Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18F-fluorination and PET tracer development

Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18F-fluorination and PET tracer development | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18 F-fluorination and PET tracer development Wei Chen, Yueqi Wang, Lili Pan, Kai Lu, Mingxing Hu, Cheng Zheng, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4325597/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In this work, we established a simplified photoredox-mediated labeling system that allows the rapid aryl 18 F-fluorination of electron-neutral and -rich arenes via 19 F- 18 F exchange or/and deoxyfluorination. Notably, this aryl radiofluorination method excludes the cumbersome azeotropic drying procedure and is scalable with the whole eluted 18 F- beyond portion synthesis. The nonaqueous tetrabutylammonium perchlorate (TBAP) solution was identified as an ideal neutral eluent to balance the elution and labeling efficiency in combination with a HPO 4 2- preconditioned anion-exchange resin (AER). Base-sensitive substrates like alkyl halide, tetrazine, and lipophilic cations were able to be directly aryl 18 F-labeled under the weak basic conditions. Moreover, this azeotropic drying-free photolabeling method was successfully implemented on a commercial automatic radiosynthesis module. Furthermore, a broad range of unnatural amino-acid derivatives were composed and aryl 18 F-labeled under the current system, and the arylglycine derivative 18 F-FMPG was found to be a promising PET agent targeting amino acid transporters. Taken together, the mild labeling conditions combined with the simplicity of the reaction setup from all commercially available reagents and inexpensive equipment guarantees the repeatability and wide adoption of this aryl 18 F-fluorination method for PET agents and drug discovery. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Photochemistry/Photocatalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Positron emission tomography (PET) imaging is a noninvasive and powerful imaging technique that has been routinely used for early disease diagnosis, staging, and treatment response. 1 The ability to track the biodistribution and retention of radio-labeled bioactive molecules in vivo in real time also makes PET imaging a valuable tool for drug screening and evaluation at different stages. 2 Among the positron emitters, fluorine-18 ( 18 F) has a relatively low positron energy (635 keV) and preferred half-life (T 1/2 = 109.7 min) for imaging and tracer production. 3 Consequently, various 18 F-labeling methods have been developed to meet the ever-increasing demand for novel PET agent exploration and preparation, along with the upsurge of fluorine chemistry in the past decades. 4 However, compared with the 19 F-chemistry, the 18 F-fluorination reactions are much more susceptible to the reaction parameters and operation since an exceptionally low 18 F concentration was applied for the labeling reactions. Though fast consumption of the 18 F from even multiple-step synthesis is feasible to obtain enough 18 F-labeled product in a limited time, slight changes in reaction conditions would lead to discrepancies in reaction results from batch to batch. Conventionally, the 18 F-labeling starts with the preparation of reactive 18 F reagents ([ 18 F]TBAF, [ 18 F]KF/K 222 , etc .) by the 18 F-trapping, elution, and azeotropic drying. All those steps and operations might vary from lab to lab, leading to inconsistency and unrepeatable results, thus restraining the broad application of established 18 F-fluorination methods, as well as the transition of the fluorine synthetical chemistry to corresponding 18 F-labeling (Fig. 1 A). Notably, the azeotropic drying step which has been traditionally recognized as necessary in most cases since the hydrated fluoride demonstrated decreased nucleophilicity in the following fluorination reactions, however, is not only time-consuming but also leads to inconsistent reaction results due to loss of activity or incomplete removal of the moisture. 5 Meanwhile, the eluent applied for the 18 F - elution plays another crucial factor that is prone to be overlooked but could make a big difference in labeling reactions. 6 Efforts towards establishing more stable and repeatable labeling procedures have been made by excluding or simplifying the azeotropic-drying procedure and exploring the more suitable eluent combinations to enhance the 18 F-labeling efficiency. Despite much progress that has been made, the elution and labeling efficiency remains to be improved for different methods and substrates. 5 , 7 Recently, photochemistry has provided a unique pathway to efficiently label certain substrates for PET tracer discovery. 8 Notably, Li, Nicewicz and coworkers disclosed a photoredox-mediated 18 F-labeling method that enabled the aryl 18 F-fluorination of challenging electron-rich arenes through direct C-H fluorination, deoxyfluorination, and aryl halide interconversion(Fig. 1 B). 9 These methods represent a concise heating-free transformation without the use of transition metal from stable and readily accessible precursors; however, the general use of special equipment (laser), in-house prepared reaction additive (tetrabutylammonium bicarbonate, TBAB) and inevitable azeotropic drying procedure prevented their widespread adoption for PET agents or drug development. 9 Additionally, though the methods have been well verified on portion synthesis for rapid aryl 18 F-labeling of electron-rich molecules, the 18 F-labeling with the whole eluted 18 F − solution remains challenging and is less explored because the excess amounts of eluent or base are generally toxic to the labeling reactions. 10 Therefore, in this work, we’re committed to establishing a stable, easily operable, and scalable photolabeling system that allows the challenging aryl 18 F-labeling reactions to proceed efficiently without azeotropic drying, in-house prepared additive and special equipment (Fig. 1 C), which would be most desirable to radiochemists and biomedical researchers. RESULTS AND DISCUSSION Azeotropic drying-free aryl 18 F-fluorination procedure development. With the abovementioned goal, an azeotropic drying-free [ 18 F]F - reagent solution was first prepared and tested on the photoredox-mediated aryl 18 F-fluorination. As designed and illustrated in Fig. 1 C, the aqueous 18 F - produced from the cyclotron was loaded on the preconditioned anion-exchange resin (AER), followed by the N 2 gas and MeCN (5 mL) drying. After another 5 min nitrogen flushing, the AER was eluted with a nonaqueous eluent to obtain the azeotropic drying-free 18 F - solution for labeling reactions (see SI section 3.3 and 3.4). The screening and optimization results are summarised in Table 1 . No 18 F - was eluted out from the Sep-Pak Light QMA Carbonate (130 mg resin loading) using the solution of t BuOH (2.5 mL) and in-house prepared tetrabutylammonium bicarbonate (TBAB) solution (20 µL in MeCN) as eluent (entry 1), but 65% elution efficiency (EE) and more than 98% trapping efficiency were obtained when a smaller amount of sorbent-loaded anion exchange resin (KT-101, 40 mg) was used with a similar eluent. More importantly, with the obtained drying-free 18 F - solution (0.5 mL for each labeling reaction), 1-fluoro-4-methoxybenzene ( 1 ) was labeled through photoredox-mediated aryl 19 F- 18 F exchange in more than 60% radiochemical conversion Table 1 Drying-free aryl 18 F-fluorination development and optimization [a] entry AER-formation eluent EE (%) RCC (%) solvent (0.5/2.5 mL) base salt 1 Sep-Pak Light QMA-CO 3 2- t BuOH TBAB (20%, 20 µL) none - - 2 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAB (20%, 20 µL) none 65 61.8 ± 5.2 (n = 3) 3 KT-101 -HCO 3 - EtOH/MeCN (4/1) TBAB (20%, 20 µL) none 75 31.8 4 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAB (20%, 20 µL) TBAP (5 mg) 82 63.1 ± 7.2 (n = 3) 5 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (20%, 20 µL) none 66 70.4 ± 12.9 (n = 3) 6 KT-101 -HCO 3 - t BuOH/MeCN (1/1) TBAOH (20%, 20 µL) none 60 75.0 ± 0.2 (n = 3) 7 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 10 µL) none 78 72.0 ± 1.7 (n = 3) 8 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 10 µL) TBAP (3 mg) 88 75.6 ± 4.6 (n = 3) 9 [b] KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 10 µL) TBAP (2 mg) 99.5 78 10 [b] KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 4 µL) TBAP (5 mg) 99.3 68 11 [b] KT-101 -HCO 3 - t BuOH/MeCN (4/1) none TBAP (10 mg) 98.8 68 12 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 2 µL) TBAP (1 mg) 47 ± 0.82 (n = 3) 56.7 ± 7.6 (n = 3) 13 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 2 µL) TBAT (1 mg) 54 59 14 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 4 µL) none 35 62 15 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (40%, 4 µL) TBAP (1 mg) 37 66 16 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBAOH (1M MeOH solution, 10 µL) none 56 53 17 KT-101 -HCO 3 - t BuOH/MeCN (4/1) TBPH (40%, 4 µL) none 40.5 57 18 [b] KT-101 -HCO 3 - t BuOH/MeCN (4/1) none TBAP (3 mg) 81 ± 4.3 (n = 3) 56.3 ± 3.3 (n = 3) 19 [b] KT-101 -CO 3 2- t BuOH/MeCN (4/1) none TBAP (3 mg) 90.5 ± 1.1 (n = 3) 60.3 ± 6.6 (n = 3) 20 [b] KT-101 -PO 4 3- t BuOH/MeCN (4/1) none TBAP (3 mg) 76.7 ± 8.7 (n = 10) 71.2 ± 3.5 (n = 10) 21 [b] KT-101 -HPO 4 2- t BuOH/MeCN (4/1) none TBAP (3 mg) 96 ± 1.7 (n = 9) 66.9 ± 4.8 (n = 9) 22 [b,c] KT-101 -HPO 4 2- t BuOH/MeCN (4/1) none TBAP (3 mg) 92.3 ± 1.2 (n = 3) 73 ± 1.1 (n = 3) 23 [b,d] KT-101 -HPO 4 2- t BuOH/MeCN (4/1) none TBAP (3 mg) 98 66.7 [a] Aryl 18 F-fluorination conditions: 18 F − (0.19–1.11 GBq), substrate 1 (2 µL, 0.018 mmol), photocatalyst S 1 (2 mg), DCE (500 µL), 456-nm LED, rt, 15-min irradiation, N 2 atmosphere. 