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. 2023 Oct 2;8(41):37720–37730. doi: 10.1021/acsomega.3c05594

Recent Advances of S–18F Radiochemistry for Positron Emission Tomography

Xiaoyun Deng 1, Xiaohua Zhu 1,*
PMCID: PMC10586020  PMID: 37867643

Abstract

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The click chemistry of sulfur(VI) fluoride exchange (SuFEx) has facilitated the widespread application of sulfur–fluoride compounds such as sulfonyl fluorides, fluorosulfates, and sulfamoyl fluorides in various fields, especially in the development of 18F ligands for PET (positron emission tomography) imaging. In recent years, the prominent progress of sulfur–[18F]fluoride compounds has been achieved through the combination of 18F and sulfur–fluoride chemistry. These compounds serve as potential 18F tracers, 18F synthons, and reagents for 18F-fluorination, thereby complementing the range of 18F ligands, typically C–18F structures, used in PET studies. This review aims to provide an overview of S–18F labeling reactions through examples of relevant 18F compounds and highlight the advancements and breakthroughs achieved in the past decade.

1. Introduction

The extensive clinical use of 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) in cancers, cardiovascular diseases, and neurological disorders has established 18F as the most commonly used PET nuclide.1,2 Most developed 18F probes for PET imaging are obtained by C–18F formation, including aliphatic and aromatic 18F-fluorination with nucleophilic [18F]fluoride as well as electrophilic 18F-fluorination with [18F]F2 and [18F]F2-derived reagents.3,4 Over the past few decades, the rapid advancement of 18F radiochemistry has led to the establishment of various noncanonical 18F labelings involving bond formation with elements such as sulfur, boron, silicon, aluminum, and gallium. Among these radiolabeled hetero-18F compounds, the S–18F molecules represent significant building blocks and imaging agents for PET studies.5 In the S–19F chemistry, the compounds containing an SO2F group have garnered considerable focus in the fields of chemistry and biology owing to the balanced stability and reactivity of these molecules under physiological systems. These functionalities have demonstrated potential in various applications, such as serving as potent protease inhibitors, biological probes, and covalent modifiers of proteins.6−11 However, the standard synthetic methods used to obtain such compounds have relied mainly on Cl/F exchange from the corresponding chlorides.12−14 Following the introduction of the concept of “sulfur(VI) fluoride exchange” (SuFEx) as a potent reaction for click chemistry15,16 by Sharpless and colleagues in 2014, considerable efforts have been devoted to developing alternative pathways for the synthesis of SO2F compounds that have a wide range of functional group tolerance and can be obtained from readily accessible starting materials. Apart from the rapidly developing SO2F chemistry, the preparation of sulfonimidoyl fluorides was disclosed several decades ago.17 Additionally, certain sulfur multifluorinated compounds are frequently produced to be employed as fluorinating reagents.18 In the S–18F radiochemistry, since [18F]fluoride is predominantly produced through the 18O(p,n)18F nuclear reaction from a cyclotron in high radioactivity and high specific activity,3 the present methods of S–18F formation frequently employ the [18F]fluoride as the primary source of fluorine-18. Herein, we mainly focus on and summarize the synthesis and applications of S–18F compounds. Specifically, the synthetic methods of 18F-labeled aryl/alkenyl sulfonyl fluorides, fluorosulfate, sulfamoyl fluorides, and sulfur multifluorides are concisely summarized. Furthermore, to gain a more comprehensive understanding of the recent research progress, this paper extensively covers the reaction scopes, applications, and limitations.

2. Sulfonyl [18F]Fluoride

Sulfonyl-based functional groups, including sulfones, sulfinic acids, and sulfonamides, have found widespread use in various fields, such as acting as active ingredients in pharmaceuticals19 and agrochemicals,20 playing a critical role as intermediates in complex chemical syntheses,21,22 and being utilized as specialty materials and food additives.23 In general, the synthesis of these functional groups is based on the classic reactivity patterns of sulfides.24 The arrangement of the SO2 group is what links all functional groups that are derived from the sulfonyl fragment. This implies that direct introduction of the SO2 group is a simple approach to produce these molecules, which has been proved by the utilization of the SO2 surrogates, such as K2S2O5, Na2S2O5, and 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO).25 These SO2 sources have been widely used to introduce the SO2 group through metal catalysis.26−31 In particular, Willis and colleagues demonstrated the application of this catalytic system in the synthesis of (hetero)arenesulfonyl fluorides using DABSO as a SO2 source and corresponding (hetero)aryl bromides as precursors.32 Subsequently, various synthetic methods employing SO2 surrogates have been developed to convert electrophiles, such as aryl iodides, alkenyl triflates, or arenediazonium salts, into their corresponding arenesulfonyl fluorides.33−37 Studies have also been conducted on the use of aryl nucleophiles as aryl sources in catalytic protocols. Examples include the Cu(I)- or Ni(II)-catalyzed synthesis utilizing DABSO and aryl boronic acid,30,31 as well as the Bi-catalyzed system with SO2 gas and (hetero)aryl boronic acids.38 In addition, an electrochemical method was reported to directly convert conventional precursors of thiols into sulfonyl fluorides using KF as a cost-effective, safe, and readily available fluoride source.39

