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.     

Radiosynthesis of [18F]LBT‐999, a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester) is a cocaine derivative belonging to a new generation of highly selective dopamine transporter ligands (K_D:9 nM). LBT‐999 was labelled with fluorine‐18 at its fluoromethylvinyl moiety using the following two‐step radiochemical process: (a) No‐carrier‐added nucleophilic aliphatic radiofluorination from (E)‐1, 4‐ditosyloxybut‐2‐ene and the activated K[¹⁸F]F‐Kryptofix^®222 complex in acetonitrile at 70°C for 10 min giving (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene, followed by (b) condensation of the latter with 3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester in N,N‐dimethylformamide containing potassium iodide for 20 min at 90°C and (c) HPLC purification (SunFire? C18, eluent H₂O/CH₃CN/TFA (72:28:0.1 (v/v/v)). Radiochemically pure (> 95%) [¹⁸F]LBT‐999 (2.03–2.96 GBq, 37–111 GBq/μmol) was obtained in 95–100 min starting from a 44.4 GBq [¹⁸F]fluoride ion production batch (4.6–6.7% non‐decay‐corrected overall yield). Copyright © 2006 John Wiley & Sons, Ltd.     

Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans‐[18F]4‐fluoro‐l‐proline during the synthesis of cis‐[18F]4‐fluoro‐l‐proline

Fluorine‐18 labeled (2S,4S)‐4‐fluoro‐l ‐proline (cis‐[¹⁸F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2S,4R)‐N‐tert‐butoxycarbonyl‐4‐(p‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis‐[¹⁸F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis‐[¹⁸F]4‐FPro or trans‐[¹⁸F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2S,4R) precursor produced a mixture of cis‐[¹⁸F]4‐FPro and trans‐[¹⁸F]4‐FPro diastereomers with cis‐[¹⁸F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C₁₈ Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis‐[¹⁸F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis‐[¹⁸F]4‐FPro occurs during the two‐step hydrolysis (H⁺ followed by OH^?) of the intermediate, resulting in 5 ± 3% trans‐[¹⁸F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis‐[¹⁸F]4‐FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.     

A general method for the fluorine‐18 labelling of fluoroquinolone antibiotics

Fluoroquinolones are an important class of antibiotic agents with a broad spectrum of antibacterial activity. Labelling of fluoroquinolones with fluorine‐18 is of interest for the performance of pharmacokinetic measurements and the visualization of bacterial infections in humans with positron emission tomography. A two‐step radiosynthetic pathway to prepare fluorine‐18‐labelled ciprofloxacin (1‐cyclopropyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐4‐oxo‐7‐(1‐piperazinyl)‐quinoline‐3‐carboxylic acid) has previously been developed. In the present work this approach was applied to the preparation of the structurally related compounds [¹⁸F]norfloxacin (1‐ethyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐4‐oxo‐7‐(1‐piperazinyl)‐quinoline‐3‐carboxylic acid) and [¹⁸F]pefloxacin (1‐ethyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐7‐(4‐methyl‐1‐piperazinyl)‐4‐oxo‐quinoline‐3‐carboxylic acid). The first step of the radiosynthesis consisted of a ¹⁸F for ¹⁹F exchange reaction on a 7‐chloro‐substituted precursor molecule, followed by coupling reactions with the amines piperazine or 1‐methylpiperazine. Starting from 51–58 GBq of [¹⁸F]fluoride 1.9–2.0 GBq of [¹⁸F]norfloxacin or [¹⁸F]pefloxacin, ready for intravenous injection, could be obtained in a synthesis time of 130 min (3.5–3.8% overall radiochemical yield). Moreover, the preparation of [¹⁸F]levofloxacin ((‐)‐(S)‐9‐[¹⁸F]fluoro‐2,3‐dihydro‐3‐methyl‐10‐(4‐methyl‐1‐piperazinyl)‐7‐oxo‐7H‐pyrido[1,2,3‐de]‐1,4‐benzoxazine‐6‐carboxylicacid) was attempted but failed to afford the desired product in practical amounts. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[18F]fluoro‐1H‐pyrazole‐3‐carboxamide by nucleophilic [18F] fluorination: a PET radiotracer for studying CB1 cannabinoid receptors

