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.     

No‐carrier added synthesis of 18F‐labelled nucleosides using Stille cross‐coupling reactions with 4‐[18F]fluoroiodobenzene

The radiosyntheses of 5‐(4′‐[¹⁸F]fluorophenyl)‐uridine [¹⁸F]‐11 and 5‐(4′‐[¹⁸F]fluorophenyl)‐2′‐deoxy‐uridine [¹⁸F]‐12 are described. The 5‐(4′‐[¹⁸F]fluoro‐phenyl)‐substituted nucleosides were prepared via a Stille cross‐coupling reaction with 4‐[¹⁸F]fluoroiodobenzene followed by basic hydrolysis using 1 M potassium hy‐droxide. The Stille cross‐coupling reaction was optimized by screening various palladium complexes, additives and solvents. By using optimized labelling conditions (Pd₂(dba)₃/CuI/AsPh₃ in DMF/dioxane (1:1), 20 min at 65°C), 550 MBq of [4‐¹⁸F]fluoroiodobenzene could be converted into 120 MBq (33%, decay‐corrected) of 5‐(4′‐[¹⁸F]fluorophenyl)‐2′‐deoxy‐uridine [¹⁸F]‐12 within 40 min, including HPLC purification. Copyright © 2004 John Wiley & Sons, Ltd.     

Automated radiosynthesis of no‐carrier‐added 4‐[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry

4‐[¹⁸F]Fluoroiodobenzene ([¹⁸F]FIB) is a versatile building block in ¹⁸F radiochemistry used in various transition metal‐mediated C–C and C–N cross‐coupling reactions and [¹⁸F]fluoroarylation reactions. Various synthesis routes have been described for the preparation of [¹⁸F]FIB. However, to date, no automated synthesis of [¹⁸F]FIB has been reported to allow access to larger amounts of [¹⁸F]FIB in high radiochemical and chemical purity. Herein, we describe an automated synthesis of no‐carrier‐added [¹⁸F]FIB on a GE TRACERlab? FX automated synthesis unit starting from commercially available (4‐iodophenyl)diphenylsulfonium triflate as the labelling precursor. [¹⁸F]FIB was prepared in high radiochemical yields of 89 ± 10% (decay‐corrected, n = 7) within 60 min, including HPLC purification. The radiochemical purity exceeded 95%, and specific activity was greater than 40 GBq/µmol. Typically, from an experiment, 6.4 GBq of [¹⁸F]FIB could be obtained starting from 10.4 GBq of [¹⁸F]fluoride. Copyright © 2013 John Wiley & Sons, Ltd.     

N‐Arylation of indoles with 4‐[18F]fluoroiodobenzene: synthesis of 18F‐labelled σ2 receptor ligands for positron emission tomography (PET)

The palladium‐mediated N‐arylation of indoles with 4‐[¹⁸F]fluoroiodobenzene as a novel radiolabelling method has been developed. Optimized reaction conditions were elaborated by variation of different catalyst systems (CuI/1,2‐diamines and Pd₂(dba)₃/phosphine ligands), bases and solvents in the reaction of indole with 4‐[¹⁸F]fluoroiodobenzene. Optimized reaction conditions (Pd₂(dba)₃/(2‐(dicyclohexyl‐phosphino)‐2′‐(N,N‐dimethylamino)‐biphenyl, NaOBu^t, toluene, 100°C for 20 min) were applied for the synthesis of ¹⁸F‐labelled σ₂ receptor ligands [¹⁸F]‐11 and [¹⁸F]‐13 which were obtained in 91 and 84% radiochemical yields, respectively. Copyright © 2004 John Wiley & Sons, Ltd.     