In radiochemistry, 18F-labeled arenesulfonyl fluorides were usually synthesized from the precursors of sulfonyl chlorides 1 (Scheme 1), except that [18F]tosyl fluoride was identified as a side product in the preparation of 18F-labeling synthons of [18F]fluoromethyl tosylate40 and [18F]fluoromethyl-d2 tosylate41 from methylene bis(4-methylbenzenesulfonate) and methylene-d2 bis(4-methylbenzenesulfonate), respectively. The chloride precursors could be obtained by direct chlorosulfonylation42 with chlorosulfonic acid or sulfonylation followed by chlorination using cyanuric chloride.43 In 2013, Fraser and co-workers developed a highly effective approach to get 18F-labeled arenesulfonyl fluorides using an Advion NanoTek Microfluidic Synthesis System (Scheme 2).44 Another microfluidic platform, which is called magnetic droplet microfluidics (MDM), was processed to synthesize 18F-labeled arenesulfonyl fluoride via the manipulation of microliter-scale liquid droplets using magnetic particles.45 Even though these methods could shorten the reaction time and the 18F products were synthesized with excellent radiochemical yields (RCYs) and molar activities (MAs), sulfonyl chlorides were still used as the labeling precursors and the reaction was typically accomplished by nucleophilic substitution with [18F]fluoride. There have been no novel labeling approaches with readily available precursors to obtain 18F-labeled arenesulfonyl fluorides in the recent decades. The difficulties in the preparation of the complicated drug-like SO218F compounds limited the PET studies using tracers containing the SO218F group.

Scheme 1. General Radiosynthesis of 18F-Labeled Arenesulfonyl Fluorides.

Scheme 1

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Scheme 2. Radiosynthesis of 18F-Labeled Arenesulfonyl Fluorides Using Microfluidics.

Scheme 2

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RCY, radiochemical yield.

MA, molar activity.

Recently, our group developed a novel strategy to directly construct carbon–SO2–18F from arenediazonium tosylates with an SO2 source (DABSO) and [18F]fluoride (Scheme 3).46 A broad range of substrates is compatible with this approach, allowing for the synthesis of 18F-labeled pharmaceutically relevant compounds by late-stage 18F-fluorination, including 18F products derived from the corresponding substrates of flutamide (an antiandrogen drug), neratinib (an anticancer drug) intermediate, cabozantinib (an anticancer drug) intermediate, and sulfamethazine (an antibacterial drug). Additionally, the utilization of a reactive 18F-labeling synthon, containing a prosthetic group based on maleimide, facilitated the production of two 18F-labeled temperature-sensitive biomolecules that featured cysteine residues by maleimide–cysteine chemistry.47 Achieving multiple bond formations in a single reaction to obtain 18F-labeled products proves challenging within 18F radiochemistry.48−50 This difficulty arises due to the utilization of only trace amounts of [18F]fluoride (in nanomoles), which significantly limits the compatibility of forming 18F-included “multibond” compounds. Remarkably, the successful direct aryl–SO2–18F two-bond formation showcased favorable compatibility in this regard. Based on these advantages, this 18F-fluorosulfonylation method represented a notable advancement in radiosynthesizing the 18F-labeled arenesulfonyl fluorides.

Scheme 3. Radiosynthesis of 18F-Labeled Arenesulfonyl Fluorides from Arenediazonium Tosylates.

Scheme 3

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RCC, radiochemical conversion.

BSA, bovine serum albumin.

