Sulfur - fluorine bond in PET radiochemistry
© The Author(s) 2017
Received: 6 April 2017
Accepted: 14 June 2017
Published: 17 July 2017
The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups. In this review, we will show how these examples are translating into the 18F field, both for use as stable tags in finished radiopharmaceuticals and as mildly reactive fluoride-relay intermediates. Finally, we also discuss current opportunities where examples of non-radioactive S-F applications/chemistry may be translated into future 18F radiochemistry applications.
KeywordsSulfur-fluorine bond Sulfonyl fluoride 18F PET Fluoride relay Fluorosulfate Deoxyfluorination Sulfurhexafluoride
The field of 18F radiochemistry is constantly investigating the utilization of novel fluorinated pharmaceuticals, and the radiofluorination processes that can lead to their production. The sulfur-fluorine bond is starting to gain importance, both for its presence in the final structures and for utilisation as a “fluoride relay” species. This perspective review will show how some of these applications are currently utilized and reported in 18F literature, and it will also provide examples from non-radioactive fluorine chemistry that could inspire future radiofluorine applications.
Features, reactivity and uses of the S-F bond
The current literature can be divided into two modes of utilization. In the first approach, the S-18F moiety is present in the final target molecule and procedures have been developed in order to create this bond in a selective and mild fashion. In the second case, the reactive feature of the S-F bond is exploited in order to relay, in a specific fashion, the 18F label to an appropriate precursor. In this approach, the S-18F bond is created in an intermediate molecule and not present in the final target compound. Given the physicochemical trends discussed previously, most examples discussed herein belong to the sulfur (VI) oxidation family. It is almost certain, but perhaps we may be rebutted, that sulfur (II) fluoride containing functional groups are far too reactive to ever find application in fluorine-18 radiochemistry. This is not the case, however, for sulfur (IV) fluoride containing functional groups, which have many known applications in regular fluorination chemistry, and may begin to be utilized as transfer agents in fluorine-18 radiochemistry.
Therapeutics and biological tools incorporating sulfonyl fluoride moieties
Sulfur-[18F] fluorine radiolabelled reagents and compounds
Shortly after, Matesic et al. investigated the suitability of twelve aryl [18F] sulfonyl fluorides for applications in 18F-radiochemistry (Matesic et al. 2013). The [18F] sulfonyl fluorides were prepared by reacting the corresponding sulfonyl chlorides with [18F] fluoride under microfluidic conditions. These molecules bore neutral, electron-donating and electron-withdrawing functional groups. Additionally, sulfonyl chlorides containing varying degrees of steric bulk and a heterocyclic sulfonyl chloride were evaluated. Under microfluidic synthesis conditions, the [18F] sulfonyl fluorides could be prepared in less than 60 s at temperatures between 30–180 °C using a 0.5 mg/mL solution of the sulfonyl chloride precursor. The exception to this rule was the electron-withdrawing [18F] 4-nitrobenzenesulfonyl fluoride, which could not be produced at all using the parameters above. Interestingly, in the presence of 5% water in the reaction mixture, the compound could be formed in 91% radiochemical yield (RCY) at 30 °C (Pascali et al. 2014). This result is not unprecedented as several reports in recent years have described increased RCY when the molecules are prepared in solutions containing varying percentages of water (Sergeev et al. 2015). The reaction parameters of all analogues could be fine-tuned to produce >75% RCY at 30–180 °C by increasing precursor concentration, adding water, altering residence time, etc. The compounds were monitored for stability in buffers, before the stability of the leading candidates (21–23, Fig. 5) were evaluated in rat serum. After 2 h at physiological temperature in serum, the [18F] 2, 4, 6-triisopropylbenzenesulfonyl fluoride (23) was still 95% intact, suggesting that steric bulk around the sulfur-[18F] fluorine bond was more important in protecting the bond from hydrolysis, than the electron density of the molecule.
Potentially inspired by the feasibility of using microfluidic devices to radiolabel small molecules with 18F, Fiel et al., revisited the radiosynthesis of the [18F] 3-formylbenzenesulfonyl fluoride 18 in Fig. 5, using a magnetic droplet microfluidic (MDM) platform (Fiel et al. 2015). The platform consists of a Teflon sheet mounted on a stage, with a robotic arm beneath the Teflon sheet which controls the movement of the magnetic particles on the stage. [18F] Fluoride preconcentration and subsequent radiolabelling were performed on the same platform, in contrast to most traditional radiolabelling procedures whereby the [18F] fluoride is preconcentrated in a vial external to the microfluidic device. The authors were able to radiolabel the 3-formyl analogue 18 in tert-butanol in 5 min at room temperature using a total volume of 100 μL. The RCY (72 ± 1%, n =3) was comparable with that reported by Inkster et al. (73 ± 7%) (Inkster et al. 2012), however, the reaction time had decreased from 15 min to 5 min.
[18F] Ethenesulfonyl fluoride (ESF)
[18F] Fluorosulfate ion
Tracer stability studies confirmed a RCP of >95% (after 4 h) in multiple media including formulation media, acidic environment and serum. Specific uptake of the tracer was confirmed in vitro in NIS-expressing cell lines, as well as in vivo in healthy mice using PET-CT. During the imaging studies, a steady increase of radioactivity was noticed in bones, especially after 30 min; however, the authors believe that this metabolism will likely not hamper the utility of [18F] SO3F- for NIS imaging. This work represented the first ever PET-CT imaging of a compound bearing an S-18F bond.