500 µL drying-free 18 F − solution was used for entries 1–11, and all 18 F − eluate were used for entries 12–23, respectively. The EE (elution efficiency) was calculated by division of the 18 F − eluted in the reaction v-vial by the whole 18 F − ( 18 F − in the v-vial and 18 F − left on the resin). All RCCs were calculated by HPLC integration with a basic mobile phase to avoid the unconverted 18 F − fluoride being trapped on the C18 HPLC column. [b] The AER was slowly eluted with the eluent in 1 min. [c] used AER. [d] DCM (600 µL) was used instead of DCE. (RCC) with the acridinium photocatalyst S 1 . Notably, this labeling reaction was performed under a 456-nm LED light in only 15 minutes without cooling and any additional base compared to previous procedures (entry 2). 9 Encouraged by the primary results, a series of eluents were then screened under current conditions to enhance the EE and labeling efficiency (entries 3–9). Replacing the t BuOH with EtOH in the eluent improved the EE to 75% but significantly decreased the RCC of compound 1 (entry 3). We’re glad to find that with an organic soluble tetrabutylammonium perchlorate (TBAP) salt in the eluent, the EE was improved to 82% with comparable RCC (entry 4). When the stronger base, tetrabutylammonium hydroxide aqueous solution (TBAOH, 40% w/w), was used instead of TBAB, 60%-78% EE was obtained with > 70% RCC (entries 5–7). Combining the TBAOH and TBAP as eluent, both the EE and RCC were improved (entry 8), and 99% EE was successfully achieved when the AER was slowly eluted in approximately 1 minute (entries 9 and 10). We’re excited to find that excellent EE and RCC were obtained with the eluent that has TBAP only in the t BuOH/MeCN solution (entry 11). These findings are undoubtedly very attractive since rapid aryl 18 F-labeling of electron-rich arenes could be realized from the readily obtained drying-free 18 F − solution for fast reaction screening, and it’s particularly useful for heating and base-sensitive substrates since the minimal base was applied in the photolabeling reaction. Full batch drying-free aryl 18 F-fluorination optimization. After the drying-free conception has been established and verified on aryl 19 F- 18 F exchange radiofluorination, we managed to set up the labeling reactions with all the eluted 18 F − beyond a portion, which would be more useful in clinical use; meanwhile, challenges may arise since more moisture and eluents will be present in a single labeling reaction (Fig. 1 C). The volume of the eluent solvent was first decreased to 0.5 mL from 2.5 mL for the full-batch reaction under similar labeling conditions (Table. 1, entries 12–23). Encouragingly, good RCCs of compound 1- 18 F (53–66%) were still obtained when all the eluted 18 F − were applied for the labeling reactions from different eluents, though the EEs (35–56%) remain to be improved (entries 12–17), and tetrabutylphosphonium hydroxide (TBPH) and tetrabutylammonium tetrafluoroborate (TBAT) demonstrated similar elution and labeling efficiency when applied instead of TBAOH and TBAP (entries 13 and 17). To simplify the labeling reaction setup, the nonaqueous neutral t BuOH-MeCN-TBAP eluent system was selected for further optimization (entries 18–23). Acceptable EE (81%) was achieved when the AER was slowly eluted (entry 18). Considering that the anions with different basicity and valency play an essential role in both EE and RCC for 18 F-fluorination, 7 f we turn to screen the AER-preconditioning counter anions. We’re pleased to find that CO 3 2− preconditioned AER provides 91% EE with 60% RCC, while PO 4 3− offered lower EE but higher RCC of the model compound 1 , respectively (entries 19 and 20). Excitedly, the HPO 4 2− -preconditioned AER provided the highest elution efficiency (> 95%) without diminishing the RCCs (entry 21). These results demonstrated that basic counter anions play a crucial role in both the EE and RCC of the photolabeling reactions, which have not been intensively studied previously. Interestingly, we found that the AER is reusable at least three times with slightly decreased trapping and elution efficiency but higher RCC. We speculated that accumulated ClO 4 − from TBAP binding on the resin resulted in less basic anion (HPO 4 2− ) eluted in the reaction that might benefit the photoredox-mediated aryl radiofluorination. Meanwhile, the slower 18 F − and ClO 4 − exchangeand self-exchange of ClO 4 − during the elution lowered the 18 F − trapping and elution efficiency (entry 22). Lastly, replacing the 1,2-dichloroethane (DCE) with clinically more favorable dichloromethane (DCM) didn’t affect the RCC of compound 1 (entry 23). This finding makes the system more flexible and clinically applicable when thoroughly removing DCE was an issue (see SI sections 3.4 and 3.5). 11 The substrate scope of the photoredox-mediated drying-free aryl 18 F-fluorination. With the optimized conditions, we are starting to explore the reaction scope of this reformulated photolabeling system, mainly focusing on the base or heating-sensitive substrates and those underexplored in previous work (Fig. 2 ). The reactive bromoalkyl phenyl ether ( 2 ) was efficiently labeled through aryl 19 F- 18 F exchange. The addition of an electron-donating methoxyl group next to the fluorine atom increased the labeling efficiency due to the reduced oxidation potential and the enhanced stability of the arene radical cation intermediate of the substrate ( 3 ), which promotes the photoinduced electron transfer by the exited photocatalyst S 1 . Notably, no Br/ 18 F S N 2 reactions were observed from these minimal basic and heating-free labeling conditions. Excitedly, the photoredox-mediated deoxyfluorination 9 b, 12 of bromoalkyl phenyl ethers (2-deo) also works very well under current conditions to give the aryl 18 F-labeled product 2- 18 F in 78% RCC with a good molar activity (46.5 GBq/µmol) under the new labeling conditions. The benzyl bromide derivative ( 4 ) was labeled in 31% RCC, accompanied by 10% Br/ 18 F exchange product, due to the higher reactivity of bromide at the benzyl position. Aryl bromide ( 5 ) and aryl iodide ( 6 ) compounds were labeled in moderate RCCs. Through the isotopic exchange, aryl alcohols with different chains ( 7 – 9 ) were efficiently labeled, indicating that the unprotected hydroxyl group didn’t suppress the photo-induced oxidation progress. The benzoic acid methyl ester derivative, N -Boc-protected alkyl amine, and O -Boc-protected phenol were efficiently labeled from readily available precursors ( 10-deo , 11-deo , and 12-deo ). It’s worth noting that substrates bearing functional groups like alkyne, azide, or maleimide ( 13 – 16 ) that are commonly used for indirect labeling of bioactive molecules also tolerated this labeling system and provided good RCCs. Other than incorporating the 18 F on conventional electron-deficient (hetero) aryl rings, the 18 F was installed on the electron-rich phenyl rings of these substrates, which would benefit the diversification of the PET tracer construction. 3 b Heterocyclic compounds, for example, pyrimidine, quinazoline, and purine ( 17 – 19 ), were also successfully radiofluorinated via 19 F- 18 F exchange. The tetrazine derivatives ( 20 , 21 ) routinely applied for PET tracer development were 18 F-labeled in moderate RCCs, and no apparent decomposition of the starting material was found from the mild labeling conditions. 13 Lastly, substrates containing aryl or alkyl boronic ester moiety ( 22–25 ) that were barely reported for aryl 18 F-fluorination were able to be labeled either through deoxyfluorination or 19 F- 18 F exchange in moderate to good RCCs. 14 Besides functional substrates, the compatibility of this simple aryl 18 F-labeling system was further tested on a series of bioactive molecules (Fig. 2 ). The 6- O -arylated- β -D-glucopyranose and glucopyranose ( 26–30 ) were 18 F-labeled in good to excellent RCCs (29–62%). 15 Notably, with multiple free hydroxyl groups, the substrate ( 30 ) could also be labeled under current conditions, offering 30- 18 F in 30% RCC. The 2- O -arylated- β -D-mannopyranose substrate ( 31 and 31-deo ) were labeled in 16% and 77% RCC through 19 F- 18 F and deoxyfluorination. As a proof-of-concept, by simple amide consideration with the aryl fluorine-containing acid, drug molecules like the Glu-urea-Lys based prostate-specific membrane antigen (PSMA) inhibitor ( 32 ) 16 , Olaparib core skeleton ( 33 ) 17 , Ibrutinib ( 34 ) and Sitagliptin ( 35 ) that have multiple function groups can be 18 F-fluorinated from this labeling system in good RCCs. Direct aryl 18 F-labeling of lipophilic cations. Lipophilic cations have been recognized as a class of important compounds for mitochondria-targeted studies and applied to cancer and cardiovascular imaging after conjugating with radionuclides. 18 However, the aryl 18 F-labeled lipophilic cations are generally obtained from multiple-step indirect synthesis, considering the cation might not tolerate the high temperature under basic conditions from the traditional labeling methods. 