frequency. Another benefit in the use of 19F MRI is a zero background signal in biological samples. Numerous drugs now contain fluorine atoms and are therefore potential candidates for 19F MRI studies. Also, as reported in this review, compounds labelled with fluorine offer opportunities for use in biological studies. Drugs need to be sufficiently lipophilic to pass through cell membranes to reach their site of action. The lipophilic nature of the cell membrane only permits the passage of the uncharged portion of any drug. However, a drug must not be too lipophilic as this would reduce its water solubility and its bioavailability [13]. The work discussed in this review is presented in following chapters: chemical composition of fluorine-containing agents, emulsions and 19F MRI applications. 2. Chemical composition of fluorine-containing agents There is a variety of methods for creating a C–F bond using electrophilic and nucleophilic fluorination. Methods of introducing 19 F into organic compounds using nucleophilic and electrophilic fluorinating reagents have been developed over the last 70 years
http://dx.doi.org/10.1016/j.biopha.2014.07.012 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Bartusik D, Aebisher D. 19F applications in drug development and imaging – a review. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.07.012
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[14]. Nucleophilic fluorination involves a negatively charged fluoride ion. Electrophilic fluorination utilizes an ‘‘F+’’ reagent. The fluorine atom is a strong electron-withdrawing group by the inductive effect, due to its high electronegativity. Thus, fluorine will stabilize an adjacent carbocation in electrophilic aromatic substitution reactions. An example of the first synthesis of a fluorine-containing drug is synthesis of 5-fluorouracil and its analogues [15–18]. A large range of electrophilic fluorination reagents has been developed. The reactions of various types of substrates with different fluorinated agents have been investigated to form C–F bonds. Initially, alternative sources of positive fluorine made use of the O–F moiety (i.e., fluoroxy per-fluoroalkanes, acyl hypofluorites, and sulfonyl hypofluorites). An example of the use of RO-F (organofluoroxy) is the reagent fluoroxytrifluoromethane, which has been used for the fluorination of pharmaceutical products [19,20]. In 1981, acetyl hypofluorite was successfully used to fluorinate aromatic rings [21]. In 1985, acetyl hypofluorite was used to addition of fluorine to double bonds [22] and fluorination of lithium enolates [23]. In 2001, acetyl hypofluorite was used for the synthesis of a-fluorocarboxylic acid derivatives [24]. In 1986, other XO-F electrophilic fluorinating agents have been developed, such as xenon difluoride (XeF2), perchloryl fluoride (FClO3), and cesium fluoroxysulfate (CsSO4F) [25,26]. Another examples of electrophilic fluorinating reagents are the nitrogen–fluorine (N–F) reagents. From 1985 to 1995, the N-fluoropyridinium salts were developed and have become an important source of electrophilic fluorine for fluorination [27–29]. N-fluoropyridinium salts allow the fluorination of nucleophilic substrates and their reactivity were adjusted by substitution of the pyridine heterocycle. In order to increase N-fluoropyridinium salts reactivity, a stronger electron-withdrawing group was required [30]. N-fluoropyridinium salts have found a wide range of applications, including fluorination of aryl groups, nucleosides, steroids and other organic substrates [30,31]. The next group of compounds is N-alkyl-N-fluorosulfonamides developed by Barnette et al. [32]. As a next class of fluorinating reagents, N-alkylN-fluorosulfonamides demonstrated the reactivity with acids, ketones and arenes. N-alkyl-N-fluorosulfonamides are easily prepared by the treatment of N-alkylsulfonamides with diluted elemental fluorine. The most frequently used method is the thermal decomposition of aryldiazonium tetrafluoroborates (the Balz–Schiemann reaction) with various modifications [33] and electrophilic fluorination, which effectively delivers ‘‘F+’’ [30,34]. The difficulties associated with direct addition of fluorine have stimulated the development of alternate sources of electrophilic fluorination that can be easily and safely employed in organic syntheses [30]. Enantioselective electrophilic fluorination can be achieved by the use of a variety of chiral N–F reagents. In 1988, Differding