Fluorine-18: Radiochemistry and Target-Specific PET Molecular Probes Design

The positron emission tomography (PET) molecular imaging technology has gained universal value as a critical tool for assessing biological and biochemical processes in living subjects. The favorable chemical, physical, and nuclear characteristics of fluorine-18 (97% β+ decay, 109.8 min half-life, 635 keV positron energy) make it an attractive nuclide for labeling and molecular imaging. It stands that 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is the most popular PET tracer. Besides that, a significantly abundant proportion of PET probes in clinical use or under development contain a fluorine or fluoroalkyl substituent group. For the reasons given above, 18F-labeled radiotracer design has become a hot topic in radiochemistry and radiopharmaceutics. Over the past decades, we have witnessed a rapid growth in 18F-labeling methods owing to the development of new reagents and catalysts. This review aims to provide an overview of strategies in radiosynthesis of [18F]fluorine-containing moieties with nucleophilic [18F]fluorides since 2015.


INTRODUCTION
Positron emission tomography (PET) is a non-invasive and quantitative imaging technology for assessing biological processes in vivo (Preshlock et al., 2016). Due to the high sensitivity of PET, the concentration of radiolabeled probes required was as few as the picomolar scale (10 −6 -10 −8 g). Therefore, the mass effect is not to be highly considered in probe design and labeling experiments. Compared with alternative positron-emitting radioisotopes (e.g., 11 C, 13 N, 15 O, 68 Ga, 89 Zr), 18 F has distinct physical advantages, including 1) simple decay profile (97% positron emission and 3% electron capture), 2) lower positron energy (maximal positron energy of 0.635 MeV) resulting in short positron range and high resolution, 3) favorable physical half-life (109.8 min half-life) suitable for labeling and in vivo evaluation, and 4) flexible for labeling viable molecules by different labeling strategies. Based on these unique and advantageous characteristics of fluorine-18, 18 F-labeled radiotracers have become a hot topic in molecular probe design. Whereas challenges still exist, considering fast labeling and favorable radiochemical yields have to be given higher priority in clinical practice. In recent years, many efforts have been made to develop new methods and new reagents for radiosynthesis of [ 18 F]fluorine-containing moieties. Radiofluorination and radiofluoroalkylation reactions have been excellently reviewed by Gouverneur and co-workers (Preshlock et al., 2016), and Vugts and co-workers (Born et al., 2017) from 2010. Herein, this review focused on summarizing the recent developments in 18 F-labeling methods and application in PET tracer design since 2015, according to the structures of desired radiolabeled complexes in each case, the following characteristics will be discussed: 1) radiosynthesis of fluoroalkanes with [ 18 F]fluorides; 2) radiosynthesis of fluoroarenes with [ 18 F]fluorides; 3) radiosynthesis of fluoroalkenes with [ 18 F]fluorides; 4) heteroatom-18 F bonds formation ( Figure 1). Unless otherwise mentioned, radiochemical yield (RCY) and radiochemical conversion (RCC) are calculated without time-decay; R means both electron-donating groups and electron-withdrawing groups are capable of this reaction.

RADIOSYNTHESIS OF FLUOROALKANES WITH [ 18 F]FLUORIDES
Nucleophilic [ 18 F]fluorination has been commonly used to generate aliphatic C-18 F bonds (Deng et al., 2019). However, labeling precursors with alcohol-derived leaving groups or halides are easily decomposed or eliminated to the corresponded alkenes under harsh conditions (high temperatures and basicity) (D'Angelo and Taylor, 2016;Cai et al., 2008). To resolve this issue, nucleophilic [ 18 F]fluorination of aliphatic alcohol and halides under mild conditions remained to be discussed. Other novel labeling precursors, such as carboxylic acid, and carbene precursors will be also discussed ( Figure 2).