3 b Using our labeling protocol, no labeling product was initially observed from the quaternary ammonium cation substrate ( 36 ), whereas 36% RCC was obtained after the counter anion bromide was exchanged to perchlorate ( 37 ) to avoid the competition nucleophilic attack between bromide and 18 F-fluoride, and improved RCC was obtained when one of the alkyl groups on the nitrogen atom was replaced with an aryl group ( 38 ). With the perchlorate as the counter anion, the substrate bearing a shorter carbon chain ( 39 ), however, didn’t give any product, but good RCC was obtained after a methoxy group was added next to the fluorine on the phenyl ring ( 40 ). The choline analog substrates ( 41 and 42) that could potentially be used for imaging of cell membrane proliferation were also workable. 19 Other lipophilic cations like pyridinium ( 43 – 46 ) and triphenylphosphonium salts ( 47 and 48 ) used for cardiovascular imaging were successfully aryl 18 F-labeled. 18 b, 20 Interestingly, similar labeling tendencies that substrates possessing shorter carbon chains provided lower RCCs were observed among those tested compounds (Fig. 3 ). We speculated that an intramolecular cation–π interaction between the phenyl ring and the tethered quaternary ammonium might disrupt the photoredox process 21 or the shorter chain substrates are more hygroscopic, thus inhibiting the labeling reaction which needs further study though. Construction and labeling of unnatural amino-acid derivatives for PET tracer discovery. Radiolabeled amino acids represent one of the most important metabolic imaging agents in oncology and have gained increased clinical interest over the past decades for brain tumors and neuroimaging, considering their low background uptake compared to 18 F-FDG. 22 However, the synthesis of aryl 18 F-labeled amino acids was limited since the chemical construction of the labeling precursor is burdensome, and the tracers were generally produced in relatively lower RCYs. 23 We were particularly interested in applying unnatural amino acids for PET agent exploration. With the established labeling protocol, a series of amino-acid derivatives were rapidly composed and labeled (Fig. 3 ). Specifically, the O -arylated threonine, hydroxyproline, and (homo) serine derivatives ( 49–56 ) were labeled in moderate to excellent RCCs through halide interconversion. Notably, iodine-containing substrates ( 55 and 56 ) work well too. The glutamine, phenylalanine, and a-arylglycine derivatives ( 57–62 ) were easily constructed and labeled in good to excellent RCCs. The b -phenylalanine, a-guanidino acid, and amino phosphonic acid derivatives ( 63 – 65 ) were efficiently aryl 18 F-labeled from deoxyfluorination or isotopic exchange. Additionally, the boron-containing amino acid derivatives ( 66 and 67 ) were successfully aryl 18 F-labeled, which would potentially be applied for the boron neutron capture therapy (BNCT) drug discovery. 24 Lastly, substrate 68 , which has been reported for the efficient preparation of PET tracer [ 18 F]FDOPA, 9 c was labeled in excellent RCCs under the current drying-free conditions. It was also successfully labeled on a simple LED reactor (ProBOX) in up to 70% RCC from 7.4 GBq 18 F − with DCM instead of DCE as the solvent (see SI section 3.11). To further demonstrate the practicability, we applied our azeotropic drying-free labeling method on a commercial radiosynthesis module using substrate L- 68 as an example, and the [ 18 F]FDOPA was successfully produced in 14.8% non-decay corrected RCY (radiochemical yield) with 99% ee (enantiomeric excess) from two-step automation procedure (Fig. 3 , see SI section 3.12 for synthesis detail). Among the unnatural amino acids, the a-arylglycine fragment was frequently presented in natural products and drugs. 25 However, the arylglycine itself has rarely been investigated as an imaging agent by targeting the amino-acid transporters, which have been proven overexpressed in many types of tumors for the survival and proliferation of cancer cells. 26 To the best of our knowledge, no aryl 18 F-labeled arylglycines have ever been reported for PET imaging studies. 27 After rapid deprotection of the 60- 18 F , the PET tracer, namely 18 F-FMPG , was obtained from quick cartridge isolation (see SI section 4.1 for details) and evaluated in melanoma (B16F10) and breast cancer (MCF-7) tumor models (Fig. 4 ). We’re excited to find that apparent accumulation of 18 F-FMPG in the B16F10 (SUV max = 2.39 ± 0.27) and MCF-7 (SUV max = 2.65 ± 0.32) tumor models and low background uptake were observed at 0.5 h post-injection with 5.42 ± 1.04 and 6.76 ± 0.94 tumor/muscle ratio, respectively. The configuration effect of the tracer was further studied in MCF-7 models. The optical pure precursors were obtained through a simple chiral column resolution and efficiently labeled to provide the two enantiomers, L - 18 F-FMPG and D - 18 F-FMPG , after deprotection. The absolute configuration of the two isomers was confirmed by the comparison with commercial standards (see SI section 4.3 for details). PET imaging studies showed that the L - 18 F-FMPG exhibited higher tumor uptake and longer retention at 0.5 h, 1 h, and 2 h post-injection compared with D - 18 F-FMPG , but much higher tumor/muscle ratios (0.5 h: 12.19 ± 3.03 vs 5.63 ± 0.95; 1 h: 9.57 ± 2.48 vs 5.52 ± 0.87; 2 h: 8.70 ± 2.47 vs 5.78 ± 2.47) were detected from the latter one. These results demonstrated that despite the lack of a b -methylene group compared to other reported amino-acid PET tracers, the 18 F-FMPG is still a potential substrate of the amino-acid transporters and demonstrates similar properties and preferences. The simple preparation and high in vivo tumor/muscle ratios demonstrated that the 18 F-FMPG is a promising PET agent targeting amino acid transporters and is worth further evaluation for clinical translation. CONCLUSION Through extensive optimization and screening of the AER formation and eluents, a straightforward photoredox-mediated aryl 18 F-fluorination method was established. This labeling system was featured by excluding the cumbersome azeotropic-drying procedure, in-house prepared additive and could be performed with all commercially available reagents and equipment under a cheap LED light. A nonaqueous neutral eluent was discovered to effectively balance the elution and labeling efficiency, which is particularly useful for the aryl 18 F-fluorination of the base-sensitive substrates. The success and advantages of this simplified photoredox-labeling method were demonstrated by the direct aryl 18 F-fluorination of various essential functional compounds, drug molecules, lipophilic cations, and the automatic synthesis of clinical PET tracer [ 18 F]FDOPA on a commercial module. Moreover, a broad of unnatural (including boron-containing) amino-acid derivatives was rapidly composed and aryl 18 F-labeled through this method, eventually leading to the discovery of the a -arylglycine 18 F-FMPG as a novel and promising PET agent targeting amino acid transporters. We anticipate this simple operable aryl 18 F-labeling method to be widely adopted to assist the PET tracer and drug development. Declarations ASSOCIATED CONTENT Supporting Information . All the data generated or analyzed during this study are included in this article (and its Supplementary Information files). AUTHOR INFORMATION Corresponding Author Wei Chen − Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. E-mail: [email protected] Author Contributions † Y.W., L.P., and K.L. contributed equally. W.C. conceived the project. W.C., Y.W., L.P., K.L, M.H., C.Z., and Y.X. performed the radiolabelling reactions and data analysis. L.P. performed the chemical synthesis and data analysis. M.H., Y.W., K.L., Y.X., C.Y., and H.S. assisted in the chemical synthesis. Y.W. prepared the PET tracers, conducted the animal imaging studies and accomplished PET imaging data collection and analysis. M.L. assisted in the animal studies. X.W. and H.W. contributed to the initial discussion. W.C. wrote the manuscript with contributions from all the authors. Notes The authors have filed a provisional patent on the basis of the research in this manuscript. ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (22371193, 22377083), Sichuan Science and Technology Program (2023NSFSC0645), the Institutional Joint Innovation Fund from Sichuan University and Nuclear Power Institute of China (HG2022163 and HG2023141) and the 1•3•5 Project for Disciplines of Excellence at West China Hospital, Sichuan University (ZYGD23016, ZYYC23003). We thank Dr. Y.L. and L.Z. for their assistance with the cyclotron operation and F.S. and Q.P. at the Core Facilities of West China Hospital for the help with NMR and HRMS measurements. References (a) J. S. Fowler, N. D. Volkow, G. J. Wang, Y. S. Ding, S. L. Dewey, J Nucl Med 1999 , 40 , 1154-1163; (b) S. M. Ametamey, M. Honer, P. A. Schubiger, Chem Rev 2008 , 108 , 1501-1516. (a) D. X. Sun, W. Gao, H. X. Hu, S. M. Zhou, Acta Pharm Sin B 2022 , 12 , 3049-3062; (b) K. K. Ghosh, P. 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Supplementary Files SISimplifiedradiolabelingprocesstowardrapidphotoredoxcatalyzedaryl18FfluorinationandPETtracerdevelopment.pdf SI-Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18F-fluorination and PET tracer development Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4325597","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":412654611,"identity":"8d4c98c3-3bbf-4f81-a1aa-27565e4d4660","order_by":0,"name":"Wei 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\u003csup\u003e18\u003c/sup\u003eF-labeling procedure and photoredox-mediated aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination.