New fluorine-18 labeled benzaldehydes as precursors in the synthesis of radiopharmaceuticals for positron emission tomography

4,5-Bis(butoxy)-2-nitrobenzaldehyde and 4,5-bis(tert-butoxycarbonyloxy)-2-nitrobenzaldehyde, as well as their fluorine-18 labeled derivatives (the half-life of F¹⁸ is T_1/2 = 110 min) were synthesized for use as precursors in the synthesis of fluorine-18 labeled catecholamines and 6-[¹⁸F]fluoro-l-DOPA ((S)-3-[4,5-dihydroxy-2-[¹⁸F]fluorophenyl]-2-aminopropionic acid), important radiopharmaceutical agents (RPAs) for positron emission tomography. An advantageous feature of the newly obtained substituted nitrobenzaldehydes is the presence of labile protective groups which can be removed without using aggressive chemicals and severe conditions, which is of fundamental importance for automation of the RPA synthesis in modern synthesis apparatus. A high and stable radiofluorination yield achieved under the optimum fluorination conditions (Kryptofix 222 [K/K2.2.2.]⁺[¹⁸F^–], DMF, 140 °C, 10 min) using 4,5-bis(butoxy)-2-nitrobenzaldehyde as a substrate (83±6%, the number of experiments was n = 15) makes this compound a precursor of choice for the radioactive synthesis.     

Alpha selective epoxide opening with F: synthesis of 4-(3-[F]fluoro-2-hydroxypropoxy)benzaldehyde ([F]FPB) for peptide labeling

Strained tricyclic ring systems such as epoxides are rarely used as precursors for the introduction of anionic fluorine-18 into organic compounds intended for positron emission tomography (PET). Here we report the alpha selective ring opening of epoxides for the introduction of fluorine-18 into small as well as larger biomolecules via 1- and 2-step protocols. [¹⁸F]fluoromisonidazole ([¹⁸F]MISO), a tracer for hypoxia imaging, and the tumor targeting peptide Tyr³-octreotate (TATE) were radiolabeled using epoxide opening reactions. In the latter case, the new prosthetic labeling synthon 4-(3-[¹⁸F]fluoro-2-hydroxypropoxy)benzaldehyde ([¹⁸F]FPB) has been used for ¹⁸F-introduction.     

Synthesis of 6-[18F]fluoroveratraldehyde by nucleophilic halogen exchange at electron-rich precursors

Summary Fluorodehalogenation reactions were used to prepare 6-[¹⁸F]fluoroveratraldehyde. The synthesis of 6-[¹⁸F]fluoroveratraldehyde is the first step in the multi-step synthesis of the clinically important tracer 6-[¹⁸F]fluoro-L-dopa. In the literature yields ranging from 20-50% are reported when using nitro and trimethylammoniumtriflate precursors. However, no data exist concerning the use of different leaving groups such as halogens. Therefore, 6-bromo, 6-chloro and 6-fluoroveratraldehyde were tested in the nucleophilic aromatic substitution by [¹⁸F]fluoride. In DMF, 6-[¹⁸F]fluoroveratraldehyde was obtained with radiochemical yields of (57±1.0)% and (66±3.6)% in 20 minutes at 160 °C using 50 mg/ml bromo and chloro precursor, respectively. The fluoro precursor gave a radiochemical yield of (87±0.8)% at 140 °C. Temperature, solvent and concentration strongly affected the ¹⁸F-labeling. Among the halogens the ability as a leaving group was F>>Cl>Br. The halogenated veratraldehydes provide a good alternative for the synthesis of ca and nca 6-[¹⁸F]fluoroveratraldehyde, as the first step of the synthesis for [¹⁸F]FDOPA since they are inexpensive, commercially available, stable, sustain hard conditions in the labeling step, and give yields better or equal to other precursors previously reported.     