The feasibility of nucleophilic displacement of bromide in the 4‐bromopyrazole ring with [¹⁸F]fluoride has been demonstrated by the synthesis of two radiolabeled compounds: N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐1H‐pyrazole‐3‐carboxamide, ([¹⁸F] NIDA‐42033) 1b and 1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐5‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carboxylic acid, ethyl ester 4 . The radiochemical yields were in the range of 1–6%. [¹⁸F]NIDA‐42033, a potential radiotracer for the study of CB₁ cannabinoid receptors in the animal brain by positron emission tomography, has been synthesized in sufficient quantities with specific radioactivity greater than 2500 mCi/μmol and radiochemical purity >95%. Copyright © 2002 John Wiley & Sons, Ltd.     

One‐step radiosynthesis of [18F]LBT‐999: a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3‐beta‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2‐beta‐carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (K_D : 9 nM for the DAT and IC₅₀ > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine‐18‐labelling of LBT‐999 was based on the robust and reliable two‐step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene followed by a N‐alkylation reaction with the appropriate nor‐tropane moiety. In the present work, a simple one‐step fluorine‐18‐labelling of LBT‐999 is reported, based on a chlorine‐for‐fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high‐performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[¹⁸F]F–Kryptofix^®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C‐18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Typically, 3.70–5.92 GBq of [¹⁸F]LBT‐999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep‐Pak‐based formulation included), starting from a 37.0 GBq [¹⁸F]fluoride batch (overall radiochemical yields: 10–16%, non‐decay‐corrected). Copyright © 2007 John Wiley & Sons, Ltd.     

The synthesis of a new probe for PET imaging reporter gene HSV1‐tk: 2‐amino‐6‐[18F] fluoro‐9‐ (4‐hydroxy‐3‐hydroxymethylbutyl) purine (6‐[18F]fluoropenciclovir)

The one step radiosynthesis of 2‐amino‐6‐ [¹⁸F]fluoro‐9‐(4‐hydroxy‐3‐hydroxymethylbutyl) purine (6‐[¹⁸F]fluoropenciclovir) 6 is reported. Radiolabeled product 6‐[¹⁸F]fluoropenciclovir 6 was prepared by radiofluorination of compound 4 with [¹⁸F]KF and isolated by a silica Sep‐Pak cartridge. The radiochemical yield of compound 6 was 45–55% decay corrected (d.c.) in six runs with radiochemical purity >98% and the radiosynthesis time was 35–42 min from end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

[18F]FPyKYNE,a fluoropyridine‐based alkyne reagent designed for the fluorine‐18 labelling of macromolecules using click chemistry

FPyKYNE (2‐fluoro‐3‐pent‐4‐yn‐1‐yloxypyridine) is a novel fluoropyridine‐based structure, designed for the fluorine‐18 labelling of macromolecules using copper‐catalysed Huisgen 1,3‐dipolar cycloaddition (click chemistry). FPyKYNE (non‐labelled as reference), as well as the 2‐bromo, 2‐nitro and 2‐trimethylammonium analogues (as precursors for labelling with fluorine‐18), was synthesized in 44, 95, 60 and 41%, respectively, from commercially available 5‐chloropent‐1‐yne and the appropriate 2‐substituted‐3‐hydroxypyridines. [¹⁸F]FPyKYNE was synthesized in one single radiochemical step by reaction of no‐carrier‐added K[¹⁸F]F‐Kryptofix^®222 (DMSO, 165°C, 3–5 min) followed by C‐18 SepPak cartridge pre‐purification and finally semi‐preparative HPLC purification on a Hewlett Packard SiO₂ Zorbax^® Rx‐SIL. Using the 2‐nitropyridine or the pyridin‐2‐yltrimethylammonium trifluoromethanesulphonate precursor for labelling (30 and 10 µmol, respectively), incorporation yields up to 90% were observed and 7.0–8.9 GBq (190–240 mCi) of [¹⁸F]FPyKYNE ([¹⁸F]‐1) could be isolated within 60–70 min (HPLC purification included), starting from a 37.0 GBq (1.0 Ci) [¹⁸F]fluoride batch (overall decay‐corrected and isolated yields: 30–35%). Copyright © 2008 John Wiley & Sons, Ltd.     