\u003cstrong\u003e \u003c/strong\u003eA, General procedure and reaction factors of conventional \u003csup\u003e18\u003c/sup\u003eF-labeling. B, Photoredox-catalyzed aryl\u003csup\u003e 18\u003c/sup\u003eF-fluorination. C, Azeotropic drying-free aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination reaction design and setup illustration; azeotropic drying free, neutral eluent and weak basic conditions, LED irradiation, cooling free, 15-min irradiation, capable for the whole eluted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/d5bcc081f3191a036514aaf9.png"},{"id":75898440,"identity":"22805f65-0037-4e3c-a5e5-8117fad0ef0a","added_by":"auto","created_at":"2025-02-10 10:47:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":199115,"visible":true,"origin":"","legend":"\u003cp\u003eSubstrate scope of the photoredox-mediated drying-free aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination. Aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination conditions: \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e (0.19 -3.7 GBq), HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e (1M) preconditioned AER, eluents (3 mg TBAP, 100 mL MeCN, 400 mL \u003csup\u003et\u003c/sup\u003eBuOH), the AER was slowly eluted in 1 min, 0.01 mmol substrates unless otherwise noted, photocatalyst \u003cstrong\u003eS\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e (2 mg), DCE (500 μL), 456-nm LED, rt, 15-min irradiation, N\u003csub\u003e2\u003c/sub\u003e atmosphere. All RCCs were calculated by HPLC integration with a basic mobile phase to avoid the unconverted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e- \u003c/sup\u003efluoride being trapped on the C18 HPLC column. [a] 0.02 mmol substrates.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/5013ae6819ca75a7d5930789.png"},{"id":75898451,"identity":"59450199-9291-42c6-b552-0eeaf80b7ad2","added_by":"auto","created_at":"2025-02-10 10:47:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":322608,"visible":true,"origin":"","legend":"\u003cp\u003eDirect aryl \u003csup\u003e18\u003c/sup\u003eF-labeling of lipophilic cations, unnatural amino-acid derivatives, and automatic synthesis. Aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination conditions: \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e (0.19 -3.7 GBq), HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e (1M) preconditioned AER, eluents (3 mg TBAP, 100 mL MeCN, 400 mL \u003csup\u003et\u003c/sup\u003eBuOH), the AER was slowly eluted in 1 min, 0.01 mmol substrates unless otherwise noted, photocatalyst \u003cstrong\u003eS\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e\u003csub\u003e \u003c/sub\u003e(2 mg), DCE (500 μL), 456-nm LED, rt, 15-min irradiation, N\u003csub\u003e2\u003c/sub\u003e atmosphere. All RCCs were calculated by HPLC integration with a basic mobile phase to avoid the unconverted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e- \u003c/sup\u003efluoride being trapped on the HPLC column.\u003csup\u003e \u003c/sup\u003e[a] 0.02 mmol substrate; [b] 4 mg \u003cstrong\u003eS\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e was used; [c] scale-up synthesis on an LED reactor; [d] DCM instead of DCE was used. ND, not detected, see SI section 3.12 for details of automatic synthesis.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/8ac34f66c0e4175def3a3dc0.png"},{"id":75898443,"identity":"7d4de190-c42a-493d-8e44-e7d54149c82b","added_by":"auto","created_at":"2025-02-10 10:47:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":380675,"visible":true,"origin":"","legend":"\u003cp\u003ePET imaging study in tumor model with \u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e.\u003cstrong\u003e \u003c/strong\u003eA, PET imaging of the \u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, \u003cem\u003e\u003cstrong\u003eL\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, and \u003cem\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e in B16F10 and MCF-7 tumor models (from left to right) at 0.5 h, 1 h, 2 h post-injection. B, tumor uptake of \u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, \u003cem\u003e\u003cstrong\u003eL\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, and \u003cem\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e (SUV\u003csub\u003emax\u003c/sub\u003e) in B16F10 and MCF-7 tumor models (from left to right) at 0.5 h, 1 h, 2 h post-injection. C, tumor/muscle ratio of \u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, \u003cem\u003e\u003cstrong\u003eL\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e, and \u003cem\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FMPG\u003c/strong\u003e (SUV\u003csub\u003emax\u003c/sub\u003e) in B16F10 and MCF-7 tumor models (from left to right) at 0.5 h, 1 h, 2 h post-injection.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/f7b3c0003f90a3ca5f501b2b.png"},{"id":75900186,"identity":"2cd635ab-394c-4b8d-a53c-80ec5d80a47b","added_by":"auto","created_at":"2025-02-10 11:03:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2323437,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/4dce6686-0784-4ee6-8cb7-778e30240273.pdf"},{"id":75898448,"identity":"fc6520f9-b7fa-402a-956f-8089393ef1be","added_by":"auto","created_at":"2025-02-10 10:47:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19414491,"visible":true,"origin":"","legend":"\u003cp\u003eSI-Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18F-fluorination and PET tracer development\u003c/p\u003e","description":"","filename":"SISimplifiedradiolabelingprocesstowardrapidphotoredoxcatalyzedaryl18FfluorinationandPETtracerdevelopment.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/179ff0cc99e3b3cc7dd930b6.pdf"},{"id":75899706,"identity":"52dc8343-8c6f-497b-acf0-fc8e6d6dfedb","added_by":"auto","created_at":"2025-02-10 10:55:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36864,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4325597/v1/66b34735af123d409d2c62d8.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nThe authors have filed a provisional patent on the basis of the research in this manuscript.","formattedTitle":"\u003cp\u003eSimplified radiolabeling process toward rapid photoredox-catalyzed aryl \u003csup\u003e18\u003c/sup\u003eF-fluorination and PET tracer development\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePositron emission tomography (PET) imaging is a noninvasive and powerful imaging technique that has been routinely used for early disease diagnosis, staging, and treatment response.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The ability to track the biodistribution and retention of radio-labeled bioactive molecules in vivo in real time also makes PET imaging a valuable tool for drug screening and evaluation at different stages.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Among the positron emitters, fluorine-18 (\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF) has a relatively low positron energy (635 keV) and preferred half-life (T\u003csub\u003e1/2\u003c/sub\u003e = 109.7 min) for imaging and tracer production.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Consequently, various \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling methods have been developed to meet the ever-increasing demand for novel PET agent exploration and preparation, along with the upsurge of fluorine chemistry in the past decades.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e However, compared with the \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-chemistry, the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination reactions are much more susceptible to the reaction parameters and operation since an exceptionally low \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF concentration was applied for the labeling reactions. Though fast consumption of the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF from even multiple-step synthesis is feasible to obtain enough \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled product in a limited time, slight changes in reaction conditions would lead to discrepancies in reaction results from batch to batch.\u003c/p\u003e \u003cp\u003eConventionally, the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling starts with the preparation of reactive \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF reagents ([\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF]TBAF, [\u003csup\u003e18\u003c/sup\u003eF]KF/K\u003csub\u003e222\u003c/sub\u003e, \u003cem\u003eetc\u003c/em\u003e.) by the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-trapping, elution, and azeotropic drying. All those steps and operations might vary from lab to lab, leading to inconsistency and unrepeatable results, thus restraining the broad application of established \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination methods, as well as the transition of the fluorine synthetical chemistry to corresponding \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Notably, the azeotropic drying step which has been traditionally recognized as necessary in most cases since the hydrated fluoride demonstrated decreased nucleophilicity in the following fluorination reactions, however, is not only time-consuming but also leads to inconsistent reaction results due to loss of activity or incomplete removal of the moisture.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Meanwhile, the eluent applied for the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e elution plays another crucial factor that is prone to be overlooked but could make a big difference in labeling reactions.