et al. developed the first enantioselective fluorination reaction using the chiral N-fluorosultam [35]. In 1995, Davis et al. [36] and in 2010, Zhai et al. [37] described fluorination reactions using chiral N-fluorosultams with enolates. Other researchers have developed metal catalysed enantiomeric electrophilic fluorination using palladium, zinc, nickel and copper chiral complexes [38–40]. They applied chiral complexes methodology to fluorination of b-ketoesters, b-ketophosphonates and cyanoacetates [41]. Also, prolines are known to catalyse enantioselective intramolecular aldol condensations [42]. The chiral a-fluorination of aldehydes was developed by Jørgensen and et al. [43] and Barbas et al. [44]. Enders and Hu¨ttl also reported the a-fluorination of ketones [42]. While these methods are well established, there are still synthetic challenges due to the high reactivity of 19F and corresponding lack of selectivity and high toxicity [45]. In 1998, N-fluoropyridinium salts were mostly developed by Umemoto et al. [46] and have been used to fluorinate aromatic rings and enol ethers. One of the achievements in organofluorine chemistry was the development
fluoroketone inhibitors of hydrolytic enzymes [47–49]. Fluorinated methyl ketones, which are inhibitors containing the difluoroketomethylene dipeptide isostere, difluorostatone, and difluorostatine analogues, are the most commonly studied classes of fluorinecontaining protease inhibitors [50]. The use of fluorinated aldehydes and ketones as inhibitors of hydrolases was described by Brodbeck et al. [51]. These achievements were the beginning of a new class of structurally complex fluorinated protease inhibitors, especially inhibitors of HIV protease [52]. In nature, the fluoride anion occurs only in insoluble mineral forms and the first naturally occurring fluorinase enzyme was discovered in 2002 [53]. On the other hand, N-fluorosulfonamides are among the weakest fluorinating agents. This type of N–F compound, which possesses only a single sulfonyl group and an N-alkyl or N-aryl substituent, is not reactive enough to fluorinate less reactive substrates, such as enol ethers or arenes. N-fluorosulfonimides constitute a superior class of electrophilic fluorinating agents that are effective in the fluorination of aromatics, alkenes, carbanions, and ketone enolates. The direct electrophilic fluorination of aromatics complements other available methods for the synthesis of fluoroaromatics, such as the Balz–Schiemann reaction. The most popular fluorinated reagents used in electrophilic substitution are N-fluorosulfonamides, N-fluorosulfonimides, N-fluorocarboxamides, N-fluoroheterocycles, N-fluoroammonium compounds and N-fluoroiminium compounds. The other general strategy used to fluorinate substrates involves nucleophilic fluorination using the fluoride ion itself or reagents able to release fluoride ion. In aliphatic nucleophilic substitution reactions, fluoride as the leaving group, is the most inert halogen, because of the very strong C–F bond and the high charge density of the fluoride ion. The availability of fluoride ion can be increased in aprotic solvents by using a bulky cation, which delocalizes the positive charge and reduces ion pairing. One example of such a reagent is tetrabutylammonium fluoride (TBAF). TBAF is a common fluorinating agent that is available as a trihydrate. The presence of water reduces the nucleophilicity of fluoride. Another approach of fluorination consists of the use of hydrogen fluoride (HF) with amines e.g. triethylamine [54]. In the case of the use of SbF5/HF, the reagent SbF5/HF (1:1) was 10 times more acidic than sulphuric acid [54]. Sulfur fluorides can serve as nucleophilic fluorination sources. Mono hydro-fluorination has been achieved from allylic amines and sulfonamides [55]. Difluorination has been performed with the corresponding alkyne [56] and from allylic amines in the presence of N-bromo succinimide [57]. Most recently, Thibaudeau et al. reported the preparation of 3- and 4-fluoropiperidines from N,N-diallylic amines and amides [58]. One example of the application of the super acid SbF5/HF involves the preparation of difluoro-cinchona alkaloid derivatives from the corresponding alkyne [59–61]. Another example is the preparation of vinflunine, which is a recently marketed fluorinated anticancer drug [62]. An antitumour agent vinflunine is currently in phase III clinical trials for treatment of bladder and lung cancers [63–65].