Radiolabeling of a high potency cannabinoid subtype‐1 receptor ligand,N‐(4‐fluoro‐benzyl)‐4‐(3‐(piperidin‐1‐yl)‐indole‐1‐sulfonyl)benzamide (PipISB), with carbon‐11 or fluorine‐18

PipISB [N‐(4‐fluoro‐benzyl)‐4‐(3‐(piperidin‐1‐yl)‐indole‐1‐sulfonyl)benzamide, 9] was identified as a selective high potency CB₁ receptor ligand. Here we describe the labeling of 9 with positron‐emitters to provide candidate radioligands for imaging brain CB₁ receptors with positron emission tomography (PET). The radiolabeling of 9 was achieved by two methods, method A with carbon‐11 and method B with fluorine‐18. In method A, [¹¹C]9 was prepared in one step from [¹¹C]carbon monoxide, itself prepared from cyclotron‐produced [¹¹C]carbon dioxide. In method B, [¹⁸F]9 was prepared from cyclotron‐produced [¹⁸F]fluoride ion in a two‐stage, four‐step synthesis with [¹⁸F]4‐fluoro‐benzyl bromide as a labeling agent. The radiosynthesis time for method A was 44 min; decay‐corrected radiochemical yields (RCYs) from [¹¹C]carbon monoxide ranged from 3.1 to 11.6% and specific radioactivities ranged from 21 to 67 GBq/µmol. The radiosynthesis time for method B was 115 min; RCYs from [¹⁸F]fluoride ion ranged from 1.5 to 5.6% and specific radioactivities ranged from 200 to 348 GBq/µmol. With these methods, [¹¹C]9 and [¹⁸F]9 may be prepared in adequate activity and quality for future evaluation as PET radioligands. Copyright © 2008 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.     

A general synthesis of 2′‐deoxy‐2′‐[18F]fluoro‐1‐β‐D‐arabinofuranosyluracil and its 5‐substituted nucleosides

Several 2′‐deoxy‐2′‐[¹⁸F]fluoro‐1‐β‐D‐arabinofuranosyluracil derivatives have been synthesized. Coupling of 1‐bromo‐2‐deoxy‐2‐[¹⁸F]fluoro‐3,5‐di‐O‐benzoyl‐α‐D‐arabinofuranose 2 with protected uracil derivatives 3a–e followed by hydrolysis and high‐performance liquid chromatography purification produced the radiolabeled nucleosides 4a–e in 15–30% yield (d. c.), >99% radiochemical purity and 55.5–103.6 GBq/µmol specific activities. Copyright © 2003 John Wiley & Sons, Ltd.     