The nucleophilic substitution reaction for [18F]fluoride-ion on the series of N6-benzoyl-2",3"-isopropylideneadenosine-5"-sulfonates

The reaction of the nca [¹⁸F]fluoride ion was investigated toward a series of N⁶-benzoyl 2",3"-isopropylidene-adenosine-5"-sulfonates including the methane-(mesylate), p-toluene-(tosylate), p-nitro-benzene-(nosylate)- and 2,2,2-trifluoro-ethane-sulfonate (tresylate) derivatives under usual nucleophilic substitution conditions. In these reactions cyclisation of the title compounds was observed whilst the radiofluorination took place only with low yield. The fluorine-18 uptake was found to be 1.17% for mesylate, 1.46% for tosylate, 0.99% for nosylate and 0.40% for tresylate under the conditions applied.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET), a fluorine-18 labeled analogue of tyrosine, has been synthesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is completed within 50 min. The radiochemical yield is about 40% (no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [¹⁸F]FET shows rapid, high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle (T/M) and tumor-to-blood (T/B) of [¹⁸F]FET are similar to those of [¹⁸F]FDG, but the ratios of tumor-to-brain (T/Br) are 2–3 times higher than that of [¹⁸F]FDG. Autoradiography of [¹⁸F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET. Supported by the Knowledge Innovation Project of Chinese Academy of Sciences (No. KJCX1-SW-08) and the National Natural Science Foundation of China (Grant No. 30371634)     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

Synthesis,quality control and tissue distribution of 2-[18F]-nicotinic acid diethylamide,a potential agent for regional cerebral function studies

2-[¹⁸F]-nicotinic acid diethylamide was prepared by nucleophilic aromatic substitution in an acetamide melt of the corresponding chloro-compound and purified by high pressure liquid chromatography. Optimization of the reaction conditions led to a maximum radiochemical yield of about 50% within less than one half-life of¹⁸F. Tissue distribution of 2-[¹⁸F]-nicotinic acid diethylamide in various organs of mice showed a very fast accumulation of activity in the brain (mean body concentration MBC-239%) with a brain to blood ratio of 1.34.     

An efficient synthesis of ([F]fluoropropyl)quinoline-5,8-diones by rapid radiofluorination-oxidative demethylation

Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spectrum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-diones have received considerable attention in positron emission tomography (PET) molecular imaging studies. In this paper, we describe an efficient synthetic route for the regioselective preparation of fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and C6 positions by tert-alcohol media fluorination, followed by oxidative demethylation of the corresponding dimethoxy compound using N-bromosuccinimide (NBS) in the presence of catalytic amounts of sulfuric acid. Moreover, F-18 labeled [¹⁸F]fluoropropylquinoline-5,8-diones [¹⁸F]21-23 were prepared from the corresponding mesylate precursors by a method of rapid and efficient one-pot, two-step reactions: radiofluorination using TBA [¹⁸F]F generated under no-carrier-added (NCA) conditions; oxidative demethylation, resulting in a 45% radiochemical yield of [¹⁸F]21-23 (decay-corrected) with a total synthesis time (including HPLC purification) of 75 min and high radiochemical purity (>99%), as well as high specific activity (∼230 GBq/μmol).     

Development of metallocomplex amino acids synthons for the asymmetric preparation of α-amino acids by stereoselective introduction of a side chain. Evaluation of the model asymmetric preparation of alanine and β-13C monolabelled α-aminoisobutyric acid

In this communication the evaluation of eleven new metallocomplex alanine synthons bearing C₂-symmetric benzyl groups with electron-donating and electron-withdrawing substituents is described. α-Methylated glycine synthons (alanine complexes) were evaluated alongside alanine synthons in order to obtain a deeper understanding of the relationship between their structures and stereochemistry of monoalkylated products and to choose several candidates for their further tests for stereospecific preparation of 6-[¹⁸F]FDOPA. Glycine-derived analogues of the complexes 3–5 are the best candidates for the development of a 6-[¹⁸F]FDOPA preparation procedure. In the model epimerisation reaction they demonstrated the best performance, much better compared to the previously described compound 2. Complexes 3, 5 and 8 are the best in asymmetric preparation of β-¹³C monolabelled α-aminoisobutyric acid. They have to be tested in the preparation of α-methyl amino acids like 6-[¹⁸F]-α-methylDOPA and 2-[¹⁸F]-α-methyltyrosine.     

[F]Fluoromethyl iodide ([F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups

In this study, we report the synthesis and reactivity of [¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F]fluoromethylated compounds. [¹⁸F]FCH₂I was prepared by reacting diiodomethane (CH₂I₂) with [¹⁸F]KF, and purified by distillation in radiochemical yields of 14-31% (n = 25). [¹⁸F]FCH₂I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1-7, but was unstable in basic solutions. [¹⁸F]FCH₂I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [¹⁸F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [¹⁸F]FCH₂I were stable for purification, formulation and storage. In contrast, the [¹⁸F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [¹⁸F]FCH₂I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [¹⁸F]fluoromethyl compounds was a main decomposition route.     

