Radiosynthesis of the HIV integrase inhibitor [18F]MK‐0518 (Isentress)

The human immunodeficiency virus integrase inhibitor, [¹⁸F]MK‐0518, was prepared via a three‐step, one‐pot radiosynthesis. [¹⁸F]4‐Fluorobenzylamine was produced from the fluorination of 4‐cyano‐N,N,N‐trimethylammonium triflate with [¹⁸F]fluoride and reduction with borane methylsulfide complex in 50–68% radiochemical yield. The final step, the coupling of [¹⁸F]4‐fluorobenzylamine with an ester coupling partner, achieved an overall uncorrected radiochemical yield after HPLC purification of ～2%, based on the starting [¹⁸F]fluoride. In a typical run, the total synthesis time was about 90 min and gave 0.37–1.74 GBq (10–47 mCi) of [¹⁸F]MK‐0518. The radiochemical purity of [¹⁸F]MK‐0518 was>98% and the specific activity was 243–1275 Ci/mmol (EOS, n=4). A convenient three‐step, one‐pot radiosynthesis of [¹⁸F]MK‐0518 via [¹⁸F]4‐fluorobenzylamine has been developed, giving sufficient quantities of [¹⁸F]MK‐0518 for animal positron emission tomography studies. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiosynthesis of 3‐(2′‐[18F]fluoro)‐flumazenil ([18F]FFMZ)

Recently, two fluorine‐18 labelled derivatives of flumazenil were described: 5‐(2′‐[¹⁸F]fluoroethyl)‐5‐desmethylflumazenil (ethyl 8‐fluoro‐5‐[¹⁸F]fluoroethyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylate; [¹⁸F]FEFMZ) and 3‐(2′‐[¹⁸F]fluoro)‐flumazenil (2′‐[¹⁸F]fluoroethyl 8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a]‐[1,4]diazepine‐3‐carbo‐ xylate; [¹⁸F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [¹⁸F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two‐step procedure was developed: First, [¹⁸F]fluoride was reacted with 2‐bromoethyl triflate using the kryptofix/acetonitrile method to yield 2‐bromo‐[¹⁸F]fluoroethane ([¹⁸F]BFE). In the second step, distilled [¹⁸F]BFE was reacted with the tetrabutylammonium salt of 3‐desethylflumazenil (8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylic acid) to yield [¹⁸F]FFMZ. The synthesis of [¹⁸F]FFMZ allows for the production of up to 7 GBq of this PET‐tracer, enough to serve several patients. [¹⁸F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of 2‐[(2‐chloro‐2′‐[18F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (18F‐fluorocyclophosphamide), a potential tracer for breast tumor prognostic imaging with PET

A fluorine‐18 labeled analog of the widely used chemotherapeutic agent cyclophosphamide was synthesized as a tracer for prognostic imaging with positron emission tomography. 2‐[(2‐Chloro‐2′‐[¹⁸F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (¹⁸F‐fluorocyclophosphamide), was prepared by direct halogen exchange reaction from the parent cyclophosphamide. In small‐scale syntheses, radiochemical yields of up to 4.9% and specific activities of 960 Ci/mmol were achieved in a total synthesis time of 60–75 min. The [¹⁸F]‐labeled cyclophosphamide analog with radioactive purity >99% and chemical purity >96% was suitable for in vivo (microPET imaging) and ex vivo studies of a murine model of human breast tumors. Copyright © 2005 John Wiley & Sons, Ltd.     

Copper‐mediated reduction of 2‐[18F]fluoroethyl azide to 2‐[18F]fluoroethylamine

¹⁸F‐labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing amine, amide, and N‐heterocyclic moieties. Herein, we report that 2‐[¹⁸F]fluoroethylamine can be obtained from 2‐[¹⁸F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved in near quantitative analytical yields within 30 min by heating a solution of 2‐[¹⁸F]fluoroethyl azide in the presence of copper wire and aqueous trifluoroacetic acid. Subsequent reaction of 2‐[¹⁸F]fluoroethylamine with benzoyl chloride in the presence of triethylamine provided N‐[¹⁸F]fluoroethyl benzamide in 63% decay‐corrected radiochemical yield from 2‐[¹⁸F]fluoroethyl azide. The utility of the Cu(0)/H⁺ azide reduction method was further exemplified by preparation of the potential GABA_A tracer 9H‐β‐carboline N‐2‐[¹⁸F]fluoroethylamide, which was obtained in 46% decay‐corrected radiochemical yield by reaction of 2‐[¹⁸F]fluoroethylamine with the corresponding 9H‐β‐carboline pentafluorophenyl ester. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of 18F‐labelled biphenyls via SUZUKI cross‐coupling with 4‐[18F]fluoroiodobenzene