More recent literature has indicated that sulfonyl fluorides are viable as [18F] deoxyfluorinating reagents (Takamatsu et al. 2002; Guo and Ding 2015), and indeed some applicative value has been demonstrated by perfluorobutanesulfonyl fluoride (PFBS) (Vorbrüggen H. The conversion of primary or secondary alcohols with nonaflyl fluoride into their corresponding inverted fluorides. Synthesis (Stuttg) 2008; Bennua-Skalmowski and Vorbruggen 1995). Inspired by these contributions, Nielsen et al. have reported the synthesis and use of [18F] PyFluor (2-pyridinesulfonyl fluoride, 41) (Nielsen et al. 2015). In this work, the authors first studied a range of sulfonyl fluorides (comprising PFBS) to fluorinate a model alcohol, using 1.1 eq of fluorinating reagent and 2 eq of 1,8-diazabicyclo-[5.4.0] undec-7-ene (DBU) or 7-methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene (MTBD) as a base. This preliminary set of experiments revealed PyFluor as the most promising reagent, with the highest fluorination yield and selectivity (towards dexoyfluorination reaction). The postulated mechanism involves the formation of an intermediate sulfonate between Pyfluor and the alcohol, and its subsequent fluorination by nucleophilic substitution by the liberated fluoride ion. DBU or MTBD act as Brønsted bases and are proposed to help stabilize the developing fluoride ion, rendering it available to nucleophilic reaction. The wide scope demonstrated, allowed for Pyfluor to now be commercially available through Sigma-Aldrich as a deoxyfluorinating reagent.
[18F] SF6 production and uses
[18F] Fluoride atoms produced by the irradiation of SF6 gas through the19F(n,2n)18F nuclear reaction in fast neutron generators were first reported in the 1970s (Colebourne and Wolfgang 1963). Even though these 18F atoms lost the majority of their kinetic energy in the presence of SF6 (Smail et al. 1972), they were still able to undergo addition onto olefins, ethylene and acetylene to produce the 18F-fluorinated analogues (Williams and Rowland 1971), and this observation was even proposed as a useful method for scavenging undesired 18F atoms. The production of [18F] SF6 remained largely unexplored in the radiochemistry literature for 40 years, until Gómez-Vallejo reported the cyclotron production of [18F] SF6 in 2016 (Gómez-Vallejo et al. 2016). In this method, the authors verified that new cyclotrons are able to exploit the (p, pn) route to obtain c.a. fluorinated gases (in this test CF4 was also produced), but the yield obtained are insufficient for imaging uses. Therefore, they optimized a double irradiation method, in which [18O] O2 was used as target material in the first irradiation, and CF4 or SF6 were used to fill the target in a second irradiation. In this way, almost 7 GBq of [18F] SF6 was produced using an integrated current of 4 μA and the authors hinted at the possibility of using such 18F-radiolabelled fluorinated gases for in vivo PET imaging assessment of lung ventilation. The availability of [18F] SF6 may also turn useful in multimodal imaging approaches, due the current use of SonoVue® (from Bracco), an SF6 microbubble formulation, as an ultrasound contrast imaging agent.
Desulfurization of aromatic sulfonyl fluorides
SF5 functional group
In summary, the SF5 group can be prepared only via nucleophilic sources of fluorine; it is envisaged that such moiety could represent a useful 18F functional group which incorporates five fluorine atoms and therefore, like in the case of the trifluoroborate moiety (Liu et al. 2013), provide a way to increase the maximum molar radioactivity of 18F-radiopharmaceuticals up to five times. In addition, the heightened practice of introducing this functionality in new drugs will open the opportunity and the interest to access a wider range of radiopharmaceuticals labelled with an 18F version of the SF5 group.
Use of SF6 as fluorinating agent
Deoxyfluorination mediated by aryl fluorosulfonates
The authors first synthesized a series of sulfonates 57 and evaluated these as substrates in nucleophilic fluorination reactions. In these experiments they found out that the ipso fluorination was generally favoured compared to substitution to NO2 or Cl nucleofuges, with overall reactivity still governed by the nature of para- and ortho- electron-withdrawing groups. A one-pot procedure was also tested, in which a substituted phenol (56) was successfully reacted with sulfuryl fluoride (SO2F2) and a nucleophilic source of fluoride, affording the desired fluorinated arenes (60) in good yield under mild conditions. The proposed mechanism, supported by calculations and product distribution analysis, involves a pentacoordinate intermediate (58, 59), which is formed via the attack of a fluoride anion on the sulfur centre, and its subsequent rearrangement to the fluoroarene product. It is likely that the potential of this route for translation into 18F chemistry will be investigated, possibly by modifying the precursor composition which will affect and allow optimisation of the steric/electronic characteristics of the proposed transition state.
The use of sulfur-fluoride bonds represents a growing trend in drug development, hampered by the discovery of the substantial stability of several moieties containing such bond. It is therefore forecasted that the investigation of creating these bonds with 18F will be of relevance in the future of radiopharmaceutical field. Added to this, the specific reactivity of the S-F bond has facilitated the development of several fluorinating agents currently employed in traditional organic chemistry. The thorough understanding of their working principles may provide access to new mild and selective radiofluorinating agents for potential use in late-stage labelling.
A.T. King gratefully acknowledges the Australian Institute of Nuclear Science and Engineering for providing a Honours scholarship. B. Z. gratefully acknowledges the Australian Institute of Nuclear Science and Engineering for providing a PGRA scholarship.
GP led the conceptualization of the work. GP, LM, BZ and BHF led the writing of the manuscript. ATK, AJR and ATU contributed to the writing of the manuscript. All the authors reviewed the manuscript.
The authors declare that they have no competing interests.
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