3. Chemical composition of emulsions containing fluorine In addition to synthesis of C–F bond described in previous paragraph, water-oil emulsions with chemicals containing 19F is a new approach in medicinal chemistry. Fluorine biocompatible emulsions are based on non-polar perfluorocarbon oil (PFC) with enhanced capacity to dissolve gas, such as oxygen (O2), nitrogen (N2) and carbon dioxide (CO2). PFC compounds are linear or cyclic carbon molecules with all protons substituted by fluorine atoms [66]. PFCs are extremely hydrophobic and do not dissolve in blood directly. Consequently, PFC form emulsions with water and are
Please cite this article in press as: Bartusik D, Aebisher D. 19F applications in drug development and imaging – a review. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.07.012
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biologically inert, thus, remaining unmetabolized in the organism [66–68]. PFC emulsions show typical particle diameters in the range between 20–500 nm [69]. Typically, PFC emulsions have 10–40% volume/volume (v/v) PFC content in water [70,71]. Cell labelling was also possible using the fluorine emulsion [72,73]. Alternatively, phospholipids are often used as a surfactant in PFC water-oil emulsions [69,74]. Egg yolk phospholipids, for example, have been used in the preparation of blood substitute PFC nanoemulsions used for human applications [75,76]. Thus, in general, PFC emulsions are currently used for pre-clinical research. Not only can PFC compounds be emulsified, they can also be encapsulated. For example, PFC loaded alginate capsules have been proposed as a means of delivery [77]. Previous studies show that the in vivo biodynamics of PFC emulsion depends on the PFC compound used [10]. Research also shows that PFC emulsions are cleared from the bloodstream by mononuclear phagocyte system (MPS) activity and thus mainly embedded into organs (e.g., spleen and liver) [10,70,78,79]. The half-life of the PFC emulsion in the blood stream is normally in the range of several hours. Other than 19 F signals found in the organs of the MPS, signal can often be detected in other organs, especially the lungs [80]. This is because the PFC compounds are exhaled in a slow process through the lungs. As mentioned above, PFC emulsions have been investigated as potential blood substitutes since the early 1960s [81]. Importantly, the concentration of O2 in the PFC emulsion correlates linearly with the pO2 in its surroundings [82]. Contrary to haemoglobin, in which the oxygen is bound, the oxygen is physically dissolved in PFC emulsions. This feature is due to the low interactions (i.e. low van der Waals interactions) in the PFC molecules [83]. Since oxygen is paramagnetic, it influences the relaxation times of the PFC molecules in its proximity [84,85]. PFC has substantial advantages when applied in medical diagnostics as an anaesthetics and contrast media. The molecular weight of the carbon backbone determines the boiling point (volatility). Small carbon molecules have a low boiling point whereas those with more carbons are heavier oils [86,87]. Because of their non-polar structure, PFC possesses unique respiratory gas transport potentials [87–90]. Gases are carried in PFC by increased solubility (compared to water based fluids). At a constant temperature, the amount of gas dissolved in a given type PFC is directly proportional to the partial pressure of that gas in equilibrium with that liquid PFC [90,91].
4. Imaging application 19 F MRI is a powerful medical imaging modality with excellent tissue contrast without background. The 19F nucleus is not a natural component of human body. Therefore, drugs containing 19F can be easy monitored by 19F MRI in vivo without background signals. These studies also extend to fluorinated proteins, which have been synthesized and characterized as potential in vivo 19F MRI agents. For example, if the label is attached to the antibody, 19F MRI can be used to track the antibody in vivo or ex vivo after cell treatment. Proteins labelled with fluorine include bovine serum albumin, gamma-globulin, and purified immunoglobulin (IgG) [92]. These compounds exhibit useful biocompatibility for in vivo studies. Fluorine labelling of proteins is possible due to reactions in which the amino groups in proteins are selectively trifluoroacetylated using S-ethyl trifluorothioacetate. In another approach, trifluoroacetamidosuccinic anhydride has been used to prepare the corresponding fluorinated derivatives of proteins [92]. Anticarcino-embryonic antigen antibody conjugated with perfluorochemical (perfluorotributylamine) was administered to nude mouse. Tumor imaging based on the 19F NMR was examined after excision of the tumors from nude mice [93]. Current detection limits are reported to be in the range of 1015–1016 fluorine spins
3