4‐[18F]fluorophenyl ureas via carbamate‐4‐nitrophenyl esters and 4‐[18F]fluoroaniline

Four different no carrier added (n.c.a.) 4‐[¹⁸F]fluorophenylurea derivatives are synthesized as model compounds via two alternative routes. In both cases carbamate‐4‐nitrophenylesters are used as intermediates. Either n.c.a. 4‐[¹⁸F]fluoroaniline reacts with carbamates of several amines, or the carbamate of n.c.a. 4‐[¹⁸F]fluoroaniline is formed at first and an amine is added subsequently to yield the urea derivative. The choice of the appropriate way of reaction depends on the possibilities of precursor synthesis. The radiochemical yields reach up to 80% after 50 min of synthesis time while no radiochemical by‐products can be determined. These high yields were possible due to an optimized preparation of n.c.a. 4‐[¹⁸F]fluoroaniline with a radiochemical yield of up to 90%. From the various ways of its radiosynthesis, the substitution with n.c.a. [¹⁸F]fluoride on dinitrobenzene is chosen, using phosphorous acid and palladium black for reduction of the second nitro group. Copyright © 2006 John Wiley & Sons, Ltd.     

Hydroacylation of 4‐[18F]fluorobenzaldehyde: a novel method for the preparation of 4′‐[18F]phenylketones

To assess the potential of intermolecular hydroacylation reactions as a new fluorine‐18 labeling method, model reactions of [¹⁸F]fluorobenzaldehyde with three different olefins (1‐hexene ( 2a ), allylbenzene ( 2b ), and 3‐phenoxypropene ( 2c )) in the presence of Wilkinson's catalyst were performed. The procedure gave high radiochemical yields (38–62%) of [¹⁸F]fluorophenylketones with short reaction times (15 min). The intermolecular hydroacylation reaction provides a new method for the preparation of fluorine‐18 labeled compounds. Copyright © 2002 John Wiley & Sons, Ltd.     

Automated production at the curie level of no‐carrier‐added 6‐[18F]fluoro‐ l‐dopa and 2‐[18F]fluoro‐ l‐tyrosine on a FASTlab synthesizer

An efficient, fully automated, enantioselective multi‐step synthesis of no‐carrier‐added (nca) 6‐[¹⁸F]fluoro‐L‐dopa ([¹⁸F]FDOPA) and 2‐[¹⁸F]fluoro‐L‐tyrosine ([¹⁸F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high‐ performance liquid chromatography (HPLC) purification has been developed. A PTC (phase‐transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand‐alone HPLC. [¹⁸F]FDOPA and [¹⁸F]FTYR were produced in 36.3 ± 3.0 % (n = 8) and 50.5 ± 2.7 % (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95 %, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [¹⁸F]FDOPA and [¹⁸F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment.     

Alternative solvents for electrophilic synthesis of 6‐[18F]fluoro‐L‐DOPA

Owing to the ozone layer‐depleting properties of chlorofluorocarbon compounds, alternative solvents for electrophilic fluorination reactions are desirable. Chloroform, dichloromethane, acetone or their deuterated analogues were examined as substitutes for Freon‐11 in the electrophilic synthesis of 6‐[¹⁸F]fluoro‐L ‐DOPA ([¹⁸F]FDOPA). CDCl₃, CD₂Cl₂ and C₃D₆O were found to be suitable solvents in this reaction, with the deuterated solvents providing significantly higher yields than Freon‐11. There were no differences among the solvents in the specific radioactivity, the radiochemical purity, the chemical purity or the microbiological quality of the final product. However, the radiochemical yield of [¹⁸F]FDOPA was increased when acetic acid was added to the precursor solution prior to the fluorination reaction. Copyright © 2009 John Wiley & Sons, Ltd.     

Application of n.c.a. 4‐[18F]fluorophenol in diaryl ether syntheses of 2‐(4‐[18F]fluorophenoxy)‐benzylamines

The availability of no‐carrier‐added (n.c.a.) 4‐[¹⁸F]fluorophenol offers the possibility of introducing the 4‐[¹⁸F]fluorophenoxy moiety into potential radiopharmaceuticals. Besides alkyl–aryl ether synthesis using n.c.a. 4‐[¹⁸F]fluorophenol the diaryl ether coupling is an attractive synthetic method to enlarge the spectrum of interesting labelling procedures. As examples the syntheses of n.c.a. 2‐(4‐[¹⁸F]fluorophenoxy)‐N,N‐dimethylbenzylamine and n.c.a. 2‐(4‐[¹⁸F]fluorophenoxy)‐N‐methylbenzylamine were realized by an Ullmann ether synthesis of corresponding 2‐bromobenzoic acid amides using tetrakis(acetonitrile)copper(I) hexafluorophosphate as catalyst and a subsequent reduction of the amides formed. The radiochemical yield of the coupling varied between 5 and 65% based on labelled 4‐[¹⁸F]fluorophenol. Both compounds are structural analogues of recently published radiotracers for imaging the serotonin reuptake transporter sites (SERT). However, in vitro binding assays of both molecules showed only a low affinity towards monoamine transporters. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and stability of S‐(2‐[18F]fluoroethyl)‐L‐homocysteine for potential tumour imaging