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Efforts towards establishing more stable and repeatable labeling procedures have been made by excluding or simplifying the azeotropic-drying procedure and exploring the more suitable eluent\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ecombinations to enhance the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling efficiency. Despite much progress that has been made, the elution and labeling efficiency remains to be improved for different methods and substrates.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecently, photochemistry has provided a unique pathway to efficiently label certain substrates for PET tracer discovery.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Notably, Li, Nicewicz and coworkers disclosed a photoredox-mediated \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling method that enabled the aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination of challenging electron-rich arenes through direct C-H fluorination, deoxyfluorination, and aryl halide interconversion(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e These methods represent a concise heating-free transformation without the use of transition metal from stable and readily accessible precursors; however, the general use of special equipment (laser), in-house prepared reaction additive (tetrabutylammonium bicarbonate, TBAB) and inevitable azeotropic drying procedure prevented their widespread adoption for PET agents or drug development.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Additionally, though the methods have been well verified on portion synthesis for rapid aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling of electron-rich molecules, the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling with the whole eluted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e solution remains challenging and is less explored because the excess amounts of eluent or base are generally toxic to the labeling reactions.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Therefore, in this work, we\u0026rsquo;re committed to establishing a stable, easily operable, and scalable photolabeling system that allows the challenging aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling reactions to proceed efficiently without azeotropic drying, in-house prepared additive and special equipment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC), which would be most desirable to radiochemists and biomedical researchers.\u003c/p\u003e"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003e \u003cb\u003eAzeotropic drying-free aryl\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-fluorination procedure development.\u003c/b\u003e With the abovementioned goal, an azeotropic drying-free [\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF]F\u003csup\u003e-\u003c/sup\u003e reagent solution was first prepared and tested on the photoredox-mediated aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination. As designed and illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC, the aqueous \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e produced from the cyclotron was loaded on the preconditioned anion-exchange resin (AER), followed by the N\u003csub\u003e2\u003c/sub\u003e gas and MeCN (5 mL) drying. After another 5 min nitrogen flushing, the AER was eluted with a nonaqueous eluent to obtain the azeotropic drying-free \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e solution for labeling reactions (see SI section 3.3 and 3.4). The screening and optimization results are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. No \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e was eluted out from the Sep-Pak Light QMA Carbonate (130 mg resin loading) using the solution of \u003csup\u003et\u003c/sup\u003eBuOH (2.5 mL) and in-house prepared tetrabutylammonium bicarbonate (TBAB) solution (20 \u0026micro;L in MeCN) as eluent (entry 1), but 65% elution efficiency (EE) and more than 98% trapping efficiency were obtained when a smaller amount of sorbent-loaded anion exchange resin (KT-101, 40 mg) was used with a similar eluent. More importantly, with the obtained drying-free \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF\u003csup\u003e-\u003c/sup\u003e solution (0.5 mL for each labeling reaction), 1-fluoro-4-methoxybenzene (\u003cb\u003e1\u003c/b\u003e) was labeled through photoredox-mediated aryl \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange in more than 60% radiochemical conversion\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDrying-free aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination development and optimization\u003csup\u003e[a]\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eentry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAER-formation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eeluent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEE (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCC (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003esolvent (0.5/2.5 mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ebase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003esalt\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSep-Pak Light QMA-CO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAB (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAB (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEtOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAB (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAB (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (5 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e70.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (20%, 20 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 10 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e72.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 10 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 10 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (2 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e99.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 4 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (5 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e99.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (10 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e98.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 2 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (1 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e56.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 2 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAT (1 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 4 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (40%, 4 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (1 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBAOH (1M MeOH solution,\u003c/p\u003e \u003cp\u003e10 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTBPH (40%, 4 \u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e56.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-CO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-PO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e3-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e76.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e71.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003csup\u003e[b]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8 (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003csup\u003e[b,c]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e92.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003csup\u003e[b,d]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eKT-101\u003c/b\u003e-HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003et\u003c/sup\u003eBuOH/MeCN (4/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTBAP (3 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[a] Aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination conditions: \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e (0.19\u0026ndash;1.11 GBq), substrate \u003cb\u003e1\u003c/b\u003e (2 \u0026micro;L, 0.018 mmol), photocatalyst \u003cb\u003eS\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (2 mg), DCE (500 \u0026micro;L), 456-nm LED, rt, 15-min irradiation, N\u003csub\u003e2\u003c/sub\u003e atmosphere. 500 \u0026micro;L drying-free \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e solution was used for entries 1\u0026ndash;11, and all \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e eluate were used for entries 12\u0026ndash;23, respectively. The EE (elution efficiency) was calculated by division of the \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e eluted in the reaction v-vial by the whole \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e (\u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e in the v-vial and \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e left on the resin). All RCCs were calculated by HPLC integration with a basic mobile phase to avoid the unconverted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e fluoride being trapped on the C18 HPLC column. [b] The AER was slowly eluted with the eluent in 1 min. [c] used AER. [d] DCM (600 \u0026micro;L) was used instead of DCE.\u003c/p\u003e \u003cp\u003e(RCC) with the acridinium photocatalyst \u003cb\u003eS\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e. Notably, this labeling reaction was performed under a 456-nm LED light in only 15 minutes without cooling and any additional base compared to previous procedures (entry 2).