per voxel at high field strength [94,95]. Cells are normally labelled with 1011–1013 fluorine spins [94–96]. This has translated to an in vitro detection limit of 200–6000 PFC labelled cells per voxel [94– 96]. Furthermore, the visualization of 4–106 cells in 7 min on a human scanner working at 1.5 Tesla field strength has been also reported [94–96]. PFCs, such as perfluorotributylamine (PFTB) and perfluorooctyl bromide (PFOB) have several 19F NMR resonances. Therefore, PFCs with a single resonance, such as hexafluorobenzene (HFB) and perfluoro-15-crown-5-ether (PFCE) have found extensive use. 19 F MRI is an extremely useful method for detecting the binding of fluorinated antibody compounds to a target. 19F has a large chemical shift range and it is extremely sensitive to relaxation changes caused by binding, which can provide higher resolution than 1H NMR relaxation experiments. 19F NMR has been used to characterize the multifunctional calcium dependent calmodulin protein bound to the fluorinated antipsychotic inhibitor, trifluoperazine (TFP) to determine that TFP binding can occur without calcium present [97]. Additionally, fluorine incorporation often improves the pharmacokinetic properties and potency of the drug. Binding interactions between the plasma protein human serum albumin and drugs can have detrimental effects on the drug’s pharmacokinetic properties. 19F MR has been used to report on specific interactions between human serum albumin (HSA) and fluorinated dugs prior to lengthy pharmacokinetic studies [98]. As mentioned previously, fluorine atoms can be selectively incorporated into pharmaceuticals to alter biological activity. There is a number of fluorine-containing drugs that are studied by 19F MRI. In particular, in vivo 19F MRI results showed a 2.5-fold greater accumulation of gemicatabine in the cancer xenograph in comparison with the control model [99]. 19F MR studies analyzing the chemical shift and relaxation properties of side products have been used to monitor the metabolic pathway of 5-fluorouracil [100,101]. Brix et al. evaluated the biodistribution and pharmacokinetics studied trifluoromethylated derivatives of the 3aminobenzamide enzyme in rats with prostate adenocarcinoma [102]. 3-Aminobenzamide enzyme is responsible for the early repair of spontaneous and stimulated DNA strand breaks. The successful synthesis and evaluation of fluoro-nitrophenyl-galactopyranosides to detect b-gal activity in vitro by 19F MRI was reported previously [103]. In particular, 2-fluoro-4-nitrophenyl-Dgalactopyranoside was found to be highly responsive to the action of b-gal, and the cleavage product aglycone 2-fluoro-4-nitrophenol results in a pH dependent chemical shift of 4–6 ppm in 19F resonance [104]. 5. Conclusion In the synthesis of drugs, fluorine is often introduced to increase lipophilicity, bioavailability and metabolic stability [1–20]. The initial investigations demonstrate the potential of fluorinated drugs and proteins as in vivo MRI probes. In vivo, 19F MRI is excellent method to track 19F migration in tissue. The continuous improvement in drug design can permit tracking of fluorinecontaining drugs in clinical platforms. Additionally, the development of PFC particles that can specifically accumulate in region of interest can enhance the 19F MRI sensitivity. References [1] Sham HL. In: Ojima I, McCarthy JR, Welch JT, editors. Biomedical Frontiers of Fluorine Chemistry. Washington, DC: American Chemical Society; 1996. p. 184–95. [2] Woo LW, Fischer DS, Sharland CM, Trusselle M, Foster PA, Chander SK, et al. Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography. Mol Cancer Ther 2008;7(8):2435–44.
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Review 19
F applications in drug development and imaging – a review
Dorota Bartusik a,*, David Aebisher b a b
Southern Polytechnic State University, Department of Biology and Chemistry, 1100 South Marietta Parkway, Marietta, GA 30060, USA Shorter University, Natural Sciences Department, 315 Shorter Ave, Rome, GA 30165, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 June 2014 Accepted 8 July 2014
To control drugs in vivo, new approaches are needed. Considerable progress has been made towards the applications of fluorine (19F) in pharmacotherapy in this regard. To date, many authors have showed that by using 19F labelled drugs and non-invasive magnetic resonance imaging (MRI) techniques together, drug biodistribution can be tracked. This review presents methods for 19F incorporation into pharmaceuticals by forming C–F bonds and drug fluorine oil-water emulsions. Inadequate drug delivery is a major cause of drug resistance, which can be improved using approaches discussed herein aided by 19F MRI. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: 19 F drugs 19 F MRI
1. Introduction Fluorine-19 (19F) was discovered by Professor Henri Moissan of the University of Paris in 1886. For the discovery and successful isolation of 19F, he was awarded the Nobel Prize for chemistry in 1906. Subsequent research in organofluorine chemistry has demonstrated that the presence of the 19F nucleus in an organic molecule can dramatically change the properties of compounds, including stability, lipophilicity and bioavailability [1,2]. It is known that the carbon–fluorine C–F bond is the strongest single bond in organic chemistry [3,4]. This can be explained by the high electronegativity of the fluorine atom causing the C–F bond to be highly polarized with electron density displaced towards 19F. The number of fluorinated drugs released on the pharmaceutical market is rapidly increasing annually [5]. The first widely used fluorinated drug, 5-fluorouracil, was introduced in 1957 before which there were no drugs containing 19F in the pharmacy market [6]. Over the past few decades, magnetic resonance imaging (MRI) has proven to be extremely successful in medical applications. More recently, the biomedical applications of MRI have been gaining more use in the field of clinical pharmacy. Only four years after the invention of proton (1H) MRI by Lauterbur in 1973 [7], 19F MRI images were performed for the first time [8]. In 1977, perfluorocarbon compounds (PFC), which form emulsions that can carry drugs, were analyzed by 19F MRI [8]. Emulsified PFC compounds have been investigated as potential blood substitutes
* Corresponding author. Tel.: +1 678 915 3265. E-mail address: [email protected] (D. Bartusik).