The 18F-labeled sulfonyl fluorides containing bifunctional groups have been developed in the past decade and successfully coupled to the biological molecules that are not easily labeled with 18F directly. As shown in Scheme 4, a sufficiently stable 18F-labeled arenesulfonyl fluoride (5) bearing a formyl group was prepared as an 18F synthon and reacted with the 9-amino acid bombesin analogue (6, BBN-ONH2) to give [18F]BBN-OX-MESIT-SO2F (7) through oxime formation with an acceptable yield.51 In PBS (10% DMSO), this radiolabeled biomolecule was observed to remain stable for a duration of 2 h at 37 °C. However, in murine serum, it underwent extensive conversion to radiolabeled metabolites in less than 15 min. Thus, the stability of the biomolecules containing a SO218F group should be considered when constructing SO218F compounds as the labeling reagents.52

Scheme 4. Radiosynthesis of the 18F-Labeled Arenesulfonyl Fluoride (5) and [18F]BBN-OX-MESIT-SO2F Peptide.

Scheme 4

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Another SO218F synthon (10, [18F]FS-PTAD) comprising a cyclic diazodicarboxamide group was prepared in a high RCY by two steps, starting from 18F-fluorination of the precursor 4-[4-(chlorosulfonyl)phenyl]urazole (8) followed by complete conversion with the oxidizing agent (Scheme 5).53 Immediately, an ene-like reaction (the tyrosine click reaction here)54,55 of [18F]FS-PTAD with l-tyrosine could afford an 18F-labeled tyrosine derivative [18F]FS-tyrosine (11). This rapid and efficient labeling methodology with multiple steps was demonstrated to be suitable to yield 18F-labeled tyrosine derivatives as potential ligands for use in PET studies, even though only a slight accumulation of the labeling product 11 was found in two primary human glioblastoma cell lines and F98 rat glioma cell by cell uptake experiments.

Scheme 5. Radiosynthesis of [18F]FS-PTAD and [18F]FS-Tyrosine.

Scheme 5

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DBDMH, 1,3-dibromo-5,5-dimethylhydantoin.

NBS, N-bromosuccinimide.

In addition to acting as labeling synthons, 18F-labeled sulfonyl fluorides could also be used for 18F-fluorination in certain cases.56 As shown in Scheme 6, the reaction of 2-pyridinesulfonyl chloride (12) with [18F]KF/K222 afforded the fluorinating agent [18F]PyFluor (13) in an excellent radiochemical conversion (RCC). With this SO218F compound in hand, deoxy-radiofluorination of an aliphatic hydroxyl compound (14) was realized as the aliphatic C–18F bond was formed under mild conditions, generating 18F compound 15 in 15% RCC. The traditional approach to convert alcohols into alkyl–18F compounds involves a two-step sequence that consists of forming leaving groups, such as −OTs or −OMs, from alcohols, followed by aliphatic 18F-fluorination. This “one-pot” direct deoxy-radiofluorination using [18F]PyFluor represents a breakthrough in 18F-labeling of alkyl compounds since the unstable tosylate precursors of conventional radiofluorination3,4,57 limits the preparation of 18F-labeled alkyl fluorides.

Scheme 6. Radiosynthesis of [18F]PyFluor and Its Application of Deoxy-Radiofluorination.

Scheme 6

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MTBD, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

Unlike 18F-labeled arenesulfonyl fluorides, the 18F-labeled alkenesulfonyl fluorides showed good reactivity without bearing additional highly reactive functional groups.58,59 In 2018, Fraser and co-workers reported the first radiochemical synthesis of [18F]ethenesulfonyl fluoride (20, [18F]ESF) and its conjugation with amino acids and proteins through Michael addition (Scheme 7).58 The synthesis was performed in a microfluidic reactor system via a 18F/19F isotopic exchange method with nonradiolabeled ESF (17) or treatment of the precursor 2,4,6-trichlorophenylethenesulfonate (19, TCPE) with [18F]fluoride (Scheme 7, M1 or M2). Both of these methods did not require chromatographic purification and could be operated in a straightforward way to obtain [18F]ESF in good radiochemical yields. As shown in Scheme 7, the addition of [18F]ESF to compounds containing amino groups can produce 18F-labeled alkyl sulfonyl fluorides (21) through Michael conjugation. Nevertheless, it has been observed that these radiolabeling products exhibit instability in both injectable formulation and rat serum. Encouragingly, [18F]ESF has shown exceptional performance in 18F-fluorinating reactions.60 Unlike deoxy-radiofluorination of alcohols with the reagent [18F]PyFluor, this radiofluorination strategy could be implemented in a wide variety of scopes, including aromatic chloride, nitro, ammonium, boronic acid, and iodonium ylide compounds as well as aliphatic tosylate, p-nitrobenzenesulfonate, and trifluoromesulfonate precursors. Comparable radiofluorinating RCYs to those using a conventional [18F]fluoride source in most cases provided the alternative possibility to produce 18F radiopharmaceuticals. In addition, it significantly minimizes the required reaction equipment, potentially reducing it to just a heating/stirring aluminum block and disposable vials in the simple setup.