\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Encouraged by the primary results, a series of eluents were then screened under current conditions to enhance the EE and labeling efficiency (entries 3\u0026ndash;9). Replacing the \u003csup\u003et\u003c/sup\u003eBuOH with EtOH in the eluent improved the EE to 75% but significantly decreased the RCC of compound \u003cb\u003e1\u003c/b\u003e (entry 3). We\u0026rsquo;re glad to find that with an organic soluble tetrabutylammonium perchlorate (TBAP) salt in the eluent, the EE was improved to 82% with comparable RCC (entry 4). When the stronger base, tetrabutylammonium hydroxide aqueous solution (TBAOH, 40% w/w), was used instead of TBAB, 60%-78% EE was obtained with \u0026gt;\u0026thinsp;70% RCC (entries 5\u0026ndash;7). Combining the TBAOH and TBAP as eluent, both the EE and RCC were improved (entry 8), and 99% EE was successfully achieved when the AER was slowly eluted in approximately 1 minute (entries 9 and 10). We\u0026rsquo;re excited to find that excellent EE and RCC were obtained with the eluent that has TBAP only in the \u003csup\u003et\u003c/sup\u003eBuOH/MeCN solution (entry 11). These findings are undoubtedly very attractive since rapid aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling of electron-rich arenes could be realized from the readily obtained drying-free \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e solution for fast reaction screening, and it\u0026rsquo;s particularly useful for heating and base-sensitive substrates since the minimal base was applied in the photolabeling reaction.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFull batch drying-free aryl\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-fluorination optimization.\u003c/b\u003e After the drying-free conception has been established and verified on aryl \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange radiofluorination, we managed to set up the labeling reactions with all the eluted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e beyond a portion, which would be more useful in clinical use; meanwhile, challenges may arise since more moisture and eluents will be present in a single labeling reaction (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). The volume of the eluent solvent was first decreased to 0.5 mL from 2.5 mL for the full-batch reaction under similar labeling conditions (Table. 1, entries 12\u0026ndash;23). Encouragingly, good RCCs of compound \u003cb\u003e1-\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF\u003c/b\u003e (53\u0026ndash;66%) were still obtained when all the eluted \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e were applied for the labeling reactions from different eluents, though the EEs (35\u0026ndash;56%) remain to be improved (entries 12\u0026ndash;17), and tetrabutylphosphonium hydroxide (TBPH) and tetrabutylammonium tetrafluoroborate (TBAT) demonstrated similar elution and labeling efficiency when applied instead of TBAOH and TBAP (entries 13 and 17). To simplify the labeling reaction setup, the nonaqueous neutral \u003csup\u003et\u003c/sup\u003eBuOH-MeCN-TBAP eluent system was selected for further optimization (entries 18\u0026ndash;23). Acceptable EE (81%) was achieved when the AER was slowly eluted (entry 18). Considering that the anions with different basicity and valency play an essential role in both EE and RCC for \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination,\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003ef\u003c/sup\u003e we turn to screen the AER-preconditioning counter anions. We\u0026rsquo;re pleased to find that CO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e2\u0026minus;\u003c/sup\u003e preconditioned AER provides 91% EE with 60% RCC, while PO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e3\u0026minus;\u003c/sup\u003e offered lower EE but higher RCC of the model compound \u003cb\u003e1\u003c/b\u003e, respectively (entries 19 and 20). Excitedly, the HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2\u0026minus;\u003c/sup\u003e-preconditioned AER provided the highest elution efficiency (\u0026gt;\u0026thinsp;95%) without diminishing the RCCs (entry 21). These results demonstrated that basic counter anions play a crucial role in both the EE and RCC of the photolabeling reactions, which have not been intensively studied previously. Interestingly, we found that the AER is reusable at least three times with slightly decreased trapping and elution efficiency but higher RCC. We speculated that accumulated ClO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e from TBAP binding on the resin resulted in less basic anion (HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2\u0026minus;\u003c/sup\u003e) eluted in the reaction that might benefit the photoredox-mediated aryl radiofluorination. Meanwhile, the slower \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e and ClO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e exchangeand self-exchange of ClO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e during the elution lowered the \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e trapping and elution efficiency (entry 22). Lastly, replacing the 1,2-dichloroethane (DCE) with clinically more favorable dichloromethane (DCM) didn\u0026rsquo;t affect the RCC of compound \u003cb\u003e1\u003c/b\u003e (entry 23). This finding makes the system more flexible and clinically applicable when thoroughly removing DCE was an issue (see SI sections 3.4 and 3.5). \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe substrate scope of the photoredox-mediated drying-free aryl\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-fluorination.\u003c/b\u003e With the optimized conditions, we are starting to explore the reaction scope of this reformulated photolabeling system, mainly focusing on the base or heating-sensitive substrates and those underexplored in previous work (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The reactive bromoalkyl phenyl ether (\u003cb\u003e2\u003c/b\u003e) was efficiently labeled through aryl \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange. The addition of an electron-donating methoxyl group next to the fluorine atom increased the labeling efficiency due to the reduced oxidation potential and the enhanced stability of the arene radical cation intermediate of the substrate (\u003cb\u003e3\u003c/b\u003e), which promotes the photoinduced electron transfer by the exited photocatalyst \u003cb\u003eS\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e. Notably, no Br/\u003csup\u003e18\u003c/sup\u003eF S\u003csub\u003eN\u003c/sub\u003e2 reactions were observed from these minimal basic and heating-free labeling conditions. Excitedly, the photoredox-mediated deoxyfluorination\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003eb, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e of bromoalkyl phenyl ethers (2-deo) also works very well under current conditions to give the aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled product \u003cb\u003e2-\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF\u003c/b\u003e in 78% RCC with a good molar activity (46.5 GBq/\u0026micro;mol) under the new labeling conditions. The benzyl bromide derivative (\u003cb\u003e4\u003c/b\u003e) was labeled in 31% RCC, accompanied by 10% Br/\u003csup\u003e18\u003c/sup\u003eF exchange product, due to the higher reactivity of bromide at the benzyl position. Aryl bromide (\u003cb\u003e5\u003c/b\u003e) and aryl iodide (\u003cb\u003e6\u003c/b\u003e) compounds were labeled in moderate RCCs. Through the isotopic exchange, aryl alcohols with different chains (\u003cb\u003e7\u003c/b\u003e\u0026ndash;\u003cb\u003e9\u003c/b\u003e) were efficiently labeled, indicating that the unprotected hydroxyl group didn\u0026rsquo;t suppress the photo-induced oxidation progress. The benzoic acid methyl ester derivative, \u003cem\u003eN\u003c/em\u003e-Boc-protected alkyl amine, and \u003cem\u003eO\u003c/em\u003e-Boc-protected phenol were efficiently labeled from readily available precursors (\u003cb\u003e10-deo\u003c/b\u003e, \u003cb\u003e11-deo\u003c/b\u003e, and \u003cb\u003e12-deo\u003c/b\u003e). It\u0026rsquo;s worth noting that substrates bearing functional groups like alkyne, azide, or maleimide (\u003cb\u003e13\u003c/b\u003e\u0026ndash;\u003cb\u003e16\u003c/b\u003e) that are commonly used for indirect labeling of bioactive molecules also tolerated this labeling system and provided good RCCs. Other than incorporating the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF on conventional electron-deficient (hetero) aryl rings, the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF was installed on the electron-rich phenyl rings of these substrates, which would benefit\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ethe diversification of the PET tracer construction.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003eb\u003c/sup\u003e Heterocyclic compounds, for example, pyrimidine, quinazoline, and purine (\u003cb\u003e17\u003c/b\u003e\u0026ndash;\u003cb\u003e19\u003c/b\u003e), were also successfully radiofluorinated via \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange. The tetrazine derivatives (\u003cb\u003e20\u003c/b\u003e, \u003cb\u003e21\u003c/b\u003e) routinely applied for PET tracer development were \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled in moderate RCCs, and no apparent decomposition of the starting material was found from the mild labeling conditions.