since the early 1960s [9] and now a wide variety of PFC compounds are currently available as 19F MRI biomarkers [10,11]. In 2005, it was shown for the first time by Ahrens et al. that cells can be labelled with PFC emulsions and tracked in vivo by 19F MRI [12]. Molecules with 19F substituents are attractive for use in drug tracking by 19F MRI due to 100% 19F abundance, high 19F MR sensitivity (0.83 relative to 1H MR) and an impressively large chemical shift range ( 300 ppm). The high 19F gyromagnetic ratio, 40.05 MHz/T (approximately 6% lower than 1H), allows for the use of 1H MR hardware and software instrumentation with minimal adjustment for the 19F resonance frequency. Another benefit in the use of 19F MRI is a zero background signal in biological samples. Numerous drugs now contain fluorine atoms and are therefore potential candidates for 19F MRI studies. Also, as reported in this review, compounds labelled with fluorine offer opportunities for use in biological studies. Drugs need to be sufficiently lipophilic to pass through cell membranes to reach their site of action. The lipophilic nature of the cell membrane only permits the passage of the uncharged portion of any drug. However, a drug must not be too lipophilic as this would reduce its water solubility and its bioavailability [13]. The work discussed in this review is presented in following chapters: chemical composition of fluorine-containing agents, emulsions and 19F MRI applications. 2. Chemical composition of fluorine-containing agents There is a variety of methods for creating a C–F bond using electrophilic and nucleophilic fluorination. Methods of introducing 19 F into organic compounds using nucleophilic and electrophilic fluorinating reagents have been developed over the last 70 years
http://dx.doi.org/10.1016/j.biopha.2014.07.012 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Bartusik D, Aebisher D. 19F applications in drug development and imaging – a review. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.07.012
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[14]. Nucleophilic fluorination involves a negatively charged fluoride ion. Electrophilic fluorination utilizes an ‘‘F+’’ reagent. The fluorine atom is a strong electron-withdrawing group by the inductive effect, due to its high electronegativity. Thus, fluorine will stabilize an adjacent carbocation in electrophilic aromatic substitution reactions. An example of the first synthesis of a fluorine-containing drug is synthesis of 5-fluorouracil and its analogues [15–18]. A large range of electrophilic fluorination reagents has been developed. The reactions of various types of substrates with different fluorinated agents have been investigated to form C–F bonds. Initially, alternative sources of positive fluorine made use of the O–F moiety (i.e., fluoroxy per-fluoroalkanes, acyl hypofluorites, and sulfonyl hypofluorites). An example of the use of RO-F (organofluoroxy) is the reagent fluoroxytrifluoromethane, which has been used for the fluorination of pharmaceutical products [19,20]. In 1981, acetyl hypofluorite was successfully used to fluorinate aromatic rings [21]. In 1985, acetyl hypofluorite was used to addition of fluorine to double bonds [22] and fluorination of lithium enolates [23]. In 2001, acetyl hypofluorite was used for the synthesis of a-fluorocarboxylic acid derivatives [24]. In 1986, other XO-F electrophilic fluorinating agents have been developed, such as xenon difluoride (XeF2), perchloryl fluoride (FClO3), and cesium fluoroxysulfate (CsSO4F) [25,26]. Another examples of electrophilic fluorinating reagents are the nitrogen–fluorine (N–F) reagents. From 1985 to 1995, the N-fluoropyridinium salts were developed and have become an important source of electrophilic fluorine for fluorination [27–29]. N-fluoropyridinium salts allow the fluorination of nucleophilic substrates and their reactivity were adjusted by substitution of the pyridine heterocycle. In order to increase N-fluoropyridinium salts reactivity, a stronger electron-withdrawing group was required [30]. N-fluoropyridinium salts have found a wide range of applications, including fluorination of aryl groups, nucleosides, steroids and other organic substrates [30,31]. The next group of compounds is N-alkyl-N-fluorosulfonamides developed by Barnette et al. [32]. As a next class of fluorinating reagents, N-alkylN-fluorosulfonamides demonstrated the reactivity with acids, ketones and arenes. N-alkyl-N-fluorosulfonamides are easily prepared by the treatment of N-alkylsulfonamides with diluted elemental fluorine. The most frequently used method is the thermal decomposition of aryldiazonium tetrafluoroborates (the Balz–Schiemann reaction) with various modifications [33] and electrophilic fluorination, which effectively delivers ‘‘F+’’ [30,34]. The