Scheme 7. Radiosynthesis of [18F]ESF and Its Applications.

Scheme 7

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Apart from [18F]ESF, the Liang and Xiao groups reported a novel method to get 18F-labeled alkenesulfonyl fluorides (28) by a three-step reaction61 (Scheme 8), including Cu-catalyzed addition of Cl/SO2OCF2H to alkenes (24), dehydrochlorination, and 18F-labeling of SO2OCF2H precursor (27) with [18F]fluoride. The unique reactivity exhibited by alkenyl SO2OCF2H compounds allowed for the convenient radiosynthesis of 18F-labeled alkenesulfonyl fluorides. The strategy described enabled the 18F labeling of a diverse array of substrates in RCCs between 58% and 92%. Two of these 18F compounds were isolated and purified in moderate decay-corrected radiochemical yields. However, the molar activities needed to be further improved since 18F/19F exchange happened during the labeling process.

Scheme 8. Radiosynthesis of 18F-Labeled Alkenesulfonyl Fluorides from Alkenes.

Scheme 8

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3. [18F]Fluorosulfate

The OSO2F unit can serve as either an effective leaving group or a robust connecting building block in organic synthesis, contingent upon the specific characteristics of the substituted aryl and alkyl compounds involved. These applications encompassed various processes such as metal-mediated couplings, sulfur(VI) fluoride exchange (SuFEx) reactions, carbonylation, involvement in alkylation and acylation reactions, hydrolysis, alcoholysis, and fluorinations.62 For the radiochemistry, Blower and co-workers reported the preparation and application of the potassium [18F]fluorosulfate (30),63 which represented the first example for PET imaging using a probe bearing an S–18F bond. The production of potassium [18F]fluorosulfate is shown in Scheme 9; the reaction of [18F]KF/K222 with a Lewis acid–base SO3–pyridine complex (29) yielded the radio product with a moderate decay-corrected RCY of 31.6 ± 9.5% and a high molar activity of 48.5 ± 13.4 GBq/μmol. In both in vitro and in vivo experiments, this uncomplicated and inorganic 18F-labeled radiopharmaceutical showed specific uptake of the sodium–iodide symporter (NIS). Notably, PET/CT imaging conducted on normal mice within the initial hour postinjection displayed noticeable uptake of the potassium [18F]fluorosulfate at locations known to exhibit NIS expression. The radiosignal was blocked by coinjection of sodium perchlorate, a known NIS inhibitor,64−66 thus demonstrating the remarkable potential of potassium [18F]fluorosulfate as an outstanding PET tracer for NIS.

Scheme 9. Radiosynthesis of [18F]KSO3F from SO3– Pyridine Complex.

Scheme 9

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Aryl fluorosulfates, which are widely used OSO2F compounds, can be easily obtained through reactions involving phenols or alcohols with sulfuryl fluoride, sulfuryl chloride fluoride, fluorosulfonic acid, and fluorosulfonic anhydride as well as a solid fluorosulfuryl imidazolium triflate.62 They are more stable than arenesulfonyl fluorides in reports of sulfur(VI) fluoride exchange (SuFEx),11,15,67,68 which attracted researchers to investigate the radiosynthetic strategies and PET imaging applications of 18F-labeled aryl fluorosulfates. In 2020, Chun, Hong, and co-workers reported the pioneering research of the direct radiosynthesis of 18F-labeled aryl fluorosulfates utilizing phenols or aryl imidazole sulfonates (34, imidazylates) (Scheme 10).69 They devised two strategies both from phenols for this 18F-radiosynthesis. The first mode involved one-pot [18F]fluorosulfurylation of phenols deploying 1,1′-sulfonyldiimidazole (33, SDI) and [18F]fluoride. The second was realized by [18F]fluorination of imidazylate precursors derived from phenols. The [18F]fluorosulfurylated products with moderate to high RCYs were prepared by both methods, while Mode 2 afforded higher RCYs in most cases. The substrate scope of this [18F]fluorosulfurylation strategy was tolerated with various functional groups, such as carbonyl, azide, hydroxy, formyl, alkenyl, and alkynyl moieties. Some drug-relevant compounds and natural products were also labeled with 18F by this methodology in good RCYs.