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Lastly, substrates containing aryl or alkyl boronic ester moiety (\u003cb\u003e22\u0026ndash;25\u003c/b\u003e) that were barely reported for aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination were able to be labeled either through deoxyfluorination or \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange in moderate to good RCCs.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Besides functional substrates, the compatibility of this simple aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling system was further tested on a series of bioactive molecules (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The 6-\u003cem\u003eO\u003c/em\u003e-arylated-\u003cem\u003eβ\u003c/em\u003e-D-glucopyranose and glucopyranose (\u003cb\u003e26\u0026ndash;30\u003c/b\u003e) were \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled in good to excellent RCCs (29\u0026ndash;62%).\u003csup\u003e15\u003c/sup\u003e Notably, with multiple free hydroxyl groups, the substrate (\u003cb\u003e30\u003c/b\u003e) could also be labeled under current conditions, offering \u003cb\u003e30-\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF\u003c/b\u003e in 30% RCC. The 2-\u003cem\u003eO\u003c/em\u003e-arylated-\u003cem\u003eβ\u003c/em\u003e-D-mannopyranose substrate (\u003cb\u003e31\u003c/b\u003e and \u003cb\u003e31-deo\u003c/b\u003e) were labeled in 16% and 77% RCC through \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF and deoxyfluorination. As a proof-of-concept, by simple amide consideration with the aryl fluorine-containing acid, drug molecules like the Glu-urea-Lys based prostate-specific membrane antigen (PSMA) inhibitor (\u003cb\u003e32\u003c/b\u003e) \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, Olaparib core skeleton (\u003cb\u003e33\u003c/b\u003e) \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, Ibrutinib (\u003cb\u003e34\u003c/b\u003e) and Sitagliptin (\u003cb\u003e35\u003c/b\u003e) that have multiple function groups can be \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorinated from this labeling system in good RCCs.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDirect aryl\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-labeling of lipophilic cations.\u003c/b\u003e Lipophilic cations have been recognized as a class of important compounds for mitochondria-targeted studies and applied to cancer and cardiovascular imaging after conjugating with radionuclides.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e However, the aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled lipophilic cations are generally obtained from multiple-step indirect synthesis, considering the cation might not tolerate the high temperature under basic conditions from the traditional labeling methods.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003eb\u003c/sup\u003e Using our labeling protocol, no labeling product was initially observed from the quaternary ammonium cation substrate (\u003cb\u003e36\u003c/b\u003e), whereas 36% RCC was obtained after the counter anion bromide was exchanged to perchlorate (\u003cb\u003e37\u003c/b\u003e) to avoid the competition nucleophilic attack between bromide and \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluoride, and improved RCC was obtained when one of the alkyl groups on the nitrogen atom was replaced with an aryl group (\u003cb\u003e38\u003c/b\u003e). With the perchlorate as the counter anion, the substrate bearing a shorter carbon chain (\u003cb\u003e39\u003c/b\u003e), however, didn\u0026rsquo;t give any product, but good RCC was obtained after a methoxy group was added next to the fluorine on the phenyl ring (\u003cb\u003e40\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe choline analog substrates (\u003cb\u003e41\u003c/b\u003e and \u003cb\u003e42)\u003c/b\u003e that could potentially be used for imaging of cell membrane proliferation were also workable.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Other lipophilic cations like pyridinium (\u003cb\u003e43\u003c/b\u003e\u0026ndash;\u003cb\u003e46\u003c/b\u003e) and triphenylphosphonium salts (\u003cb\u003e47\u003c/b\u003e and \u003cb\u003e48\u003c/b\u003e) used for cardiovascular imaging were successfully aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003eb, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Interestingly, similar labeling tendencies that substrates possessing shorter carbon chains provided lower RCCs were observed among those tested compounds (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We speculated that an intramolecular cation\u0026ndash;π interaction between the phenyl ring and the tethered quaternary ammonium might disrupt the photoredox process\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e or the shorter chain substrates are more hygroscopic, thus inhibiting the labeling reaction which needs further study though.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConstruction and labeling of unnatural amino-acid derivatives for PET tracer discovery.\u003c/b\u003e Radiolabeled amino acids represent one of the most important metabolic imaging agents in oncology and have gained increased clinical interest over the past decades for brain tumors and neuroimaging, considering their low background uptake compared to \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e However, the synthesis of aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled amino acids was limited since the chemical construction of the labeling precursor is burdensome, and the tracers were generally produced in relatively lower RCYs.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e We were particularly interested in applying unnatural amino acids for PET agent exploration. With the established labeling protocol, a series of amino-acid derivatives were rapidly composed and labeled (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Specifically, the \u003cem\u003eO\u003c/em\u003e-arylated threonine, hydroxyproline, and (homo) serine derivatives (\u003cb\u003e49\u0026ndash;56\u003c/b\u003e) were labeled in moderate to excellent RCCs through halide interconversion. Notably, iodine-containing substrates (\u003cb\u003e55\u003c/b\u003e and \u003cb\u003e56\u003c/b\u003e) work well too. The glutamine, phenylalanine, and a-arylglycine derivatives (\u003cb\u003e57\u0026ndash;62\u003c/b\u003e) were easily constructed and labeled in good to excellent RCCs. The \u003cem\u003eb\u003c/em\u003e-phenylalanine, a-guanidino acid, and amino phosphonic acid derivatives (\u003cb\u003e63\u003c/b\u003e\u0026ndash;\u003cb\u003e65\u003c/b\u003e) were efficiently aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled from deoxyfluorination or isotopic exchange. Additionally, the boron-containing amino acid derivatives (\u003cb\u003e66\u003c/b\u003e and \u003cb\u003e67\u003c/b\u003e) were successfully aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled, which would potentially be applied for the boron neutron capture therapy (BNCT) drug discovery.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Lastly, substrate \u003cb\u003e68\u003c/b\u003e, which has been reported for the efficient preparation of PET tracer [\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF]FDOPA,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003ec\u003c/sup\u003e was labeled in excellent RCCs under the current drying-free conditions. It was also successfully labeled on a simple LED reactor (ProBOX) in up to 70% RCC from 7.4 GBq \u003csup\u003e18\u003c/sup\u003eF\u003csup\u003e\u0026minus;\u003c/sup\u003e with DCM instead of DCE as the solvent (see SI section 3.11). To further demonstrate the practicability, we applied our azeotropic drying-free labeling method on a commercial radiosynthesis module using substrate \u003cb\u003eL-\u003c/b\u003e\u003cb\u003e68\u003c/b\u003e as an example, and the [\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF]FDOPA was successfully produced in 14.8% non-decay corrected RCY (radiochemical yield) with 99% ee (enantiomeric excess) from two-step automation procedure (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, see SI section 3.12 for synthesis detail).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the unnatural amino acids, the a-arylglycine fragment was frequently presented in natural products and drugs.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e However, the arylglycine itself has rarely been investigated as an imaging agent by targeting the amino-acid transporters, which have been\u003c/p\u003e \u003cp\u003eproven overexpressed in many types of tumors for the survival and proliferation of cancer cells.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e To the best of our knowledge, no aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled arylglycines have ever been reported for PET imaging studies.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e After rapid deprotection of the \u003cb\u003e60-\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF\u003c/b\u003e, the PET tracer, namely \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e, was obtained from quick cartridge isolation (see SI section 4.1 for details) and evaluated in melanoma (B16F10) and breast cancer (MCF-7) tumor models (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). We\u0026rsquo;re excited to find that apparent accumulation of \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e in the B16F10 (SUV\u003csub\u003emax\u003c/sub\u003e = 2.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27) and MCF-7 (SUV\u003csub\u003emax\u003c/sub\u003e = 2.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32) tumor models and low background uptake were observed at 0.5 h post-injection with 5.