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.     

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.     

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.     

Efficient synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐[18F]fluoropyridin‐4‐yl)vinyl)pyridine ([18F]NIDA 52289), a very high affinity radioligand for nicotinic acetylcholine receptors

6‐Chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐[¹⁸F]fluoropyridin‐4‐yl)vinyl)pyridine ([¹⁸F]NIDA 52289), a very high affinity radioligand for studying nicotinic acetylcholine receptors (nAChRs) by positron‐emission tomography, was synthesized through Kryptofix 222 assisted no‐carrier‐added nucleophilic [¹⁸F]fluorination of 6‐chloro‐3‐((1‐(tert‐butoxycarbonyl)‐2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐bromopyridin‐4‐yl)vinyl)pyridine, followed by acidic deprotection. The overall radiochemical yield of the radiosynthesis was 10% (non‐decay‐corrected), the specific radioactivity was in the range of 93–326 GBq/µmol (2.5–8.8 mCi/µmol) and the radiochemical purity was greater than 99%. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of fluorine‐18‐labelled 5‐ and 6‐fluoro‐2‐pyridinamine

A one‐pot radiosynthesis method to prepare the new fluorine‐18‐labelled fluoropyridine derivatives 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine in two to three reaction steps was developed. The first step consisted of no‐carrier‐added nucleophilic aromatic substitution of commercially available halogen‐substituted 2‐pyridinecarboxamide or 2‐pyridinecarbonitrile derivatives with K[¹⁸F]F‐K₂₂₂ in DMSO at 150–180°C. The [¹⁸F]fluoride incorporation yields ranged from 67 to 98% for all studied precursor molecules. It is remarkable that 5‐bromo‐2‐pyridinecarbonitrile gave almost quantitative [¹⁸F]fluoride incorporation at the meta‐position (5‐position) of the pyridine ring after only 5 min of heating at 150°C. After base‐catalysed hydrolysis of the [¹⁸F]fluorinated pyridinecarbonitriles into their corresponding carboxamides, the latter were transformed in a Hofmann‐type rearrangement reaction into the respective amines by treatment of crude reaction mixtures with bromine and aqueous base (20–30% conversion yield). Reaction mixtures were purified by reversed‐phase semipreparative HPLC followed by strong cation exchange solid‐phase extraction to afford 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine in non‐decay‐corrected radiochemical yields of 6–10% in a total synthesis time of 83–112 min. The preparation of 5‐[¹⁸F]fluoro‐2‐pyridinamine is one of very few examples demonstrating the feasibility of nucleophilic meta‐[¹⁸F]fluorination of a pyridine derivative. Both 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine are new potentially useful radiolabelled synthons for radiopharmaceutical chemistry. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[18F]fluoropyridin‐4‐yl)pyridine ([18F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

6‐Chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[¹⁸F]fluoropyridin‐4‐yl)pyridine ([¹⁸F]NIDA 522131), a potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by positron‐emission tomography, was synthesized via no‐carrier‐added nucleophilic [¹⁸F]fluorination of 6‐chloro‐3‐((1‐(tert‐butoxycarbonyl)‐2‐(S)‐azetidinyl)methoxy)‐5‐(2‐iodopyridin‐4‐yl)vinyl)pyridine, followed by acidic deprotection. The overall radiochemical yield of the radiosynthesis was 4–8% (non‐decay‐corrected), the specific radioactivity was in the range of 167–335 GBq/µmol (4500–9000 mCi/µmol) and the radiochemical purity was greater than 99%. Preparation of [¹⁸F]NIDA522131 via corresponding bromo‐derivative 2 is also described. Copyright © 2004 John Wiley & Sons, Ltd.     