The SUZUKI reaction of organoboron compounds with 4‐[¹⁸F]fluoroiodobenzene has been developed as a novel radiolabelling technique in ¹⁸F chemistry. The cross‐coupling reaction of p‐tolylboronic acid with 4‐[¹⁸F]fluoroiodobenzene was used to screen different palladium complexes, bases and solvents. Optimized reaction conditions (Pd₂(dba)₃, Cs₂CO₃, acetonitrile, 60°C for 5 min) were further applied to the synthesis of various ¹⁸F‐labelled biphenyls bearing different functional groups. The reaction proceeded in excellent radiochemical yields of up to 94% within 5 min while showing good compatibility to many functional groups. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of the norepinephrine transporter tracer [18F]NS12137 via copper‐mediated 18F‐labelling

[¹⁸F]NS12137 (exo‐3‐[(6‐[¹⁸F]fluoro‐2‐pyridyl)oxy]8‐azabicyclo[3.2.1]octane) is a highly selective norepinephrine transporter (NET) tracer. NETs are responsible for the reuptake of norepinephrine and dopamine and are linked to several neurodegenerative and neuropsychiatric disorders. The aim of this study was to develop a copper‐mediated ¹⁸F‐fluorination method for the production of [¹⁸F]NS12137 with straightforward synthesis conditions and high radiochemical yield and molar activity. [¹⁸F]NS12137 was produced in two steps. Radiofluorination of [¹⁸F]NS12137 was performed via a copper‐mediated pathway starting with a stannane precursor and using [¹⁸F]F^? as the source of the fluorine‐18 isotope. Deprotection was performed via acid hydrolysis. The radiofluorination reaction was nearly quantitative as was the deprotection based on HPLC analysis. The radiochemical yield of the synthesis was 15.1 ± 0.5%. Molar activity of [¹⁸F]NS12137 was up to 300 GBq/μmol. The synthesis procedure is straightforward and can easily be automated and adapted for clinical production.     

Radiosynthesis of 4‐[18F]fluoromethyl‐L‐phenylalanine and [18F]FET via a same strategy and automated synthesis module

Currently there is still a need for more potent amino acid analogues as tumour imaging agents for peripheral tumour imaging with PET as it was recently reported that the success of O‐(2′‐[¹⁸F]fluoroethyl)‐L ‐tyrosine ([¹⁸F]FET) is limited to brain, head and neck tumours. As the earlier described 2‐Amino‐3‐(2‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (2‐[¹⁸F]FMP) suffered from intramolecular‐catalysed defluorination, we synthesized 2‐Amino‐3‐(4‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (4‐[¹⁸F]FMP) as an alternative for tumour imaging with PET. Radiosynthesis of 4‐[¹⁸F]FMP, based on Br for [¹⁸F] aliphatic nucleophilic exchange, was performed with a customized modular Scintomics automatic synthesis hotbox^three system in a high overall yield of 30% and with a radiochemical purity of \gt 99%. 4‐[¹⁸F]FMP was found to be stable in its radiopharmaceutical formulation, even at high radioactivity concentrations. Additionally, for a comparative study, [¹⁸F]FET was synthesized using the same setup in 40% overall yield, with a radiochemical purity \gt 99%. The described automated radiosynthesis allows the production of two different amino acid analogues with minor alternations to the parameter settings of the automated system, rendering this unit versatile for both research and clinical practice. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis of 3‐[18F]fluoropropyl and 4‐[18F]fluorobenzyl triarylphosphonium ions

3‐[¹⁸F]Fluoropropyl‐, 4‐[¹⁸F]fluorobenzyl‐triphenylphosphonium and 4‐[¹⁸F]fluorobenzyltris‐4‐dimethylaminophenylphosphonium cations were synthesized in multi‐step reactions from no carrier added (nca) [¹⁸F]fluoride. The time for synthesis, purification, and formulation was 56, 82, and 79 min with an average radiochemical yield of 12, 6 and 15%, respectively (not corrected for decay). The average specific radioactivity for the three radiolabeled compounds was 14.9 GB q/µmole (403 mCi/µmole) at end of synthesis (EOS). Copyright © 2004 John Wiley & Sons, Ltd.     