Aliphatic C− 18 F bonds are constructed by nucleophilic substitution of alcohol-derived leaving groups with [ 18 F] fluorides in the presence of phase transfer reagents. The transformation of alcohols into corresponding 18 F-labeled alkyl compounds typically involves two steps, the formation of alcoholderived leaving groups was firstly required, including mesylate, triflate, tosylate, and followed by nucleophilic [ 18 F]fluorination (Deng et al., 2019). Alcohols are frequently-used moiety in natural products and pharmaceutical molecules. Herein, the research on direct deoxy-radiofluorination benefits PET tracer designing. Previously, deoxy-radiofluorination required a 19 F carrier to generate adequate electrophile in situ to react with the tiny amount of 18 F anion (Jelinski, et al., 2001). Doyle and coworkers reported the first example of a no-carrier-added deoxyradiofluorination which applied direct conversion of alcohols into alkyl fluorides in one pot (Nielsen et al., 2015) ( Figure 2A1).  (Sood et al., 2020) (Figure 2A2). In addition, alcohols were active by N,N′-diisopropylcarbodiimide (DIC), and CuF 2 . Elimination byproducts are often generated when radiofluorination of sulfonate-activated secondary alcohols (Cai et al., 2008). They obtained the pure 18 F-labeled product directly from the alcohol substrate without the elimination of byproducts. Toste, O'QNeil, and co-workers developed a formal deoxy-radiofluorination for radiosynthesis of [ 18 F] trifluoromethyl moiety (Levin et al., 2017) ( Figure 2A3). The unique biological properties of the trifluoromethyl group have led to their ubiquity in pharmaceutical complexes (Tsui and Hu, 2019). They showed the borane catalyzed formal C (sp 3 )-CF 3 reductive elimination from an Au(III) complex resulted in the formation of [ 18 F]alkyl-CF 3 compounds. Radiofluorination of the Au(III)-OAc complexes, fluorine-18 substitutes acetate group, are formal deoxy-radiofluorination reactions. The Au(III) complexes (labeling precursors) were prepared by migrationinsertion of the alkyl fragment in presence of borane and bromotrimethylsilane (TMSBr) and then via anion change with AgOAc. They considered the Au(III)-OAc complexes to exhibit an appropriate blend of stability and reactivity to enable nucleophilic reductive elimination. 18 F-labeled Bayer lead compound BAY 59-3,074, a cannabinoid agonist (Vry et al., 2004), was radio-synthesized in 12% of RCC with the molar activity of 0.3 GBq/μmol. This protocol provided an important proof of concept in the radiosynthesis of [ 18 F]trifluoromethyl groups by a retrosynthetic paradigm involving C-F reductive elimination.
Except for the above-mentioned alcohol-derived leaving groups, aliphatic halides are also capable of nucleophilic [ 18 F] fluorination, while showing lower reactivity (Deng et al., 2019).
[ 18 F]5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate ([ 18 F]Umemoto reagent) has been prepared from [ 18 F]fluoride by Gouverneur and co-workers via bromine-fluorine exchange and cyclization with the molar activity of 0.08 GBq/μmol (Verhoog et al., 2018) (Figure 2B2). Compared with previous [ 18 F]trifluoromethylation methods, this method provided a direct way for [ 18 F]trifluoromethylation of unmodified peptides at the thiol cysteine residue with high chemoselectivity. Function groups such as asparagine, glutamine, methionine, glutamic acid, proline, threonine, serine, tyrosine, lysine, or arginine were compatible for this [ 18 F]trifluoromethylation with RCCs superior to 55%. Glutathione and ((1-carboxy-2-mercaptoethyl)-carbamoyl)glutamic acid, a core structure found in PET radioligands targeting prostate-specific membrane antigen (PSMA) (Schwarzenboeck et al., 2017), underwent successful thiol [ 18 F] trifluoromethylation respectively in 26 % and 10% of RCY. Radiolabeled Arg-Gly-Asp (RGD) peptides have been a focus for noninvasive assessment of angiogenesis because of their high affinity and selectivity for integrin αvβ 3 (Hatley et al., 2018). The [ 18 F]trifluoromethylation was performed with a cyclic peptide containing the RGD sequence and the radiolabeled cRGDfC and cRADfC were purified and isolated by prep-HPLC in 19% and 33% of RCY. Biodistribution studies by imaging and dissection show that [ 18 F]CF 3 -cRGDfC is predominantly excreted by the hepatobiliary route and to a lesser extent by the kidneys. The absence of uptake in the bones indicated that [ 18 F]CF 3 -cRGDfC is metabolically stable toward [ 18 F]SCF 3 elimination and that no [ 18 F]F − was released (Gadais et al., 2017). Beta-amyloid peptide fragments also underwent successful [ 18 F]trifluoromethylation in 30% of RCY.