Ortho‐[18F]Fluoronitrobenzenes by no‐carrier‐added nucleophilic aromatic substitution with K[18F]F–K222—A comparative study

The scope of the nucleophilic aromatic ortho‐fluorinations from the corresponding ortho‐halonitrobenzene precursors (halo‐to‐fluoro substitutions) with no‐carrier‐added [¹⁸F]fluoride ion as its activated K[¹⁸F]F–K₂₂₂ complex has been evaluated via the radiosynthesis of ortho‐[¹⁸F]fluoronitrobenzene, chosen as a model reaction. The parameters studied include the influence of the leaving group in the ortho position of the phenyl ring (–Cl, –Br, –l), the quantity of precursor used, the type of activation (conventional heating or microwave irradiations), the solvent, the temperature and the reaction time. The iodo‐precursor was completely unreactive and the bromo‐precursor gave only low incorporation (<10%) in the optimal conditions used (conventional heating at 145°C or microwave activation, 100 W for 120 s). Only the chloro‐precursor was found reactive in the conditions described above and up to 70% yield was observed for the formation of ortho‐[¹⁸F]fluoronitrobenzene ([¹⁸F]‐ 1 ). In all the experiments, the unwanted ortho‐[¹⁸F]fluoro‐halobenzenes, potentially resulting from the nitro‐to‐fluoro substitution, could not be detected. These results will be applied for the radiosynthesis of 5‐[¹⁸F]fluoro‐6‐nitroquipazine, a potent radioligand for the imaging of the serotonin transporter with PET. Copyright © 2002 John Wiley & Sons, Ltd.     

Reaction of [18F]4‐fluorobenzenediazonium cations with cysteine or the cysteinyl group: preparation of 18F‐labeled S‐aryl‐cysteine and a radiolabeled peptide

A reaction route for the preparation of no‐carrier‐added (n.c.a.) [¹⁸F]S‐4‐fluorophenylcysteine 7 via the [¹⁸F]‐4‐fluorobenzenediazonium ion 4 is described. The key step in this radiosynthesis is the reaction of 4 with cysteine forming [¹⁸F]4‐fluorophenyldiazocysteine 6 , which is subsequently converted into 7 by irradiation with 366 nm light. 4 was synthesized by reacting 1,4‐dinitrobenzene 1 with [¹⁸F]‐fluoride in acetonitrile in a PEEK‐capillary in a microwave oven. After dilution of the reaction mixture with methanol, the resulting [¹⁸F]4‐fluoro‐1‐nitrobenzene 2 was submitted to reduction by means of H₂ with Pd on C catalyst. The resulting [¹⁸F]4‐fluoroaniline 3 was purified by HPLC and diazotized to 4 . The preparation of 4 was optimized with regard to yield and purity. The radiochemical yield of 6 was >90% (based on 3 ) while after UV irradiation and HPLC purification 45% of 7 (based on 3 ) was obtained (yields corrected for decay). The suitability of this method for labeling peptides with fluorine‐18 was demonstrated by application to the tripeptide, glutathione (GSH; γ‐L‐glutamyl‐L‐cysteinyglycine) 8 . Copyright © 2002 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.     

18F‐Labelled vorozole analogues as PET tracer for aromatase

One‐ and two‐step syntheses for the ¹⁸F‐labelling of 6‐[(S)‐(4‐chlorophenyl)(1H‐1,2,4‐triazol‐1‐yl)methyl]‐1‐(2‐[¹⁸F]fluoroethyl)‐1H‐benzotriazole, [¹⁸F]FVOZ, 1 and 6‐[(S)‐(4‐chlorophenyl)(1H‐1,2,4‐triazol‐1‐yl)methyl]‐1‐[2‐(2‐[¹⁸F]fluoroethoxy)ethyl]‐1H‐benzotriazole, [¹⁸F]FVOO, 2 were developed. In the two‐step synthesis, the nucleophilic fluorination step was performed by reacting (S)‐6‐[(4‐chlorophenyl)‐(1H‐1,2,4‐triazol‐1‐yl)methyl]‐1H‐benzotriazole (VOZ) with either the ¹⁸F‐labelled ethane‐1,2‐diyl bis(4‐methylbenzenesulfonate) or the oxydiethane‐2,1‐diyl bis(4‐methylbenzenesulfonate). The radiochemical yields were in the range of 9–13% after the 110–120 min total syntheses and the specific radioactivities were 175±7 GBq/µmol and 56 GBq/µmol for compounds 1 and 2, respectively. In the one‐step synthesis, the precursor 2‐{6‐[(4‐chlorophenyl)(1H‐1,2,4‐triazol‐1‐yl)methyl]‐1H‐1,2,3‐benzotriazol‐1‐yl}ethyl 4‐methylbenzenesulfonate (7) or 1‐[2‐(2‐bromoethoxy)ethyl]‐6‐[(4‐chlorophenyl)(1H‐1,2,4‐triazol‐1‐yl)methyl]‐1H‐benzotriazole (8) was directly labelled via an ¹⁸F nucleophilic substitution to give the corresponding tracer. The labelled compounds were obtained in 36–99% radiochemical yield after 75‐min syntheses. The specific radioactivities are 100 GBq/µmol for compound 1 and 80 GBq/µmol for compound 2. In vitro autoradiography using frozen rat brains illustrated specific binding in the medial amygdala, the bed nucleus of stria terminalis and the preoptic area, all of which corresponded well to the result of ¹¹C‐labelled vorozole. Copyright © 2008 John Wiley & Sons, Ltd.     