Automated synthesis and purification of [18F]fluoro‐[di‐deutero]methyl tosylate

Automated synthetic procedures of [¹⁸F]fluoro‐[di‐deutero]methyl tosylate on a GE TRACERlab FX F‐N module and a non‐commercial synthesis module have been developed. The syntheses included azeotropic drying of the [¹⁸F]fluoride, nucleophilic ¹⁸F‐fluorination of bis(tosyloxy)‐[di‐deutero]methane, HPLC purification and subsequent formulation of the synthesized [¹⁸F]fluoro‐[di‐deutero]methyl tosylate (d₂‐[¹⁸F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated ¹⁸F‐fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.     

Automated synthesis of N‐(2‐[18F]Fluoropropionyl)‐l‐glutamic acid as an amino acid tracer for tumor imaging on a modified [18F]FDG synthesis module

N‐(2‐[¹⁸F]Fluoropropionyl)‐l ‐glutamic acid ([¹⁸F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [¹⁸F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [¹⁸F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2‐step on‐column hydrolysis procedure, including ¹⁸F‐fluorination and on‐column hydrolysis reaction. [¹⁸F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [¹⁸F]fluoride using the tosylated precursor 2 . The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [¹⁸F]FPGLU, a brominated precursor 3 was also used for the preparation of [¹⁸F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n  = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on‐column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module.     

Simple and high radiochemical yield synthesis of 2′‐Deoxy‐2′‐[18F]fluorouridine via a new nosylate precursor

We synthesized 2'‐deoxy‐2'‐[¹⁸F]fluorouridine ( 7 ) as a radiotracer for positron emission tomography from a new nosylate precursor ( 6 ). This new precursor was synthesized from uridine in four steps. The overall synthetic yield was 9.4% and we have high stability of >98% purity up to 6 months at 4°C. The optimal manual [¹⁸F]fluorination conditions were 30 mg of the precursor 6 in 500 µl of acetonitrile at 145°C for 15 min with 370 MBq of [¹⁸F]fluoride. The [¹⁸F]fluorination yield was 76.5±2.7% (n = 3). After hydrolysis of protecting groups with 1 N HCl and purification by HPLC, the overall radiochemical yield and purity were 26.5±1.4% and 98.2±2.5%, respectively. The preparation time was 70.0±10.5 min (n = 3 for each result). We also developed an automated method with a radiochemical yield and purity of 24.0±2.8 and 98.0±1.5% (n = 10) using a GE TracerLab MX chemistry module. This new nosylate precursor for 2'‐deoxy‐2'‐[¹⁸F]fluorouridine synthesis showed higher radiochemical yields and reproducibility than previous methods. Copyright © 2006 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.     

Trifluoromethanesulfonic acid,an alternative solvent medium for the direct electrophilic fluorination of DOPA: new syntheses of 6‐[18F]fluoro‐L‐DOPA and 6‐[18F]fluoro‐D‐DOPA

Previous work from this laboratory has shown that the direct fluorination of 3, 4‐dihydroxy‐phenyl‐L ‐alanine (L ‐DOPA) in anhydrous HF (aHF) or BF₃/HF with F₂ is an efficient method for the synthesis of 6‐fluoro‐L ‐DOPA. Since then, ¹⁸F‐labeled 6‐fluoro‐L ‐DOPA ([¹⁸F]6‐fluoro‐L ‐DOPA) has been used to study presynaptic dopaminergic function in the human brain and to monitor gastrointestinal carcinoid tumors. This work demonstrates that the reactivity and selectivity of F₂ toward L ‐DOPA in CF₃SO₃H is comparable with that in aHF. This new synthetic procedure has led to the production of [¹⁸F]fluoro‐L ‐DOPA and [¹⁸F]fluoro‐D‐DOPA isomers in 17±2% radiochemical yields (decay corrected with respect to [¹⁸F]F₂). The 2‐ and 6‐FDOPA isomers were separated by HPLC and subsequently characterized by ¹⁹F NMR spectroscopy. The corresponding [¹⁸F]‐FDOPA enantiomers have been obtained in clinically useful quantities by a synthetic approach that avoids the use of aHF. Copyright © 2007 John Wiley & Sons, Ltd.     