Establishment of a kinetic model for the intramolecular catalyzed hydrolysis of [18F]‐benzylfluoride containing amino acid analogues by linking experimental and DFT studies

In an earlier publication, we suggested that the faster radiodefluorination kinetics of no‐carrier‐added (S)‐3‐(2‐[¹⁸F]fluoromethyl‐phenyl)‐2‐amino‐propionic acid (2‐[¹⁸F]FMLP), as compared to 4‐[¹⁸F]‐fluoromethyl‐l ‐phenylalanine (4‐[¹⁸F]FMLP), was caused by an intramolecular interaction between the CH₂F group on the 2‐position of the phenyl ring and the ammonium group of the amino acid. As the presence of nonradioactive (S)‐3‐(2‐fluoromethyl‐phenyl)‐2‐amino‐propionic acid (2FMLP) in a concentration up from 10^?6 mol/L reduces considerably the defluorination rate due to the formation of dimers, conventional experimental methods, like spectroscopy, cannot be performed for the study of the hydrolysis in no‐carrier‐added conditions occurring at a concentration range of about 5.0 10^?10 mol/L. In the present study, we aim to provide a proof that supports aforementioned hypothesis as well as to establish a kinetic model and to put forward accompanying rate equations for this hydrolysis reaction by combining ab initio quantum chemical calculations and kinetic data. The calculations of the optimized geometries and the corresponding energies of the reactants involved in the hydrolysis of 2‐[¹⁸F]FMLP and 4‐[¹⁸F]FMLP were performed at the DFT[B3LYP/6‐31⁺⁺G**] level of theory. Interpretation of these data reveals that in 2‐[¹⁸F]FMLP three intramolecular hydrogen bond interactions can be identified that are not present in 4‐[¹⁸F]FMLP. The most important interaction is the one between the amino acid ammonium group and the benzylic fluorine atom, rendering the rupture of the C? F bond much more favorable. These findings align with the experimental data and enabled us to put forward the rate expressions that define the unexpected pseudo–zero‐order defluorination reaction of 2‐[¹⁸F]FMLP at neutral pH. This study also proves that in the development of [¹⁸F]‐benzylfluoride containing tracers present‐day quantum chemical calculations are capable of predicting intramolecular interactions, affecting their reactivity toward hydrolysis at the no‐carrier‐added level. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 705–711, 2012     

Mono- and dimethylbenzyls as new protecting groups for no-carrier-added nucleophilic aromatic radiofluorination

In this work, we tested the applicability of several methyl substituted benzyl groups as an alternative to the methyl group for the protection of the hydroxyl groups in the nucleophilic aromatic radiofluorination. As a model synthesis, the no-carrier-added (n.c.a.) preparation of 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine from O-protected 3-hydroxy-6-methyl-2-nitropyridine was chosen. Conditions for acidolytic and hydrogenolytic cleavage of heteroaryl esters were studied. Among various protecting groups tested, 4-methylbenzyl and 2,4-dimethylbenzyl groups proved to be the best by resulting in about 70% yields of [¹⁸F]-labelled product after hydrolysis with 32% HCl at 120 °C for 10 min. Furthermore, 4-methylbenzyl ester cleaved readily under catalytic transfer hydrogenation condition using ammonium formate and 10% Pd/C in boiling methanol to give 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine in radiochemical yield of 75% within a reaction time of 10 min. Conditions for the cleavage of both 4-methylbenzyl and 2,4-dimethylbenzyl esters are well suited for the implementation into an automated synthesis module.     

A practical route for synthesizing a PET ligand containing [F]fluorobenzene using reaction of diphenyliodonium salt with [F]F

The aim of this study was to develop a practical route for preparing a fluorine-18 ([¹⁸F]) labelled ligand ([¹⁸F]1) containing [¹⁸F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [¹⁸F]F⁻. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [¹⁸F]DAA1106 ([¹⁸F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared.     