Nucleophilic [18F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups

As model reactions for the introduction of ¹⁸F into protected aromatic amino acids, the replacement of NO₂, Cl, Br and F by [¹⁸F]fluoride in 2‐isophthalaldehyde and 2‐terephthalaldehyde derivatives which model ¹⁸F‐DOPA and ¹⁸F‐tyrosine was investigated by comparing labelling yields and reaction rates with those of corresponding mono‐aldehyde compounds. All isophthalaldehydes showed maximum radiochemical yields (79 to 86%) at 140°C and in comparison with the corresponding mono‐aldehydes the reaction proceeded faster. At lower temperature the reaction already resulted in high yields, e.g. 2‐nitroisophthalaldehyde was labelled with a yield of 78% at 25°C after 7 min, whereas 2‐nitrobenzaldehyde only reached a yield of 1.7% under the same reaction conditions. The ¹⁸F/NO₂ exchange in nitroterephthalaldehydes proceeded more slowly and with lower radiochemical yields when compared with corresponding isophthalaldehydes and monoaldehydes. The decarbonylation of ¹⁸F‐labelled aromatic dialdehydic compounds with 4 eq. of Wilkinson's catalyst at 150°C in benzonitrile resulted in high yields, e.g. 2‐[¹⁸F]fluoro‐5‐methoxyisophthalaldehyde and 4‐[¹⁸F]fluoro‐2‐methoxy‐5‐methylisophthalaldehyde were decarbonylated efficiently with yields of 67±3% and 72±2%, respectively. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of [18F]‐labeled 2′‐deoxy‐2′‐fluoro‐5‐methyl‐1‐β‐D‐arabinofuranosyluracil ([18F]‐FMAU)

Synthesis of 2′‐deoxy‐2′‐[¹⁸F]fluoro‐5‐methyl‐1‐β‐D‐arabinofuranosyluracil ([¹⁸F]‐FMAU) is reported. 2‐Deoxy‐2‐[¹⁸F]fluoro‐1,3,5‐tri‐O‐benzoyl‐α‐D‐arabinofuranose 2 was prepared by the reaction of the respective triflate 1 with tetrabutylammonium[¹⁸F]fluoride. The fluorosugar 2 was converted to its 1‐bromo‐derivative 3 and coupled with protected thymine 4 . The crude product mixture ( 5a and 5b ) was hydrolyzed in base and purified by HPLC to obtain the radiolabeled FMAU 6a . The radiochemical yield of 6a was 20–30% decay corrected (d.c.) in four steps with an average of 25% in four runs. Radiochemical purity was >99% and average specific activity was 2300 mCi/μmol at the end of synthesis (EOS). The synthesis time was 3.5–4.0 h from the end of bombardment (EOB). Copyright © 2002 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.     

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 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.