N3‐Substituted thymidine analogues III: radiosynthesis of N3‐[(4‐[18F]fluoromethyl‐phenyl)butyl]thymidine ([18F]‐FMPBT) and N3‐[(4‐[18F]fluoromethyl‐phenyl)pentyl] thymidine ([18F]‐FMPPT) for PET

Radiosyntheses of two N³‐substituted thymidine analogues, N³‐[(4[¹⁸F]fluoromethyl‐phenyl)butyl]thymidine ([¹⁸F]‐FMPBT) and N³‐[(4[¹⁸F]fluoromethyl‐phenyl)pentyl]thymidine ([¹⁸F]‐FMPPT), are reported. The precursor compounds 9 and 10 were synthesized in six steps and the standard compounds 13 and 14 were synthesized from these precursors. For radiosynthesis, compounds 9 and 10 were fluorinated with n‐Bu₄N[¹⁸F] to produce [¹⁸F]‐ 11 and [¹⁸F]‐ 12 , which by acid hydrolysis yielded [¹⁸F]‐ 13 and [¹⁸F]‐ 14 , respectively. The crude products were purified by high‐performance liquid chromatography to obtain [¹⁸F]‐FMPBT and [¹⁸F]‐FMPPT. The average decay‐corrected radiochemical yield for [¹⁸F]‐ 13 was 15% in five runs, and that for [¹⁸F]‐ 14 was 10% in four runs. The radiochemical purity was >99% and the specific activity was >74 GBq/µmol at the end of synthesis. The synthesis time was 80–90 min from the end of bombardment. 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.     

Fully automated synthesis and purification of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine

We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethylpiperazine (p‐[¹⁸F]MPPF). No‐carrier‐added [¹⁸F]F^? was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K₂CO₃ (0.7 mg). The nucleophilic [¹⁸F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH₄/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[¹⁸F]MPPF (retention time = 9.5 min). p‐[¹⁸F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.     

2‐, 3‐ and 4‐[18F]Fluoropyridine by no‐carrier‐added nucleophilic aromatic substitution with K[18F]F‐K222 – a comparative study

Compared to homoaromatic and aliphatic nucleophilic radiofluorinations, only few references can be found in the literature describing nucleophilic substitutions with [¹⁸F]fluoride ion of heteroaromatic compounds such as pyridines and only reactions involving fluorination processes at the ortho‐position (2‐position) have been more intensively studied. In the present paper, the scope of the nucleophilic aromatic fluorinations at the meta‐ and para‐position of the pyridine ring with no‐carrier‐added [¹⁸F]fluoride ion as its activated K[¹⁸F]F‐K₂₂₂ complex has been evaluated and compared to the nucleophilic aromatic fluorinations at the ortho‐position in this pyridine series. The syntheses of 3‐ and 4‐[¹⁸F]fluoropyridines were chosen as model reactions and compared to the radiosynthesis of 2‐[¹⁸F]fluoropyridine. The parameters studied include the influence of the position of the leaving group at the pyridine ring, as well as the quantity of the precursor used, the type of activation (conventional heating, microwave irradiation), the solvent, the temperature and the reaction time. Using the corresponding nitro precursor, high yields were obtained at the 2‐position (94% yield) using microwaves (100 W) for 2 min in DMSO. Good yields (up to 72%) were observed at the 4‐position using the same conditions while practically no reaction was observed at the 3‐position. About 60% yield was also obtained at both the 2‐ and 4‐position using the corresponding nitro precursor at 145°C for 10 min in DMSO. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and radiosynthesis of N5‐[18F]fluoroethyl‐Pirenzepine and its metabolite N5‐[18F]fluoroethyl‐LS 75