Radiosynthesis of novel 18F‐labelled derivatives of indiplon as potential GABAA receptor imaging tracers for PET

The involvement of gamma amino butyric acid (GABA) receptors in a variety of neurological and psychiatric diseases has promoted the development and use of radiolabelled benzodiazepines (BZ) for brain imaging by PET. However, these radioligands are unable to distinguish between the various subtypes of GABA_A receptors. Novel non‐BZ such as the pyrazolo‐pyrimidine indiplon proved to be selective for the α₁‐subunit of the GABA_A receptor. Here, we describe the syntheses of four novel ¹⁸F‐labelled indiplon derivatives. Radiosyntheses were performed via n.c.a. ¹⁸F‐nucleophilic substitution starting from the tosyl, bromo, and 4‐nitrobenzoyl precursors to obtain fluorine substituted N‐alkylamide side chain derivatives of indiplon, followed by multistep purification using semi‐preparative high‐performance liquid chromatography and solid phase extraction. Tosyl and bromo precursors were converted into ¹⁸F‐labelled indiplon derivatives with good and reproducible radiochemical yield (RCY) (35–70%, decay corrected), high radiochemical purity (≥98.5%), and high specific activity ( > 150 GBq/µmol). By contrast, a low RCY (5–10%) and specific activity (10–15 GBq/µmol) were achieved for the 4‐nitrobenzoyl precursor. Copyright © 2008 John Wiley & Sons, Ltd.     

Radiosynthesis and ‘click’ conjugation of ethynyl‐4‐[18F]fluorobenzene — an improved [18F]synthon for indirect radiolabeling

Reproducible methods for [¹⁸F]radiolabeling of biological vectors are essential for the development of new [¹⁸F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi‐step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [¹⁸F]radiolabeling of such molecules, our group has synthesized ethynyl‐4‐[¹⁸F]fluorobenzene ([¹⁸F]2, [¹⁸F]EYFB) in a single step (14 ± 2% non‐decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne‐functionalized synthon [¹⁸F]2 was then conjugated to two azido‐functionalized vector molecules via CuAAC reactions. The first ‘proof of principle’ conjugation of [¹⁸F]2 to 1‐azido‐1‐deoxy‐β‐d ‐glucopyranoside (3) gave the desired radiolabeled product [¹⁸F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [¹⁸F]2 to matrix‐metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [¹⁸F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [¹⁸F]4 and [¹⁸F]6 including [¹⁸F]F^? drying, two‐step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [¹⁸F]2 and the conjugated products, [¹⁸F]4 and [¹⁸F]6, were all greater than 98%. The specific activities of [¹⁸F]2 and [¹⁸F]6 were low, 5.97 and 0.17 MBq nmol^?1, respectively.     

Radiosynthesis of 1′‐[18F]fluoroethyl‐β‐D‐lactose ([18F]‐FEL) for early detection of pancreatic carcinomas with PET

Introduction: The hepatocellular carcinoma–intestine–pancreas and pancreatitis‐associated proteins, also known as lactose‐binding protein, is upregulated in peritumoral pancreatic tissue. Previously, we reported ethyl‐ β ‐D ‐galactopyranosyl‐(1,4′)‐2′‐deoxy‐2′‐[¹⁸F]fluoro‐ β ‐D ‐glucopyranoside (Et‐[¹⁸F]‐FDL), a radiofluorinated lactose analog for positron emission tomography (PET) of small pancreatic carcinomas in mice. However, synthesis of the precursor for Et‐[¹⁸F]‐FDL involves 11 steps, which is quite lengthy, and produces overall low yields. Here, we report on synthesis and radiolabeling of another analog of lactose, the 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose for PET imaging of pancreatic carcinomas. Methods: Two precursor compounds, 1′‐bromoethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose 4, and 1′‐p‐toluenesulfonylethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose 5, were synthesized in two and three steps, respectively; then, cold fluorination and radiofluorination of these precursors were performed. The reaction mixture was passed through a silica gel Sep‐pack cartridge, eluted with EtOAc, and the 1′‐[¹⁸F]fluoroethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose ([¹⁸F]‐6) purified by HPLC. After hydrolysis of the protecting groups, the 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose [¹⁸F]‐7 was neutralized, diluted with saline, filtered through a sterile Millipore filter, and analyzed by radio‐TLC. Results: The average decay‐corrected radiochemical yield was 9% (n = 7) with>99% radiochemical purity and specific activity of 55.5 GBq/ µ mol. Conclusion : A new analog of lactose, 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose, has been synthesized in good yields, with high purity and high specific activity suitable for PET imaging of early pancreatic carcinomas. Copyright © 2011 John Wiley & Sons, Ltd.     