The F‐18 labelled methionine derivative S‐(2‐[¹⁸F]fluoroethyl)‐L‐homocysteine ([¹⁸F]FEHCys) was prepared by a one‐pot two‐step synthesis via the protected S‐(2‐bromoethyl)‐L‐homocysteine 1 and S‐(2‐chloroethyl)‐L‐homocysteine 2 precursors. The bromoethyl derivative 1 gave higher radiochemical yields (40% at 5 min) at 100°C compared with the chloro‐analogue (22% at 100°C in 30 min). However, [¹⁸F]FEHCys was found to be unstable in aqueous systems being transformed to the corresponding hydroxyl derivative within 20 min. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of a phenolic precursor and its efficient O‐[18F]fluoroethylation with purified no‐carrier‐added [18F]2‐fluoroethyl brosylate as the labeling agent

[¹⁸F]2‐Fluoroethyl‐p‐toluenesulfonate also called [¹⁸F]2‐fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [¹⁸F]2‐Fluoroethyl‐4‐bromobenzenesulfonate, also called [¹⁸F]2‐fluoroethyl brosylate ([¹⁸F]F(CH₂)₂OBs), was used as an alternative radiolabeling agent to prepare [¹⁸F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O‐fluoroethylating the phenolic precursor. Purified by reverse‐phase HPLC, the no‐carrier‐added [¹⁸F]F(CH₂)₂OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried [¹⁸F]F(CH₂)₂OBs with the phenolic precursor was performed by heating in DMF and successfully produced [¹⁸F]FEOHOMADAM, after HPLC purification, in RCY of 21%. Copyright © 2013 John Wiley & Sons, Ltd.     

Fully automated,high yielding production of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB), and its use in microwave‐enhanced radiochemical coupling reactions

A General Electric Medical Systems (GEMS) Tracerlab FX_FN fluorine‐18 synthesis module has been reconfigured to allow rapid (45 min), fully automated production of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) using the established three‐step, one‐pot synthesis procedure. Purification is by sep‐pak only and [¹⁸F]SFB is routinely obtained in 38% non‐decay corrected yield,>1 Ci/µmol specific activity, and >95% radiochemical purity (n=20). Moreover, this report includes our preliminary research efforts into improving peptide coupling reactions with [¹⁸F]SFB using microwave‐enhanced radiochemistry. Reaction times can be reduced by>90%, when compared with traditional thermal reactions, with no significant effect on radiochemical reaction yield. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 2‐[18F]fluoroadenosine (2‐[18F]FAD) as potential radiotracer for studying malignancies by PET

2‐[¹⁸F]fluoroadenosine (2‐[¹⁸F]FAD), a potential radioligand for assessment of adenylate metabolism, was synthesized by carrier‐added and no‐carrier‐added procedures via nucleophilic radiofluorination of 2‐fluoroadenosine and 2‐iodoadenosine. The radiochemical yield, specific radioactivity and radiochemical purity of carrier‐added and no‐carrier‐added 2‐[¹⁸F]FAD were 5%, 22–30 mCi/µmol and 99%, and 0.5%, 1200–1700 mCi/µmol and 99%, respectively. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 18F‐labelled stilbenes from 4‐[18F]fluorobenz‐aldehyde using the Horner–Wadsworth–Emmons reaction

The first application of the Horner–Wadsworth–Emmons reaction in ¹⁸F‐chemistry is described. This carbonyl‐olefination reaction was performed via a ‘multi‐step/one‐pot’ reaction by the coupling of benzylic phosphonic acid esters (3,5‐bis‐methoxymethoxybenzyl)‐phosphonic acid diethyl ester 2e , (4‐methoxy‐methoxybenzyl)‐phosphonic acid diethyl ester 3e and (4‐dimethyl‐aminobenzyl)phosphonic acid diethyl ester 4d ) with 4‐[¹⁸F]fluorobenzaldehyde to give the corresponding ¹⁸F‐labelled stilbenes [¹⁸F]2g , [¹⁸F]3g and [¹⁸F]4e exclusively as the expected E‐isomers. The radiochemical yields ranged from 9% to 22% (based upon [¹⁸F]fluoride, including HPLC purification). The specific activity reached up to 90 GBq/µmol. Copyright © 2007 John Wiley & Sons, Ltd.     