The well established M₁ selective muscarinergic antagonist Pirenzepine 11‐[2‐(4‐methyl‐piperazin‐1‐yl)‐acetyl]‐5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M₁ antagonism exclusively. One of the aspects discussed is a specific interaction with poly ADP‐ribose polymerase (PARP‐1). 1 undergoes metabolism to form LS 75 5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (2). In order to study deviations in Pirenzepine efficacy from pure M₁ binding in vivo using PET, appropriate positron emitter labelled analogues of 1 and 2 were synthesised. Non‐radioactive reference compounds 3 and 4 were tested for PARP‐1 inhibition. The n‐octanol–water partition coefficients of compounds 1, 2, 3 and 4 at pH 7.4 (logD_7.4) were determined. Both, 3 and 4 were labelled with ¹⁸F via 2‐[¹⁸F]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N⁵‐[¹⁸F]fluoroethyl Pirenzepine [¹⁸F]‐3 and N⁵‐[¹⁸F]fluoroethyl LS 75 [¹⁸F]‐4. Radiotracers [¹⁸F]‐3 and [¹⁸F]‐4 were obtained in radiochemical yields of 15±4 % and 30±5% after 120 and 110 min, respectively. Metabolism of both compounds was investigated in vitro in human and rat plasma, respectively. Compound 3 did not show activity as an inhibitor of PARP‐1. Contrary, 4 displays moderate PARP‐1 inhibition potency. The new radiotracer [¹⁸F]‐4 can be applied for molecular imaging using autoradiography and PET. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

Alternative synthesis for the preparation of 16α‐[18F]fluoroestradiol

We have developed a new precursor, 3,17β‐O‐bis(methoxymethyl)‐16β‐O‐p‐nitrobenzenesulfonylestriol (14c) of 16α‐[¹⁸F]fluoroestradiol ([¹⁸F]FES). Although we could not selectively protect the C17 alcohol in the presence of the C16 alcohol, we were able to prepare and chromatographically isolate the desired C16 TBDMS, C17,C3‐dimethoxymethyl (diMOM) protected estriol derivative and convert into the ultimate fluorination precursor. The MOM protective group proved to be more quickly removed than the cyclic sulfate group. The di‐MOM protective precursor at the C3 and C17 alcohols instead of a cyclic sulfate group shortened hydrolysis time. We prepared three different sulfonate precursors at C16 alcohol. After checking their reactivity in the [¹⁸F]fluorination step and considering the stability of the precursors, we obtained the best results with nosylate precursor 14c.     

Synthesis and bioevaluation of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[18F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone as potential myocardial perfusion imaging agent with PET

This study reports the synthesis and characterization of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[¹⁸F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone ([¹⁸F]Fmp2) for myocardial perfusion imaging (MPI). The tosylate precursor and non‐radioactive compound [¹⁹F]Fmp2 were synthesized and characterized by infrared, ¹H‐NMR, ¹³C‐NMR, and mass spectra (MS). The radiotracer [¹⁸F]Fmp2 was obtained by one‐step nucleophilic substitution of tosyl with ¹⁸F, and evaluated as an MPI agent in vitro and in vivo. Starting from [¹⁸F]KF/K₂₂₂ solution, the typical decay‐corrected radiochemical yield (RCY) was 38 ± 8.8% with high radiochemical purity (>98%). The specific activity was calculated as 10 GBq/µmol at the end of synthesis determined by HPLC analysis. In the mice biodistribution, [¹⁸F]Fmp2 showed very high initial heart uptake (53.35 ± 5.47 %ID/g at 2 min after injection) and remarkable retention. The heart/liver, heart/lung, and heart/blood ratios were 7.98, 8.20, and 53.13, respectively at 2 min post‐injection. In the Positron Emission Tomography (PET) imaging study of Chinese mini‐swine, the standardized uptake value of the liver decreased modestly during the 2 h post‐injection, while the heart uptake and heart/liver ratios continued to increase with time. [¹⁸F]Fmp2 exhibited good stability, high heart uptake and low lung uptake in mice and Chinese mini‐swine. It may be worthy of further modification to improve liver clearance for MPI in the future.     

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.