Automated synthesis of hypoxia imaging agent [18F]FMISO based upon a modified Explora FDG4 module

A new automated synthesis procedure of 1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), a specific hypoxia imaging agent with great significances for the noninvasive, dynamic hypoxia evaluation of cancer, was developed by modifying Explora FDG₄ module, a commercial [¹⁸F]FDG production system, in this study. Its radiochemical synthesis was carried out via two sequent reaction steps, i.e. the nucleophilic displacement of labeling precursor 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-tosyl-propanediol (NITTP) with activated ¹⁸F- ion at 100 °C for 8 minutes, and the following hydrolysis with 1M HCl at 100 °C for 5 minutes and neutralization with 1M NaOH. Two-pot reaction with two independent separations was adopted to assure the good separation of final product via solid phase extraction (SPE) based upon combined Sep-pak cartridges instead of high performance liquid chromatography (HPLC). This fast, reliable preparation route of ¹⁸F-FMISO could complete within 50 minutes with about 55% of high radiochemical yield (with decay correction) and more than 98% of good radiochemical purity. The modified module could perform multiple runs of production of [¹⁸F]FMISO.     

Enantioselective syntheses of no-carrier-added (n.c.a.) (s)-4-chloro-2-[f] fluorophenylalanine and (s)-(α-methyl) -4-chloro-2-[f]fluorophenylalanine

(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methy)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[¹⁸F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[¹⁸F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S)-(α-methyl) -4-chloro-2-[¹⁸F] fluorophenylalanine. Quantities of about 20–25 mCi were obtained at the end of sy nthesi s, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%–20% corrected to the end of bombardment after a total synthesis time of 90–105 min from [¹⁸F] fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.     

The [F]2-Fluoro-1,3-thiazolyl Moiety - an Easily-Accessible Structural Motif for Prospective Molecular Imaging Radiotracers

2-Fluoro-1,3-thiazoles were rapidly and efficiently labeled with no-carrier-added fluorine-18 (t_1/2 = 109.7 min) by treatment of readily prepared 2-halo precursors with cyclotron-produced [¹⁸F]fluoride ion. The [¹⁸F]2-fluoro-1,3-thiazolyl moiety constitutes a new and easily-labeled structural motif for prospective molecular imaging radiotracers.     

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [¹¹C]MPbP (4′-[¹¹C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T_1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [¹⁸F]F-IV in a rodent model of neuroinflammation. [¹⁸F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by ¹⁸F-fluoroethylation of the precursor with Boc-protecting group (15) with [¹⁸F]2-fluoro-1-bromoethane ([¹⁸F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [¹⁸F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [¹¹C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [¹⁸F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.     

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[¹⁸F]fluorobenzoyl)-interleukin-2 ([¹⁸F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [¹⁸F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [¹⁸F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [¹⁸F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [¹⁸F]FB-IL-2. Significant improvements in the radiochemical manufacture of [¹⁸F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.     

Autoradiolysis of the 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose radiopharmaceutical

Summary To control virtually the toxic compounds and to improve quality control of the solution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), the products of its autoradiolysis were analyzed by high-performance liquid chromatography with electrospray mass spectrometric and radiometric detectors (HPLC/MS/RAD), thin layer chromatography on TLC silica plate and HPTLC on amino modified silica plate. Except Kryptofix^™ 2.2.2, glucose and fluoride anion, no by-products and impurities were observed by LC/MS analysis of fresh 2-[¹⁸F]FDG samples. The analysis performed in the time interval of 6 to 48 hours after the end of 2-[¹⁸F]FDG synthesis indicated that the activity of the autoradiolysis products separated by HPLC did not exceed 1.3%. As the main autoradiolysis products of 3.3 ^. 10^-5 to 4.4 ^. 10^-5M 2-[¹⁸F]FDG solution of original specific activity 0.5-1.5 GBq ^. cm^-3 were established: arabinose - 2.8 μM (G= 0.07/100 eV), gluconic and glucuronic acids 1.8-0.5 μM (G =0.01-0.05/100 eV), arabinose and araburonic acids occurred under 0.5 μM concentration at residual glucose contents about 0.14 mM. Radiation chemical yields of active products were calculated from molar activity of 2-[¹⁸F]FDG and the percentage of their activity: 0.5% radiochemical yield of 2-[¹⁸F]fluoroglucuronic acid corresponds to the G = 0.004/100 eV and 0.3% yield of 2-[¹⁸F]fluorogluconic acid issues G = 0.003/100 eV.     

Production of 6-l-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-l-[¹⁸F]Fluoro-m-tyrosine (6-l-[¹⁸F]FMT) represents a valuable alternative to 6-l-[¹⁸F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[¹⁸F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[¹⁸F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu₄ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for ¹¹C-labeling. This method enables an uncomplicated switch between ¹¹C- and ¹⁸F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[¹⁸F]FMT in the clinic.