During the past decades, remarkable advances have been made in the area of decarboxylative fluorination. However, these recently developed methods are mainly based on electrophilic fluorination reagents, the research on decarboxylative fluorination with nucleophilic fluorination reagents is rare (Liang et al., 2013;Brooks et al., 2014). Groves and coworkers reported manganese catalyzed decarboxylative radiofluorination and the RCCs ranged from 20 % to 50% (Huang et al., 2015) ( Figure 2C1). Compared to present decarboxylative fluorination methods which are based on electrophilic fluorination reagents, the major advantage of this fluoride-based decarboxylative fluorination reaction is its applicability to 18 Figure 2C2). This reaction is tolerated with various functional groups, such as ether, alkyl, aldehyde, ketone, pyridine, triazole, pyrazole, and dibenzofuran motifs. The higher RCCs were obtained for electron-rich arenes. Fenofibrate analog, COX-II inhibitor ZA140, and estrone analog were also successfully radiolabeled. Doyle and coworkers developed another redox-neutral decarboxylative radiofluorination of N-hydroxyphthalimide esters with [ 18 F]KF under photoredox catalytic conditions with the typical molar activity of 36.6 GBq/μmol (Webb et al., 2020) ( Figure 2C3). To stable the carbocation intermediate, the reacting carbon atom bearing bi-alkyl or aryl is necessary. A common limitation in nucleophilic fluorination methods in delivering secondary benzylic fluorides elimination to styrene byproducts (Sladojevich et al., 2013). However, less than 5% elimination products were observed in the fluorination of the secondary substrates. Gemfibrozil analog and ribose analog could be prepared in 9% and 42% of RCC. Significantly, radiosynthesis of radiolabeled ribose analogs by conventional substitution reactions was limited due to the sulfonate precursor readily decomposed at room temperature (D'Angelo and Taylor, 2016).
Diazo compounds are known as carbene precursors to react rapidly with transition metals to form electrophilic metal carbenoids under mild conditions (Ford et al., 2015). Doyle and co-workers developed copper-catalyzed radiofluorination of α-diazocarbonyl compounds in mild conditions with [ 18 F]  (Liu et al., 2011). They showed the RCY of this radiofluorination protocol is significantly higher than in the previous literature. Some known radiotracers for positron emission tomography were readily accessible using this practical approach. (Turkman et al., 2011) was labeled in 39% of RCC (only 8% of RCY by the previous S N 2).