Scheme 10. Radiosynthesis of 18F-Labeled Aryl Fluorosulfates from Phenols or Aryl Imidazole Sulfonates (Imidazylates).

Scheme 10

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Based on SuFEx reactions,11,15,67,68 Sharpless, Yang, Wu, and co-workers bridged click chemistry and 18F-radiosynthesis, developing an ultrafast process to synthesize 18F-labeled aryl fluorosulfates (Scheme 11).70 Within a brief duration of just 30 s at room temperature, the conversion of [18F]fluoride using nonradioactive aryl fluorosulfates (36), obtained from phenols and sulfuryl fluoride, was effectively and successfully achieved. Subsequently, a rapid (<1 min) C18-cartridge separation process was employed to isolate the 18F-labeled aryl fluorosulfates. Interestingly, the precursors of aryl fluorosulfates have been reported as intermediates for a deoxyfluorination protocol producing aryl fluorides from phenols.71 In this radiolabeling strategy, using the fluorosulfate precursors that possess extensive structural and functional diversity enabled the 18F labeling to get the corresponding radioproducts in excellent RCYs of 83–100% and high molar activities. PET imaging of a healthy mouse using one particular 18F-labeled product revealed the absence of a nonspecific radiosignal in the bones, thereby indicating the good stability of [18F]arenefluorosulfate without 18F-defluorination in vivo. For further investigations, a specific olaparib analog incorporating an aryl fluorosulfonyl component was labeled with 18F and then employed for PET imaging in a xenograft model of a human breast cancer, which was established using the MCF-7 cell line known for its elevated expression of PARP1. Additionally, in order to evaluate the specificity of the probe, blocking experiments were conducted by administering a preinjection of excess olaparib, a well-established PARP1 inhibitor. As a result, accumulation of the 18F-labeled olaparib analog in blocking experiments decreased obviously in tumors compared with that in nonblocking imaging studies, which supported this probe a potential PARP1-specific ligand for PET imaging.

Scheme 11. [18F]SuFEx of Aryl Fluorosulfates.

Scheme 11

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4. Sulfamoyl [18F]Fluoride

In the S–F chemistry, the sulfamoyl fluoride stands out as a highly stable yet efficient synthetic precursor or synthon for various valuable compounds, such as sulfamides15 and azide derivatives72 obtained by substitution and click chemistry, respectively. For the radiochemistry, Chun, Hong, and co-workers developed the radiosynthesis of 18F-labeled sulfamoyl fluorides (39) from the precursors of cold sulfamoyl fluorides,73 generated from corresponding amines, by 18F/19F isotopic exchange methodology (Scheme 12). This 18F-labeling strategy was performed efficiently with sulfamoyl precursors produced from aromatic and aliphatic secondary amines as well as primary amines that possessed mono- or bis-SO2F moieties. They also attempted the direct 18F-fluorosulfurylation of amines based on their initial method69 to produce 18F-labeled aryl fluorosulfates from phenols using 1,1′-sulfonyldiimidazole (SDI) and [18F]fluoride. Unfortunately, despite their efforts, the desired radioproduct could not be obtained.

Scheme 12. Radiosynthesis of 18F-Labeled Sulfamoyl Fluorides through 18F/19F Isotopic Exchange.

Scheme 12

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Recently, they successfully achieved the direct radiofluorosulfurylation for synthesizing 18F-labeled sulfamoyl fluorides from amines (Scheme 13).74 This approach involved the in situ generation of an [18F]FSO2+ transfer species by eluting the 18F-trapped QMA cartridge with an acetonitrile–water solution containing the imidazolium salt 42, which has been used to synthesize the aryl fluorosulfates and sulfamoyl fluorides.16 Mechanistic analysis conducted by using 19F NMR unveiled the formation of [18F]FSO2+ as a mixture comprising [18F]SO2F2 and [18F]fluorosulfuryl imidazolium salt. The eluted [18F]FSO2+ exhibited reactivity toward various amine substrates, including primary aliphatic and aromatic amines as well as secondary aliphatic and aromatic amines. This method enabled the synthesis of 18F-labeled sulfamoyl fluorides without the need of cryptand or strictly anhydrous conditions for the 18F-labeling process. In addition, it is also applicable to diverse phenolic substrates, which can be converted into 18F-labeled fluorosulfates (Scheme 13). Compared to previous methods (Schemes 10 and 11), this approach allows for the direct 18F labeling of fluorosulfates using phenols to obtain 18F-labeled fluorosulfates. However, it requires the prior preparation of 18F-labeling reagents, resulting in an additional radio reaction step.