difficulties associated with direct addition of fluorine have stimulated the development of alternate sources of electrophilic fluorination that can be easily and safely employed in organic syntheses [30]. Enantioselective electrophilic fluorination can be achieved by the use of a variety of chiral N–F reagents. In 1988, Differding et al. developed the first enantioselective fluorination reaction using the chiral N-fluorosultam [35]. In 1995, Davis et al. [36] and in 2010, Zhai et al. [37] described fluorination reactions using chiral N-fluorosultams with enolates. Other researchers have developed metal catalysed enantiomeric electrophilic fluorination using palladium, zinc, nickel and copper chiral complexes [38–40]. They applied chiral complexes methodology to fluorination of b-ketoesters, b-ketophosphonates and cyanoacetates [41]. Also, prolines are known to catalyse enantioselective intramolecular aldol condensations [42]. The chiral a-fluorination of aldehydes was developed by Jørgensen and et al. [43] and Barbas et al. [44]. Enders and Hu¨ttl also reported the a-fluorination of ketones [42]. While these methods are well established, there are still synthetic challenges due to the high reactivity of 19F and corresponding lack of selectivity and high toxicity [45]. In 1998, N-fluoropyridinium salts were mostly developed by Umemoto et al. [46] and have been used to fluorinate aromatic rings and enol ethers. One of the achievements in organofluorine chemistry was the development
fluoroketone inhibitors of hydrolytic enzymes [47–49]. Fluorinated methyl ketones, which are inhibitors containing the difluoroketomethylene dipeptide isostere, difluorostatone, and difluorostatine analogues, are the most commonly studied classes of fluorinecontaining protease inhibitors [50]. The use of fluorinated aldehydes and ketones as inhibitors of hydrolases was described by Brodbeck et al. [51]. These achievements were the beginning of a new class of structurally complex fluorinated protease inhibitors, especially inhibitors of HIV protease [52]. In nature, the fluoride anion occurs only in insoluble mineral forms and the first naturally occurring fluorinase enzyme was discovered in 2002 [53]. On the other hand, N-fluorosulfonamides are among the weakest fluorinating agents. This type of N–F compound, which possesses only a single sulfonyl group and an N-alkyl or N-aryl substituent, is not reactive enough to fluorinate less reactive substrates, such as enol ethers or arenes. N-fluorosulfonimides constitute a superior class of electrophilic fluorinating agents that are effective in the fluorination of aromatics, alkenes, carbanions, and ketone enolates. The direct electrophilic fluorination of aromatics complements other available methods for the synthesis of fluoroaromatics, such as the Balz–Schiemann reaction. The most popular fluorinated reagents used in electrophilic substitution are N-fluorosulfonamides, N-fluorosulfonimides, N-fluorocarboxamides, N-fluoroheterocycles, N-fluoroammonium compounds and N-fluoroiminium compounds. The other general strategy used to fluorinate substrates involves nucleophilic fluorination using the fluoride ion itself or reagents able to release fluoride ion. In aliphatic nucleophilic substitution reactions, fluoride as the leaving group, is the most inert halogen, because of the very strong C–F bond and the high charge density of the fluoride ion. The availability of fluoride ion can be increased in aprotic solvents by using a bulky cation, which delocalizes the positive charge and reduces ion pairing. One example of such a reagent is tetrabutylammonium fluoride (TBAF). TBAF is a common fluorinating agent that is available as a trihydrate. The presence of water reduces the nucleophilicity of fluoride. Another approach of fluorination consists of the use of hydrogen fluoride (HF) with amines e.g. triethylamine [54]. In the case of the use of SbF5/HF, the reagent SbF5/HF (1:1) was 10 times more acidic than sulphuric acid [54]. Sulfur fluorides can serve as nucleophilic fluorination sources. Mono hydro-fluorination has been achieved from allylic amines and sulfonamides [55]. Difluorination has been performed with the corresponding alkyne [56] and from allylic amines in the presence of N-bromo succinimide [57]. Most recently, Thibaudeau et al. reported the preparation of 3- and 4-fluoropiperidines from N,N-diallylic amines and amides [58]. One example of the application of the super acid SbF5/HF involves the preparation of difluoro-cinchona alkaloid derivatives from the corresponding alkyne [59–61]. Another example is the preparation of vinflunine, which is a recently marketed fluorinated anticancer drug [62]. An antitumour agent vinflunine is currently in phase III clinical trials for treatment of bladder and lung cancers [63–65].
