Synthesis of 4‐[18F]fluoroiodobenzene and its application in sonogashira cross‐coupling reactions

The first application of a Sonogashira cross‐coupling reaction in ¹⁸F chemistry has been developed. The reaction was exemplified by the cross‐coupling of terminal alkynes (ethynylcyclopentyl carbinol 6 , 17α‐ethynyl‐3,17β‐estradiol 7 and 17α‐ethynyl‐3‐methoxy‐3,17β‐estradiol 8 ) with 4‐[¹⁸F]fluoroiodobenzene. 4,4′‐Diiododiaryliodonium salts were used as precursors for the synthesis of 4‐[¹⁸F]fluoroiodobenzene, enabling the convenient access to 4‐[¹⁸F]fluoroiodobenzene in 13–70% yield using conventional heating or microwave activation. The Sonogashira cross‐coupling of 4‐[¹⁸F]fluoroiodobenzene with terminal alkynes gave the corresponding 4‐[¹⁸F]fluorophenylethynyl‐substituted compounds [¹⁸F]‐9 , [¹⁸F]‐10 and [¹⁸F]‐13 in yields up to 88% within 20 min of starting from 4‐[¹⁸F]fluoroiodobenzene. Copyright © 2003 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.     

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.     

[18F]Fluoride recovery via gaseous [18F]HF

Acidification of target water with H₂SO₄ in a specially constructed glassy carbon/polyethylene apparatus allowed for recovery of up to 82% of [¹⁸F]fluoride as [¹⁸F]HF gas. The [¹⁸F]HF distillate was found to be acid‐free but moist; when passed through a solution of ^tBuPh₂SiOTf, it yielded [¹⁸F]^tBuPh₂SiF. The multivariate design of experiment showed that the key to high yield of [¹⁸F]HF was the efficient degassing of the reaction mixture.     

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.     

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 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.     

Baeyer‐Villiger oxidation tuned to chemoselective conversion of non‐activated [18F]fluorobenzaldehydes to [18F]fluorophenols

A reaction pathway via oxidation of [¹⁸F]fluorobenzaldehydes offers a very useful tool for the no‐carrier‐added radiosynthesis of [¹⁸F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer‐Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2‐trifluoroethanol as reaction solvent in combination with Oxone or m‐CPBA as oxidation agent. The studies showed the necessity of H₂SO₄ addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2‐[¹⁸F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30‐minute reaction time. The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [¹⁸F]fluorophenols rather than [¹⁸F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron‐deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4‐[¹⁸F]fluorophenol (RCY 95%; relating to 4‐[¹⁸F]fluorobenzaldehyde) and 4‐[¹⁸F]fluoro‐m‐tyramine (RCY 32%; relating to [¹⁸F]fluoride), respectively.     

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.     

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.     

Access to 18F‐labelled isoxazoles by ruthenium‐promoted 1,3‐dipolar cycloaddition of 4‐[18F]fluoro‐N‐hydroxybenzimidoyl chloride with alkynes

4‐[¹⁸F]Fluoro‐N‐hydroxybenzimidoyl chloride (¹⁸FBIC), an ¹⁸F‐labelled aromatic nitrile oxide, was developed as building block for Ru‐promoted 1,3‐dipolar cycloaddition with alkynes. ¹⁸FBIC is obtained in a one‐pot synthesis in up to 84% radiochemical yield (RCY) starting from [¹⁸F]fluoride with 4‐[¹⁸F]fluorobenzaldehyde (¹⁸FBA) and 4‐[¹⁸F]fluorobenzaldehyde oxime (¹⁸FBAO) as intermediates, by reaction of ¹⁸FBAO with N‐chlorosuccinimide (NCS). ¹⁸FBIC was found to be a suitable and stable synthon to give access to ¹⁸F‐labelled 3,4‐diarylsubstituted isoxazoles by [Cp*RuCl(cod)]‐catalysed 1,3‐dipolar cycloaddition with various alkynes. So the radiosynthesis of a fluorine‐18–labelled COX‐2 inhibitor [¹⁸F] 1b , a close derivative of valdecoxib, was performed with ¹⁸FBIC and 1‐ethynyl‐4‐(methylsulfonyl)benzene, providing [¹⁸F] 1b in up to 40% RCY after purification in 85 minutes. The application of ¹⁸FBIC as a building block in the synthesis of ¹⁸F‐labelled heterocycles will generally extend the portfolio of available PET radiotracers.     