Scheme 13. Radiosynthesis of 18F-Labeled Sulfamoyl Fluorides and Aryl Fluorosulfates from Amines and Phenols, Respectively.

Scheme 13

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5. Sulfur [18F]Multifluoride

Compared to the previous categories of S–18F compounds, progress in the development of sulfur [18F]multifluorides has been comparatively sluggish. Diethylaminosulfur trifluoride (DAST) was typically recognized for its utility in deoxyfluorination reactions of hydroxyl and carbonyl oxygens.75 This reactive fluorinating reagent has found applications in the field of radiochemistry. After introduction of 18F into DAST with hydrogen [18F]fluoride via 18F/19F exchange, [18F]DAST (44) was generated with more than 80% of the available activity incorporated (Scheme 14).76 Deoxy-radiofluorination of several uncomplicated alcohols using this reactive agent could yield 18F-labeled fluoroalkyl compounds (45–47). However, in the early years, no 18F/19F exchange was observed for sulfur hexafluoride (SF6), a gas of another sulfur multifluoride, when it was treated with hydrogen [18F]fluoride.77 Afterward, a small yield of [18F]SF6 was formed during the production of recoil [18F]fluoride atoms78 by the 19F(n,2n)18F nuclear reaction79 in the presence of SF6.80,81 A long time later in 2016, Llop and co-workers reported a readily automatable method for the preparation of [18F]SF6,82 which involved an ion-beam-induced isotopic exchange reaction on the basis of the 19F(p,pn)18F nuclear reaction. As SF6 has been used as fluorinated gas to evaluate lung ventilation by magnetic resonance imaging (MRI),83 the radiolabeled [18F]SF6 was employed to investigate lung ventilation by PET imaging in a rat model of acute lung inflammation induced by administering lipopolysaccharide (LPS) via intratracheal nebulization.84 Successful identifications of the hypoventilated lung regions with [18F]SF6 showed promise for clinical translation. In comparison to conventional imaging strategies for lung ventilation, PET imaging utilizing [18F]SF6 offers several advantages, including enhanced sensitivity, improved spatiotemporal resolution, and the ability to provide quantitative images of lung ventilation defects.

Scheme 14. Radiosynthesis of [18F]DAST and Its Application of Deoxy-Radiofluorination.

Scheme 14

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6. Conclusions and Perspectives

Over the past decade, we have witnessed a remarkable advancement in S–18F radiochemistry for positron emission tomography. As SuFEx has progressed rapidly, it is our expectation that these endeavors will establish a vital link between radiofluorination and SuFEx chemistry. The utilization of simple precursors and fast labeling reactions for S–18F constructions has emerged as particularly noteworthy for meeting the demands of 18F probe production. The application of these S–18F compounds extends beyond PET tracers alone, and they can also be deployed as 18F synthons for the synthesis of biomolecules, as well as the 18F-fluorinating reagents for the radiolabeling of PET ligands.

When both the main part and the S–18F fragment of the radiolabeled compound exhibit good stability, it is possible to consider the direct synthesis of S–18F probes for PET tracers. Although this method for PET imaging studies has always been a focal point of research for scientists, the development of SO218F synthons is also an important area of focus in S–18F radiochemistry since many temperature-sensitive or water-soluble biomolecules cannot be directly labeled with 18F. An indirect labeling method conducted with the SO218F synthon provides a possibility for 18F labeling of these biomolecular compounds. In general, whether these S–18F compounds can be used for clinical translation depends on various factors such as their in vivo stability, pharmacological activity, toxicity, and other relevant imaging aspects. Furthermore, the development of moderately stable SO218F compounds as fluorinating agents is also a key consideration in late-stage 18F-fluorination chemistry. Such SO218F compounds often possess a certain level of stability and reactivity. It is believed that in the near future more novel and convenient methods to obtain S–18F compounds will be developed, which will be ingeniously applied in the investigation of 18F probes for PET imaging.

Acknowledgments

We thank the National Natural Science Foundation of China (82202232, 81873903, 91959119, and 82272041) for financial support.

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

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