Radiosynthesis of 6‐([18F]fluoroacetamido)‐1‐hexanoicanilide ([18F]FAHA) for PET imaging of histone deacetylase (HDAC)

Radiosynthesis of a novel substrate for histone deacetylase (HDAC), 6‐([¹⁸F]fluoroacetamido)‐1‐hexanoicanilide ([¹⁸F]FAHA, [¹⁸F]‐ 3 ) is reported. For precursor synthesis, compound 1 (6‐amino‐1‐hexanoicanilide) was prepared by the reaction of 6‐amino hexanoic acid with thionyl chloride in dichloroethane followed by addition of aniline. Compound 1 was reacted with bromoacetic anhydride in tetrahydrofuran (THF) in the presence of triethylamine to produce the precursor compound 6‐(bromoacetamido)‐1‐hexanoicanilide 2 . Fluorination reactions were performed using tetrabutylammonium fluoride in various solvents at 80°C to prepare the unlabeled reference compound 3 . Radiofluorinations were performed using either n‐Bu₄N¹⁸F or K¹⁸F/kryptofix, and the crude product was purified by high performance liquid chromatography (HPLC). The radiochemical yields were 9–13% decay corrected (d.c.) with an average of 11% using K¹⁸F/kryptofix, and specific activity >2 GBq/µmol at the end of synthesis. The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

Efficient Radiosynthesis of 2-[18F]Fluoroadenosine: A New Route to 2-[18F]Fluoropurine Nucleosides

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Radiosynthesis of 3‐(3‐[18F]fluoropropoxy)‐4‐(benzyloxy)‐N‐[(1‐dimethylaminocyclopentyl)methyl]‐5‐methoxybenzamide,a potential PET radiotracer for the glycine transporter GlyT‐2

The recently described selective and potent GlyT2 antagonist, 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide (IC₅₀=16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT‐2 transporter, 3‐(3‐[¹⁸F]fluoropropoxy)‐4‐(benzyloxy)‐N‐((1‐dimethylaminocyclopentyl) methyl)‐5‐methoxybenzamide ([¹⁸F] 3 ), a novel analog of 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one‐pot, two‐step method. The NCA radiofluorination of 1,3‐propanediol di‐p‐tosylate in the presence of K₂CO₃ and Kryptofix‐222 in acetonitrile gave 81% 3‐[¹⁸F]fluoropropyl tosylate, which was subsequently coupled with 4‐benzyloxy‐3‐hydroxy‐5‐methoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB‐C8 column, 80/20/0.1 MeOH/H₂O/Et₃N, 3.0 ml/min) gave [¹⁸F] 3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0–16.2% at EOS, and the specific activity was 1462±342 GBq/µmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of 11‐[18F]fluoroundecyltriphenylphosphonium (MitoF) as a potential mitochondria‐specific positron emission tomography radiotracer

Changes in the magnitude of the mitochondrial membrane potential occur in a range of important pathologies. To assess changes in membrane potential in patients, we set out to develop an improved mitochondria‐targeted positron emission tomography probe comprising a lipophilic triphenylphosphonium cation attached to a fluorine‐18 radionuclide via an 11‐carbon alkyl chain, which is well‐established to effectively transport to and localise within mitochondria. Here, we describe the radiosynthesis of this probe, 11‐[¹⁸F]fluoroundecyl‐triphenylphosphonium (MitoF), from no‐carrier‐added [¹⁸F]fluoride and a fully automated synthetic protocol to prepare it in good radiochemical yields (2–3 GBq at end‐of‐synthesis) and radiochemical purity (97–99%). Copyright © 2013 John Wiley & Sons, Ltd.     

Initial experience in synthesis of (2S,4R)‐4‐[18F]fluoroglutamine for clinical application

We report initial experience in synthesis of (2S,4R)‐4‐[¹⁸F]fluoroglutamine, [¹⁸F]FGln, which has been used as a tool for monitoring glutamine metabolism in cancer patients. [¹⁸F]FGln was prepared by a fully automated PET‐MF‐2V‐IT‐I synthesizer under GMP‐compliant conditions for routine clinical studies. The total radiosynthesis time was about 65 minutes, the decay‐corrected radiochemical yield was 18.0 ± 4.2% (n = 59; failure n = 15), and the radiochemical purity was greater than 90%. In some situations, the yields were low (less than 5%), and the most likely cause of this problem is the initial fluorination step; the fluoride ion might not have been fully activated. In other occasions, low final radiochemical purity was often associated with the failure of the second step—removal of protection groups by anhydrous trifluoroacetic acid. A trace amount of water led to production of undesired 4‐[¹⁸F]fluoroglutamic acid. Knowledge learned from the successes and failures of synthesis may be helpful to identify critical steps and pitfalls for preparation of this clinically useful metabolic probe, [¹⁸F]FGln, for imaging glutamine utilization in tumor of cancer patients.     