The strategy of directly and selectively transforming C-H bonds to C-18 F bonds is helpful due to the needlessness for the prefunctionalization of labeling precursors (Szpera et al., 2019). Groves, Hooker, and co-workers presented manganese porphyrin mediated direct radiofluorination of unactivated aliphatic C-H bonds with [ 18 F]fluoride (Liu et al., 2018) (Figure 2E). Similar to the earlier mentioned protocol (Huang et al., 2015), the anion exchange cartridge was eluted by acetone/acetonitrile solution of Mn III (TPFPP)OTs. Amino acid transporter, such as ACPC, leucine, valine, tyrosine analogs and leucine containing dipeptide, Lyrica analogs (an anticonvulsant drug) (Dworkin and Kirkpatrick, 2005), amantadine analogs (an antiparkinson disease drug), ezetimibe (a cholesterol-lowering drug), flutamide (a prostate cancer drug) (Baker et al., 1967), were radiolabeled efficiently at the aliphatic C-H bonds. They hypothesized that 18 F-labeled leucine and valine analogs have never been reported due to the inaccessibility of their corresponding precursors. However, C-H bonds radiofluorination occurred at the tertiary carbon atom due to the ortho-position alkyl

RADIOSYNTHESIS OF FLUOROARENES WITH [ 18 F]FLUORIDES
Aromatic nucleophilic substitution (S N Ar) reaction is a widely practiced method for the construction of [ 18 F]fluoroarenes with [ 18 F]fluoride (Preshlock et al., 2016). An activating group and a leaving group on the arene to stabilize the Meisenheimer complex are necessary for the highly efficient introduction of fluoride into fluoroarenes by S N Ar (Bunnett and Zahler, 1951). Despite significant advances in the 18   Frontiers in Chemistry | www.frontiersin.org June 2022 | Volume 10 | Article 884517 9 fluoroarene precursors carrying new activating and leaving groups remains to be discussed. Furthermore, novel halogen-[ 18 F]fluorine exchange reactions and C-H bond radiofluorination will also be discussed (Figure 3).
Phenols are frequently-used moieties in organic compounds (Qiu and Li, 2020), which makes deoxy-radiofluorination of phenols becoming an attractive strategy to achieve fluoroarenes (Tang et al., 2011). Ritter and co-workers presented a distinctive deoxy-radiofluorination method of phenols based on a concerted nucleophilic aromatic substitution (CS N Ar) reaction (Neumann et al., 2016) ( Figure 3A1). Compared with the traditional aromatic nucleophilic substitution (S N Ar) mechanism (Bunnett and Zahler, 1951), CS N Ar does not proceed via a Meisenheimer intermediate. Herein, a wide variety of functional groups including amines, amides, thioethers, and heteroarenes were tolerated for this deoxy-radiofluorination. One year later, Ritter and co-workers further utilized a ruthenium-mediated deoxy-radiofluorination of phenols (Beyzavi et al., 2017). Compared with previous work, this ruthenium-mediated deoxy-radiofluorination reaction expanded the substrate scope to even the most electron-rich phenols. Ruthenium reduced the electron density of phenols and accelerated nucleophilic aromatic substitution of phenols. They were able to perform the reaction in a fully automated mode and get the isolated protected [ 18 F] fluorophenylalanine derivative in 24% of activity yield with the molar activity of 93 GBq/μmol. Site-specific deoxyradiofluorination of small peptides with [ 18 F]fluoride also had been reported by Ritter and co-workers (Rickmeier and Ritter, 2018). Small peptides that could potentially be used as PET tracers, such as the c (RGDfk) analog (an angiogenesis monitoring PET tracer) (Cai and Conti, 2013), MG 11 analog (a gastrin-releasing peptide receptor tracer) (Good et al., 2008), were successfully labeled by this protocol. In their previous work, the substrates with C-terminal free carboxylic acid suffered from low yields during radiolabeling (Neumann et al., 2016). In this work, they showed the protection of C-terminal free carboxylic acid with p-methoxybenyzl (PMB) ester effectively increased the RCY. The typical peptide was automated radio-synthesized with the molar activity of 99 GBq/μmol. Nicewicz, Li, and co-workers demonstrated another deoxy-radiofluorination mechanism called cation-radicalaccelerated S N Ar (CRA-S N Ar) (Tay et al., 2020) ( Figure 3A2). A novel strategy for polarity-reversed photoredox catalyzed