3. Chemical composition of emulsions containing fluorine In addition to synthesis of C–F bond described in previous paragraph, water-oil emulsions with chemicals containing 19F is a new approach in medicinal chemistry. Fluorine biocompatible emulsions are based on non-polar perfluorocarbon oil (PFC) with enhanced capacity to dissolve gas, such as oxygen (O2), nitrogen (N2) and carbon dioxide (CO2). PFC compounds are linear or cyclic carbon molecules with all protons substituted by fluorine atoms [66]. PFCs are extremely hydrophobic and do not dissolve in blood directly. Consequently, PFC form emulsions with water and are
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biologically inert, thus, remaining unmetabolized in the organism [66–68]. PFC emulsions show typical particle diameters in the range between 20–500 nm [69]. Typically, PFC emulsions have 10–40% volume/volume (v/v) PFC content in water [70,71]. Cell labelling was also possible using the fluorine emulsion [72,73]. Alternatively, phospholipids are often used as a surfactant in PFC water-oil emulsions [69,74]. Egg yolk phospholipids, for example, have been used in the preparation of blood substitute PFC nanoemulsions used for human applications [75,76]. Thus, in general, PFC emulsions are currently used for pre-clinical research. Not only can PFC compounds be emulsified, they can also be encapsulated. For example, PFC loaded alginate capsules have been proposed as a means of delivery [77]. Previous studies show that the in vivo biodynamics of PFC emulsion depends on the PFC compound used [10]. Research also shows that PFC emulsions are cleared from the bloodstream by mononuclear phagocyte system (MPS) activity and thus mainly embedded into organs (e.g., spleen and liver) [10,70,78,79]. The half-life of the PFC emulsion in the blood stream is normally in the range of several hours. Other than 19 F signals found in the organs of the MPS, signal can often be detected in other organs, especially the lungs [80]. This is because the PFC compounds are exhaled in a slow process through the lungs. As mentioned above, PFC emulsions have been investigated as potential blood substitutes since the early 1960s [81]. Importantly, the concentration of O2 in the PFC emulsion correlates linearly with the pO2 in its surroundings [82]. Contrary to haemoglobin, in which the oxygen is bound, the oxygen is physically dissolved in PFC emulsions. This feature is due to the low interactions (i.e. low van der Waals interactions) in the PFC molecules [83]. Since oxygen is paramagnetic, it influences the relaxation times of the PFC molecules in its proximity [84,85]. PFC has substantial advantages when applied in medical diagnostics as an anaesthetics and contrast media. The molecular weight of the carbon backbone determines the boiling point (volatility). Small carbon molecules have a low boiling point whereas those with more carbons are heavier oils [86,87]. Because of their non-polar structure, PFC possesses unique respiratory gas transport potentials [87–90]. Gases are carried in PFC by increased solubility (compared to water based fluids). At a constant temperature, the amount of gas dissolved in a given type PFC is directly proportional to the partial pressure of that gas in equilibrium with that liquid PFC [90,91].