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04 and 6.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94 tumor/muscle ratio, respectively. The configuration effect of the tracer was further studied in MCF-7 models. The optical pure precursors were obtained through a simple chiral column resolution and efficiently labeled to provide the two enantiomers, \u003cem\u003eL\u003c/em\u003e-\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e and \u003cem\u003eD\u003c/em\u003e-\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e, after deprotection. The absolute configuration of the two isomers was confirmed by the comparison with commercial standards (see SI section 4.3 for details). PET imaging studies showed that the \u003cem\u003eL\u003c/em\u003e-\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e exhibited higher tumor uptake and longer retention at 0.5 h, 1 h, and 2 h post-injection compared with \u003cem\u003eD\u003c/em\u003e-\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e, but much higher tumor/muscle ratios (0.5 h: 12.19\u0026thinsp;\u0026plusmn;\u0026thinsp;3.03 vs 5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95; 1 h: 9.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 vs 5.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87; 2 h: 8.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.47 vs 5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.47) were detected from the latter one. These results demonstrated that despite the lack of a \u003cem\u003eb\u003c/em\u003e-methylene group compared to other reported amino-acid PET tracers, the \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e is still a potential substrate of the amino-acid transporters and demonstrates similar properties and preferences. The simple preparation and high \u003cem\u003ein vivo\u003c/em\u003e tumor/muscle ratios demonstrated that the \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e is a promising PET agent targeting amino acid transporters and is worth further evaluation for clinical translation.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThrough extensive optimization and screening of the AER formation and eluents, a straightforward photoredox-mediated aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination method was established. This labeling system was featured by excluding the cumbersome azeotropic-drying procedure, in-house prepared additive and could be performed with all commercially available reagents and equipment under a cheap LED light. A nonaqueous neutral eluent was discovered to effectively balance the elution and labeling efficiency, which is particularly useful for the aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination of the base-sensitive substrates. The success and advantages of this simplified photoredox-labeling method were demonstrated by the direct aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination of various essential functional compounds, drug molecules, lipophilic cations, and the automatic synthesis of clinical PET tracer [\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF]FDOPA on a commercial module. Moreover, a broad of unnatural (including boron-containing) amino-acid derivatives was rapidly composed and aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled through this method, eventually leading to the discovery of the \u003cem\u003ea\u003c/em\u003e-arylglycine \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FMPG\u003c/b\u003e as a novel and promising PET agent targeting amino acid transporters. We anticipate this simple operable aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeling method to be widely adopted to assist the PET tracer and drug development.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eASSOCIATED CONTENT\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAll the data generated or analyzed during this study are included in this article (and its Supplementary Information files).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorresponding Author\u003c/p\u003e\n\u003cp\u003eWei Chen\u0026nbsp;\u0026minus;\u0026nbsp;Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab,\u0026nbsp;West China Hospital, Sichuan University,\u0026nbsp;Chengdu, Sichuan, 610041, China.\u0026nbsp;\u003cbr\u003eE-mail: \u003cstrong\[email protected]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003eY.W., L.P., and K.L. contributed equally. W.C. conceived the project. W.C., Y.W., L.P., K.L, M.H., C.Z., and Y.X. performed the radiolabelling reactions and data analysis. L.P. performed the chemical synthesis and data analysis. M.H., Y.W., K.L., Y.X., C.Y., and H.S. assisted in the chemical synthesis. Y.W. prepared the PET tracers, conducted the animal imaging studies and accomplished PET imaging data collection and analysis. M.L. assisted in the animal studies. X.W. and H.W. contributed to the initial discussion. W.C. wrote the manuscript with contributions from all the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNotes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have filed a provisional patent on the basis of the research in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (22371193, 22377083), Sichuan Science and Technology Program (2023NSFSC0645), the Institutional Joint Innovation Fund from Sichuan University and Nuclear Power Institute of China (HG2022163 and HG2023141) and the 1\u0026bull;3\u0026bull;5 Project for Disciplines of Excellence at West China Hospital, Sichuan University (ZYGD23016, ZYYC23003). We thank Dr. Y.L. and L.Z. for their assistance with the cyclotron operation and F.S. and Q.P. at the Core Facilities of West China Hospital for the help with NMR and HRMS measurements.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e(a) J. S. Fowler, N. D. Volkow, G. J. Wang, Y. S. Ding, S. L. Dewey, \u003cem\u003eJ Nucl Med \u003c/em\u003e\u003cstrong\u003e1999\u003c/strong\u003e, \u003cem\u003e40\u003c/em\u003e, 1154-1163; (b) S. M. Ametamey, M. Honer, P. A. Schubiger, \u003cem\u003eChem Rev \u003c/em\u003e\u003cstrong\u003e2008\u003c/strong\u003e, \u003cem\u003e108\u003c/em\u003e, 1501-1516.\u003c/li\u003e\n\u003cli\u003e(a) D. X. Sun, W. Gao, H. X. Hu, S. M. Zhou, \u003cem\u003eActa Pharm Sin B \u003c/em\u003e\u003cstrong\u003e2022\u003c/strong\u003e, \u003cem\u003e12\u003c/em\u003e, 3049-3062; (b) K. K. Ghosh, P. Padmanabhan, C. T. Yang, D. C. E. Ng, M. Palanivel, S. Mishra, C. Halldin, B. 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Tamemasa, \u003cem\u003eYakugaku Zasshi-Journal of the Pharmaceutical Society of Japan \u003c/em\u003e\u003cstrong\u003e1988\u003c/strong\u003e, \u003cem\u003e108\u003c/em\u003e, 246-249.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4325597/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4325597/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this work, we established a simplified photoredox-mediated labeling system that allows the rapid aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination of electron-neutral and -rich arenes via \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF-\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF exchange or/and deoxyfluorination. Notably, this aryl radiofluorination method excludes the cumbersome azeotropic drying procedure and is scalable with the whole eluted \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF- beyond portion synthesis. The nonaqueous tetrabutylammonium perchlorate (TBAP) solution was identified as an ideal neutral eluent to balance the elution and labeling efficiency in combination with a HPO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e2-\u003c/sup\u003e preconditioned anion-exchange resin (AER). Base-sensitive substrates like alkyl halide, tetrazine, and lipophilic cations were able to be directly aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled under the weak basic conditions. Moreover, this azeotropic drying-free photolabeling method was successfully implemented on a commercial automatic radiosynthesis module. Furthermore, a broad range of unnatural amino-acid derivatives were composed and aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-labeled under the current system, and the arylglycine derivative \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FMPG was found to be a promising PET agent targeting amino acid transporters. Taken together, the mild labeling conditions combined with the simplicity of the reaction setup from all commercially available reagents and inexpensive equipment guarantees the repeatability and wide adoption of this aryl \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-fluorination method for PET agents and drug discovery.\u003c/p\u003e","manuscriptTitle":"Simplified radiolabeling process toward rapid photoredox-catalyzed aryl 18F-fluorination and PET tracer development","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-10 10:47:05","doi":"10.21203/rs.3.rs-4325597/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"be8a0813-5cd8-4cce-a297-cba6cf170caf","owner":[],"postedDate":"February 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44092560,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":44092561,"name":"Physical sciences/Chemistry/Photochemistry/Photocatalysis"}],"tags":[],"updatedAt":"2025-02-10T10:47:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-10 10:47:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4325597","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4325597","identity":"rs-4325597","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}