deoxy-radiofluorination of electronrich phenol derivatives with [ 18 F]TBAF was presented. Photoredox catalyzed deoxy-radiofluorination selectively occurred in the electron-rich arenes under mild conditions with moderate-to-excellent RCYs. Highly efficient radiosynthesized 5-[ 18 F]fluorouracil ([ 18 F]FU), which is an antimetabolite used to treat certain cancers (Saleem et al., 2000), was produced in two steps, including deoxyradiofluorination and deprotection with an overall 82% of decay-corrected RCY with the molar activity of 74.7 GBq/ μmol. This method was supplementary to existing ways that involve hypervalent iodoniums (Rotstein et al., 2014) and aryl nickel complexes (Hoover et al., 2016). Hypervalent iodine (III) compounds as novel activating and leaving groups play a pivotal role in nucleophilic [ 18 F]fluorination of non-activated arenes (Deng et al., 2019). Pike and co-workers demonstrated the first example of radiofluorination with diaryliodonium salts, whereby both electron-deficient and electron-rich arenes showed a high 18 F-labeling efficiency (Pike and Aighirhio, 1995). During modifying the structure of hypervalent iodine (III) compounds, Liang, Vasdev, Chen, and co-workers utilized the ortho-effect and developed an orthooxygen-stabilized iodonium ylide agents  ( Figure 3B1). Compared with Pike's work (Pike and Aighirhio, 1995), they speculated that a secondary bonding interaction between ortho-oxygen and hypervalent iodine would provide stabilization for iodine (III) to yield thermally stable and highly reactive. The azide moiety of 18 F-labeled products, the molar activity greater than 74 GBq/μmol, easily underwent [3 + 2] cycloaddition or coupling with alkynecontaining small or biological molecules, such as ssDNA aptamer TsC (21591Da) and Sgc8 (12775Da) . In previous work, TsC aptamer radiolabeled in only 1.5% of RCY. The RCY raised to 49% of RCY by using this novel method. Recently, Liang, Liu, and co-workers reported a general protocol for the preparation of [ 18 F]fluoroisoquinolines with radiochemical conversion up to 92% with the molar activity of 56.6 GBq/μmol (Yuan et al., 2016). As proof of concept [ 18 F] fluoroaspergillitine, a fluorinated marine natural product, was prepared in 10% of isolated radiochemical yield.
Beside the diaryliodonium salts, aryldibenzothiophenium salts can be used as another catalyzer for synthesizing non-activated arene [ 18 (Fowler et al., 2015), were successfully radiosynthesized by this [ 18 (Xu et al., 2020). Significantly, they showed how electronically different dibenzothiophenes appropriately matched the electronic requirements of the arene. Heterocycles, halides, amides, and sulfonamides were tolerated for this [ 18 F]fluorination reaction and a range of small-molecule drugs were successfully labeled.
Aryl halides are the most wildly used radiofluorination precursors due to their characteristics of being stable and Frontiers in Chemistry | www.frontiersin.org June 2022 | Volume 10 | Article 884517 synthetically accessible (Preshlock et al., 2016). Halogen-fluorine exchange reactions are limited for radiofluorination of electrondeficient arenes via S N Ar (Preshlock et al., 2016). Nevertheless, it is still a huge challenge for radiofluorination of unactivated arenes via halogen-fluorine exchange. Sanford, Scott, and co-workers described the ligand-directed N-heterocyclic carbene (NHC) Cu complexes mediated radiofluorination of aryl halides with the typical molar activity of 1.6 GBq/μmol (Sharninghausen et al., 2020) ( Figure 3C1). They showed that directing groups pattern on the ortho-position of halogen substituents was necessary for this reaction. These substrates with bromo-substituent on the para-position of directing groups did not afford desired products under standard conditions. Vismodegib analog, a basal cell carcinoma treatment drug (Dlugosz et al., 2012), and PH089, an MK-2 inhibitor (Anderson et al., 2007), smoothly underwent radiofluorination. Li, Nicewicz, and co-workers demonstrated a method for constructing aryl C-18 F bonds through direct halogen-fluorine exchange on electron-rich arene halides under mild photoredox conditions (Chen et al., 2021) ( Figure 3C2). 