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 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.     

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 of [18F]fluoroacetaldehyde. Application to [18F]fluoroethylation of benzylamine under reductive alkylation conditions

The radiosynthesis of a new [¹⁸F]fluoroalkylating agent, [¹⁸F]fluoroacetaldehyde, is described. It was produced using the Kornblum method by oxidation with dimethyl sulphoxide of 2‐[¹⁸F]fluoroethyl p‐toluenesulphonate ([¹⁸F]FETos). In these conditions the oxidation proceeds smoothly and rapidly to the selective conversion of tosyl esters of primary alcohols to aldehydes with no carboxylic acids being produced. The chemical identity of [¹⁸F]fluoroacetaldehyde was determined by comparing its chromatographic properties as well as those of its 2,4‐dinitrophenylhydrazone (2,4‐DNPH) derivative with those of, respectively, the standard fluoroacetaldehyde and its 2,4‐DNPH derivative. Standard fluoroacetaldehyde was prepared by oxidation of fluoroethanol with pyridinium dichromate and characterized as its 2,4‐DNPH derivative by mass spectrometry. To test its reactivity with amines under reductive alkylation conditions, [¹⁸F]fluoroacetaldehyde was reacted with benzylamine used as model substrate. The chemical identity of the resulting radiolabelled product was determined to be [¹⁸F]N‐(2‐fluoroethyl)‐benzylamine by comparing its chromatographic properties with those of the synthesized standard N‐(2‐fluoroethyl)‐benzylamine characterized by ¹⁹F and ¹H NMR spectroscopy and mass spectrometry. This new fluorine‐18 labelled synthon may find applications in radiolabelling peptide, protein and antibody fragments as well as in aldol condensation or in the Mannich reaction. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,radiofluorination, and preliminary evaluation of the potential 5‐HT2A receptor agonists [18F]Cimbi‐92 and [18F]Cimbi‐150

An agonist PET tracer is of key interest for the imaging of the 5‐HT_2A receptor, as exemplified by the previously reported success of [¹¹C]Cimbi‐36. Fluorine‐18 holds several advantages over carbon‐11, making it the radionuclide of choice for clinical purposes. In this respect, an ¹⁸F‐labelled agonist 5‐HT_2A receptor (5‐HT_2AR) tracer is highly sought after. Herein, we report a 2‐step, 1‐pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5‐HT_2AR. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5‐HT_2AR; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within‐scan displacement challenge with a 5‐HT_2AR antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5‐HT_2AR.     

Synthesis of [18F]‐6‐deoxy‐6‐fluoro‐D‐glucose ([18F]6FDG), a potential tracer of glucose transport

With the goal of developing a PET radioligand for the in vivo assessment of glucose transport, 6-deoxy-6-[¹⁸F]fluoro-D -glucose ([¹⁸F]6FDG) was prepared in two steps from ¹⁸F⁻. Starting with D -glucose, the tosyl- and mesyl-derivatives of 3,5-O-benzylidene-1,2-O-isopropylidene-α-D -glucofuranose were prepared by known methods. Reaction of either of these precursors with ¹⁸F⁻ resulted in the formation of 3,5-O-benzylidene-6-deoxy-6-[¹⁸F]-fluoro-1,2-O-isopropylidene-α-D -glucofuranose in high yield. Subsequent hydrolysis resulted in the production of [¹⁸F]6FDG. Under optimal conditions, [¹⁸F]6FDG is produced 60–70 min after end of bombardment (EOB) in 71 ± 12% yield (decay corrected, based upon fluoride) with a radiochemical purity of ⩾96%. Preliminary experiments have indicated that [¹⁸F]6FDG may be a more representative in vivo tracer for the glucose transporter than 2FDG. Copyright © 2005 John Wiley & Sons, Ltd.