4. Imaging application 19 F MRI is a powerful medical imaging modality with excellent tissue contrast without background. The 19F nucleus is not a natural component of human body. Therefore, drugs containing 19F can be easy monitored by 19F MRI in vivo without background signals. These studies also extend to fluorinated proteins, which have been synthesized and characterized as potential in vivo 19F MRI agents. For example, if the label is attached to the antibody, 19F MRI can be used to track the antibody in vivo or ex vivo after cell treatment. Proteins labelled with fluorine include bovine serum albumin, gamma-globulin, and purified immunoglobulin (IgG) [92]. These compounds exhibit useful biocompatibility for in vivo studies. Fluorine labelling of proteins is possible due to reactions in which the amino groups in proteins are selectively trifluoroacetylated using S-ethyl trifluorothioacetate. In another approach, trifluoroacetamidosuccinic anhydride has been used to prepare the corresponding fluorinated derivatives of proteins [92]. Anticarcino-embryonic antigen antibody conjugated with perfluorochemical (perfluorotributylamine) was administered to nude mouse. Tumor imaging based on the 19F NMR was examined after excision of the tumors from nude mice [93]. Current detection limits are reported to be in the range of 1015–1016 fluorine spins
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per voxel at high field strength [94,95]. Cells are normally labelled with 1011–1013 fluorine spins [94–96]. This has translated to an in vitro detection limit of 200–6000 PFC labelled cells per voxel [94– 96]. Furthermore, the visualization of 4–106 cells in 7 min on a human scanner working at 1.5 Tesla field strength has been also reported [94–96]. PFCs, such as perfluorotributylamine (PFTB) and perfluorooctyl bromide (PFOB) have several 19F NMR resonances. Therefore, PFCs with a single resonance, such as hexafluorobenzene (HFB) and perfluoro-15-crown-5-ether (PFCE) have found extensive use. 19 F MRI is an extremely useful method for detecting the binding of fluorinated antibody compounds to a target. 19F has a large chemical shift range and it is extremely sensitive to relaxation changes caused by binding, which can provide higher resolution than 1H NMR relaxation experiments. 19F NMR has been used to characterize the multifunctional calcium dependent calmodulin protein bound to the fluorinated antipsychotic inhibitor, trifluoperazine (TFP) to determine that TFP binding can occur without calcium present [97]. Additionally, fluorine incorporation often improves the pharmacokinetic properties and potency of the drug. Binding interactions between the plasma protein human serum albumin and drugs can have detrimental effects on the drug’s pharmacokinetic properties. 19F MR has been used to report on specific interactions between human serum albumin (HSA) and fluorinated dugs prior to lengthy pharmacokinetic studies [98]. As mentioned previously, fluorine atoms can be selectively incorporated into pharmaceuticals to alter biological activity. There is a number of fluorine-containing drugs that are studied by 19F MRI. In particular, in vivo 19F MRI results showed a 2.5-fold greater accumulation of gemicatabine in the cancer xenograph in comparison with the control model [99]. 19F MR studies analyzing the chemical shift and relaxation properties of side products have been used to monitor the metabolic pathway of 5-fluorouracil [100,101]. Brix et al. evaluated the biodistribution and pharmacokinetics studied trifluoromethylated derivatives of the 3aminobenzamide enzyme in rats with prostate adenocarcinoma [102]. 3-Aminobenzamide enzyme is responsible for the early repair of spontaneous and stimulated DNA strand breaks. The successful synthesis and evaluation of fluoro-nitrophenyl-galactopyranosides to detect b-gal activity in vitro by 19F MRI was reported previously [103]. In particular, 2-fluoro-4-nitrophenyl-Dgalactopyranoside was found to be highly responsive to the action of b-gal, and the cleavage product aglycone 2-fluoro-4-nitrophenol results in a pH dependent chemical shift of 4–6 ppm in 19F resonance [104]. 5. Conclusion In the synthesis of drugs, fluorine is often introduced to increase lipophilicity, bioavailability and metabolic stability [1–20]. The initial investigations demonstrate the potential of fluorinated drugs and proteins as in vivo MRI probes. In vivo, 19F MRI is excellent method to track 19F migration in tissue. The continuous improvement in drug design can permit tracking of fluorinecontaining drugs in clinical platforms. Additionally, the development of PFC particles that can specifically accumulate in region of interest can enhance the 19F MRI sensitivity. References [1] Sham HL. In: Ojima I, McCarthy JR, Welch JT, editors. Biomedical Frontiers of Fluorine Chemistry. Washington, DC: American Chemical Society; 1996. p. 184–95. [2] Woo LW, Fischer DS, Sharland CM, Trusselle M, Foster PA, Chander SK, et al. Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography. Mol Cancer Ther 2008;7(8):2435–44.
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