Synthesis of 6‐acrylamido‐4‐(2‐[18F]fluoroanilino)quinazoline: a prospective irreversible EGFR binding probe

Acrylamido‐quinazolines substituted at the 6‐position bind irreversibly to the intracellular ATP binding domain of the epidermal growth factor receptor (EGFR). A general route was developed for preparing 6‐substituted‐4‐anilinoquinazolines from [¹⁸F]fluoroanilines for evaluation as EGFR targeting agents with PET. By a cyclization reaction, 2‐[¹⁸F]fluoroaniline was reacted with N′‐(2‐cyano‐4‐nitrophenyl)‐N,N‐dimethylimidoformamide to produce 6‐nitro‐4‐(2‐[¹⁸F]fluoroanilino)quinazoline in 27.5% decay‐corrected radiochemical yield. Acid mediated tin chloride reduction of the nitro group was achieved in 5 min (80% conversion) and subsequent acylation with acrylic acid gave 6‐acrylamido‐4‐(2‐[¹⁸F]fluoroanilino)quinazoline in 8.5% decay‐corrected radiochemical yield, from starting fluoride, in less than 2 h. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of [18F]‐labeled N‐3(substituted) thymidine analogues: N‐3([18F]fluorobutyl) thymidine ([18F]‐FBT) and N‐3([18F]fluoropentyl) thymidine ([18F]‐FPT) for PET

Syntheses of N‐3(substituted) analogues of thymidine, N‐3([¹⁸F]fluorobutyl)thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl)thymidine ([¹⁸F]‐FPT) are reported. 1,4‐Butane diol and 1,5 pentane diol were converted to their tosyl derivatives 2 and 3 followed by conversion to benzoate esters 4 and 5, respectively. Protected thymidine 1 was coupled separately with 4 and 5 to produce 6 and 7 , which were hydrolyzed to 8 and 9 , then converted to their mesylates 10 and 11 , respectively. Compounds 10 and 11 were fluorinated with n‐Bu₄N[¹⁸F] to produce 12 and 13 , which by acid hydrolysis yielded 14 and 15 , respectively. The crude products were purified by HPLC to obtain [¹⁸F]‐FBT and [¹⁸F]‐FPT. The radiochemical yields were 58–65% decay corrected (d.c.) for 14 and 46–57% (d.c.) for 15 with an average of 56% in three runs per compound. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 65–75 min from the end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

A fully automated synthesis of [18F]‐FEAU and [18F]‐FMAU using a novel dual reactor radiosynthesis module

2′‐Deoxy‐2′‐[¹⁸F]fluoro‐5‐substituted‐1‐β‐D ‐arabinofuranosyluracils, including 2′‐deoxy‐2′‐[¹⁸F]fluoro‐5‐methyl‐1‐β‐D ‐arabinofuranosyluracil [¹⁸F]FMAU and [¹⁸F]FEAU are established radiolabeled probes to monitor cellular proliferation and herpes simplex virus type 1 thymidine kinase (HSV1‐tk) reporter gene expression with positron emission tomography. For clinical applications, a fully automated CGMP‐compliant radiosynthesis is necessary for production of these probes. However, due to multiple steps in the synthesis, no such automated synthetic protocols have been developed. We report here a fully automated synthesis of [¹⁸F]‐FEAU and [¹⁸F]‐FMAU on a prototype dual reactor module TRACERlab FX FN. The synthesis was performed by using a computer‐programmed standard operating procedure, and the product was purified on a semipreparative high‐performance liquid chromatography (HPLC) integrated with the synthesis module using 12% EtOH in 50 mM Na₂HPO₄. Finally, the percentage of alcohol was adjusted to 7% by adding Na₂HPO₄ and filtered through a Millipore filter to make dose for human. The radiochemical yield on the fluorination was 40±10% (n=10), and the overall yields were 4±1% (d. c.), from the end of the bombardment; [¹⁸F]FEAU (n=7) and [¹⁸F]FMAU (n=3). The radiochemical purity was >99%, specific activity was 1200–1300 mCi/µmol. The synthesis time was 2.5 h. This automated synthesis should be suitable for production of [¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, [¹⁸F]FBAU and other 5‐substitued thymidine analogues. Copyright © 2009 John Wiley & Sons, Ltd.