18 F-labeled 2-phenoxyaniline analogs as translocator protein (TSPO)-specific PET tracers for neuroinflammation imaging have been investigated (Werry et al., 2019). Using their halogen-fluorine exchange method, the 18 F atom was successfully introduced into potential new imaging agents targeting TSPO. This novel protocol offered an opportunity to radiosynthesis and explore a series of 18 F-labeled O-methyl tyrosines as PET tracers in an MCF-7 tumor model. For clinically relevant scaling, FDA approved PET tracer [ 18 F] FDOPA was obtained with >30% of RCY and molar activity of 1.5 GBq/μmol in 100 min by using this method. For this radiofluorination reaction, substrates with O-atom, N-atom, or S-atom at ortho-or para-position of halides were necessary. Compare to traditional methods of radiofluorination, such as the Balz-Schiemann reaction, deoxy-fluorination, and S N Ar reaction, C-H bonds radiofluorination methods are favorable due to needless pre-functionalization of the substrate (Preshlock et al., 2016;Szpera et al., 2019). Sanford, Scott, and co-workers disclosed that 8-aminoquinoline directing groups enable Cu-mediated aromatic C-H bonds activation and nucleophilic radiofluorination with [ 18 F]KF (Lee et al., 2019) ( Figure 3D1). This aromatic C-H bonds radiofluorination method was applied to a series of biologically relevant molecules [ 18 F]AC261066, a RARβ2 agonist (Lund et al., 2005), was automated radio-synthesized in two steps, radiofluorination, and hydrolysis of the directing group, with 2% of decay-corrected RCY with the molar activity of 29.6 GBq/ μmol. Li, Nicewicz, and co-workers disclosed a mild condition for direct radiofluorination of aromatic C-H bonds under organic photoredox catalyzed conditions with the typical molar activity of 51.8 GBq/μmol with 2,2,6,6-tetramethylpiperidinooxy (TEMPO)  Figure 3D2). Radiofluorination mainly occurred at the para-position of electron-donating groups; when the para-position was substituted, radiofluorination occurred at the ortho-position of electron-donating groups. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of pharmaceuticals that alleviate pain and inflammation. The NSAID derivatives (Cryer and Feldman, 1998), fenoprofen methyl ester, and flurbiprofen methyl ester were radiofluorinated in 39% and 36% of decaycorrected RCYs. Restricted by the radiolabeled method, wellstudied 11 C-labeled NSAID derivatives had the disadvantage of a shorter half-life than fluorine-18. The hypolipidemic agents, clofibrate and fenofibrate, were selectively fluorinated in moderate decay-corrected RCYs. [ 18 F]FDOPA, a PD and neuroendocrine tumors PET tracer (Pretze et al., 2017), was radio-synthesized in two steps with 12% of decay-corrected RCY. Extensive and sensitive [ 18 F]FDOPA precursors were required in published routes. The protected O-Me-orthotyrosine and 4-phenyl-phenylalanine were also successfully radiofluorinated, and their deprotected forms were accessed with relative ease.

RADIOSYNTHESIS OF FLUOROALKENES WITH [ 18 F]FLUORIDES
Gem-difluoroalkene moiety presents in several drug molecules, such as numerous enzyme inhibitors, due to the similar bioisosteric to a carbonyl group (Shen et al., 2014). The [ 18 F] gem-difluoroalkenes were obtained as byproducts in radiofluorination of corresponding difluoroalkenes via an addition-elimination mechanism (Fawaz et al., 2014). Tredwell and co-workers reported the synthesis of [ 18 F]gemdifluoroalkenes with the typical molar activity of 1.0 GBq/μmol from [ 18 F]fluoride and fluoroalkenyl (4-methoxyphenyl) iodonium triflates (Frost et al., 2019) ( Figure 4A). The [ 18 F] gem-difluoroalkenes can be easily translated into 1,1-[ 18 F] difluoromethylene-containing groups. This transformation supplied another method of radiosynthesis of non-benzylic geminal [ 18 F]CF 2 groups. Monofluoroalkene moiety can be used as a peptidomimetic unit in the design of protease inhibitors as well as positron emission tomography probes based on the similar charge distribution and dipole moment between amide bond and fluoroalkene moiety (Zhang et al., 2009). Xu, Hammond, and co-workers offered a reliable protocol for the synthesis of 18 F-labeled monofluoroalkene via hydrogen-bonding enabled radiofluorination of ynamides (Zeng et al., 2018) ( Figure 4B). They demonstrated the hydrogenbonding network generated from hydrogen-bond-donor solvents accelerates the rate-determining proton-transfer step.