A facile automated synthesis of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB) for 18F‐labeled cell‐penetrating peptide as PET tracer

A fully automated synthesis of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) was carried out by a convenient three‐step, one‐pot procedure on the modified TRACERlab FX_FN synthesizer, including [¹⁸F]fluorination of ethyl 4‐(trimethylammonium triflate)benzoate as the precursor, saponification of the ethyl 4‐[¹⁸F]fluorobenzoate with aqueous tetrapropylammonium hydroxide instead of sodium hydroxide, and conversion of 4‐[¹⁸F]fluorobenzoate salt ([¹⁸F]FBA) to [¹⁸F]SFB treated with N,N,N′,N′‐tetramethyl‐O‐(N‐succinimidyl)uranium tetrafluoroborate (TSTU). The purified [¹⁸F]SFB was used for the labeling of Tat membrane‐penetrating peptide (containing the Arg‐Lys‐Lys‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Pro‐Leu‐Gly‐Leu‐Ala‐Gly‐Glu‐Glu‐Glu‐Glu‐Glu‐Glu‐Glu sequence, [¹⁸F]CPP) through radiofluorination of lysine amino groups. The uncorrected radiochemical yields of [¹⁸F]SFB were as high as 25–35% (based on [¹⁸F]fluoride) (n=10) with a synthesis time of～40 min. [¹⁸F]CPP was produced in an uncorrected radiochemical yields of 10–20% (n=5) within 30 min (based on [¹⁸F]SFB). The radiochemical purities of [¹⁸F]SFB and [¹⁸F]CPP were greater than 95%. Copyright © 2010 John Wiley & Sons, Ltd.     

One‐step reductive etherification of 4‐[18F]fluoro‐benzaldehyde with decaborane

Reductive coupling reactions between 4‐[¹⁸F]fluoro‐benzaldehyde ([¹⁸F] 1 ) and different alcohols by use of decaborane (B₁₀H₁₄) as reducing agent have the potential to synthesize 4‐[¹⁸F]fluoro‐benzylethers in one step. [¹⁸F] 1 was synthesized from 4‐trimethylammonium benzaldehyde (triflate salt) via a standard fluorination procedure (K[¹⁸F]F/Kryptofix^® 222) in dimethylformamide at 90°C for 25 min and purified by solid‐phase extraction. Subsequently, reductive etherifications of [¹⁸F] 1 were performed as one‐step reactions with primary and secondary alcohols, mediated by B₁₀H₁₄ in acetonitrile at 60°C. Various 4‐[¹⁸F]fluorobenzyl ethers (6 examples are shown) were obtained within 1–2 h reaction time in decay‐corrected radiochemical yields of 12–45%. Copyright © 2006 John Wiley & Sons, Ltd.     

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‐(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.     

Comparison of pathways to the versatile synthon of no‐carrier‐added 1‐bromo‐4‐[18F]fluorobenzene

The availability of no‐carrier‐added (n.c.a.) 1‐bromo‐4‐[¹⁸F]fluorobenzene with high radiochemical yields is important for ¹⁸F‐arylation reactions using metallo‐organic 4‐[¹⁸F]fluorophenyl compounds (e.g. of lithium or magnesium) or Pd‐catalyzed coupling. In this study, different methods for the preparation of 1‐bromo‐4‐[¹⁸F]fluorobenzene by nucleophilic aromatic substitution reactions using n.c.a. [¹⁸F]fluoride were examined. Of six pathways compared, symmetrical bis‐(4‐bromphenyl)iodonium bromide proved most useful to achieve the title compound in a direct, one‐step nucleophilic substitution with a radiochemical yield (RCY) of 65% within 10 min. Copyright © 2004 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.