To demonstrate the applicability, an 18 F-labeled biologically active estrone derivative was prepared with great efficiency (Figure 4).

HETEROATOM-18 F BONDS FORMATION
Expect the traditional 18 F-labeling strategies of C-18 F bond formation, the noncanonical strategies of hetero-18 F bond formations, such as B-18 F, Al-18 F, Si-18 F, Ga-18 F, P-18 F, and S-18 F bonds, which show the unique properties in positron emission tomography probes design. B-18 F, Al-18 F, and Si-18 F derivatives as PET tracers have been excellently reviewed by Gabbai and coworkers (Chansaenpak et al., 2016), and Schirrmacher, and coworkers (Wängler et al., 2012). Herein, B-18 F, Al-18 F, and Si-18 F bond formation warrants a brief discussion. Within the Group 13 elements, B-18 F derivatives are the most studied PET applications (Monzittu et al., 2018). The research on Al-18 F provided the first example of a metal chelate system for [ 18 F]fluoride capture in water (Laverman et al., 2010). However, B-18 F, Al-18 F, and Si-18 F derivatives have obvious weaknesses (Hong et al., 2019), such as specific pH requirement (B-18 F derivatives), the steric effect of bulky chelate synthons (Al-18 F derivatives), limited stability and high lipophilicity (Si-18 F derivatives) and potential biosafety issue due to possible metal contamination. Reid and co-workers synthesized and demonstrated 1-benzyl-4,7-dimethyl-1,4,7triazacyclononane (BnMe 2 -tacn) liganded GaF 3 complex is extremely stable in water (Bhalla et al., 2014). Then, they presented a simple and rapid method for 18 Figure 5A). This 18 F-19 F exchange method significantly decreased the concentration of the GaF 3 (BnMe 2 -tacn) compare to the previous 18 F-Cl exchange reaction (Bhalla et al., 2014). Organophosphine [ 18 F]fluorides also had been prepared by Li, Nie, and co-workers by isotopic exchange (Hong et al., 2019). They illustrated that steric hindrance is critical for the stability of organophosphine [ 18 F]fluorides ( Figure 5B). Human serum albumin (HSA), a heat-sensitive globular protein, was radiolabeled at room temperature and applied to blood pool imaging with the molar activity of 1.1 GBq/μmol. Wu, Yang, Sharpless, and co-workers reported an ultrafast (within 30 s) isotopic exchange method for the radiosynthesis of aryl [ 18 F] fluorosulfates (Ar-OSO 2 F) which was the first PET imaging application of S− 18 F based probes (Zheng et al., 2021) ( Figure 5C). 18 F-labeled olaparib analog was successfully radio-synthesized in 32% of RCY with the molar activity of 280 GBq/μmol. Aryl [ 18 F]fluorosulfates were also successfully radio-synthesized in two modes by Chun, Hong, and coworkers (Kwon et al., 2020). The radiofluorination modes include the direct one-pot radiofluorosulfurylation of phenolic precursors (Mode 1) and the radiofluorination of isolated imidazylates (Mode 2). The radiofluorination of isolated imidazylates (Mode 2) showed higher RCYs. Both Mode 1 and 2 afforded similar molar activity. 18 F-labeled acetaminophen analog was automated radio-synthesized in 9% of decaycorrected RCY with the molar activity of 42 GBq/μmol (Mode 1) and 22% of decay-corrected RCY with the molar activity of 55 GBq/μmol (Mode 2). Based on previous works, Chun, Hong, and co-workers radio-synthesized sulfamoyl [ 18 F]fluorides by the 18 F-19 F exchange method (Jeon et al., 2021). 18 F-labeled amoxapine derivative of sulfamoyl fluoride was automated radio-synthesized in 53% of RCY with 56 GBq/μmol ( Figure 5).

SUMMARY
Recently, the interest in the development of novel 18