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.     

Synthesis of [18F]‐labeled adenosine analogues as potential PET imaging agents

The syntheses of adenosine analogues, 2′‐deoxy‐2′‐[¹⁸F]fluoro‐9‐β‐D ‐arabinofuranosyladenine ([¹⁸F]‐FAA) and 3′‐deoxy‐3′‐[¹⁸F]fluoro‐9‐β‐D ‐xylofuranosyladenine ([¹⁸F]‐FXA) are reported. Adenosine ( 1 ) was converted to its methoxytrityl derivatives 2 and 3 as a mixture. After separation, these derivatives were converted to their respective triflates 4 and 5 . Each triflate was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6b or 7b , which by acidic hydrolysis yielded compounds 8b and 9b . Crude preparations were purified by HPLC to obtain the desired pure products. The radiochemical yields were 10‐18% decay corrected (d. c.) for 8b and 30‐40% (d. c.) for 9b in 4 and 3 runs, respectively. Radiochemical purity was >99% and specific activity was >74 GBq/μmol at the end of synthesis (EOS). The synthesis time was 90‐95 min from the end of bombardment (EOB). Copyright © 2003 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 [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.     

Preparation of 3′‐deoxy‐3′‐[18F]fluorothymidine ([18F]FLT) in ionic liquid, [bmim][OTf]

Although 3′‐deoxy‐3′‐[¹⁸F]fluorothymidine ([¹⁸F]FLT) is a prospective radiopharmaceutical for the imaging of proliferating tumor cell, it is difficult to prepare large amount of [¹⁸F]FLT. We herein describe the preparation of [¹⁸F]FLT in an ionic liquid, [bmim][OTf] (1‐butyl‐3‐methyl‐imidazolium trifluoromethanesulfonate). At optimized condition, [¹⁸F]fluorinationin ionic liquid with 5 µl of 1 M KHCO₃ and 5 mg of the precursor yielded 61.5 ± 4.3% (n=10). Total elapsed time was about 70 min including HPLC purification. The rapid synthesis of [¹⁸F]FLT can be achieved by removing all evaporation steps. Overall radiochemical yield and radiochemical purity were 30 ± 5% and >95%, respectively. This method can use a small amount of a nitrobenzenesulfonate precursor and can be adapted for automated production. Copyright © 2006 John Wiley & Sons, Ltd.     

A novel method for stereospecific fluorination at the 2′‐arabino‐position of pyrimidine nucleoside: synthesis of [18F]‐FMAU

Direct fluorination of a pyrimidine nucleoside at the 2′‐arabino‐position has been deemed to be extremely difficult, if not impossible. The conventional synthesis of 2′‐deoxy‐2′‐fluoro‐5‐methy‐1‐β‐D ‐arabinofuranosyluracil (FMAU) and its 5‐substituted analogs involves stereospecific fluorination of the 1,3,5‐tri‐O‐benzoyl‐α‐D ‐ribofuranose‐2‐sulfonate ester followed by bromination at the C₁‐postion, and then coupling with pyrimidine‐bis‐trimethylsilyl ether. Several radiolabeled nucleoside analogs, including [¹⁸F]FMAU, and other 5‐substituted analogs, were developed according to this methodology. However, routine production of these compounds using this multi‐step process is inconvenient and limits their clinical application. We developed a novel precursor and method for direct fluorination of preformed nucleoside analogs at the 2′‐arabino position, exemplified via radiosynthesis of [¹⁸F]FMAU. The 2′‐methylsulfonyl‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐ribofuranosiluracil was synthesized in multiple steps. Radiofluorination of this precursor with K¹⁸F/kryptofix produced 2′‐deoxy‐2′‐[¹⁸F]fluoro‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐arabinofuranosiluracil. Acid hydrolysis followed by high‐performance liquid chromatography purification produced the desired [¹⁸F]FMAU. The average radiochemical yield was 2.0% (decay corrected, n=6), from the end of bombardment. Radiochemical purity was >99%, and specific activity was >1800 mCi/µmol. Synthesis time was 95–100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of [¹⁸F]FMAU, and the method should be suitable for production of other 5‐substituted pyrimidine analogs, including [¹⁸F]FEAU, [¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, and [¹⁸F]FBAU. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiosynthesis of the fluorinated sucrose analogue, 1′‐[18F]fluoro‐1′‐deoxysucrose

Fluorinated and deoxysucrose analogues have been proven useful in probing the substrate specificity and roles of sucrose processing enzymes and transporters in plants. To synthesize an ¹⁸F‐labeled fluorodeoxysucrose analogue suitable for in vivo studies, an acyl‐protected, disaccharide‐based radiofluorination precursor (sucrose 1′‐O‐trifluoromethanesulfonyl‐2,3,4,6,3′,4′,6′‐hepta‐O‐acetate; 2) was prepared by regioselective mono‐deacetylation of sucrose octaacetate using a commercial esterase enzyme followed by conversion of the resultant sucrose heptaacetate to the corresponding triflate. Reaction of this triflate precursor with [¹⁸F]fluoride followed by base hydrolysis to remove the acetate groups and HPLC purification gave 1′‐[¹⁸F]fluoro‐1′‐deoxysucrose (4) in an overall synthesis time of 80 min and with a median decay corrected yield of 26% (n = 4). This study demonstrates the use of an enzymatic approach to aid the synthesis of a regiospecific radiofluorination precursor starting from the readily available fully acetylated sugar, thus avoiding the need for a complex classical carbohydrate protection strategy to individually protect each hydroxyl group in the molecule. Copyright © 2012 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.     

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.     

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.     

Synthesis of N‐(3‐[18F]Fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane ([18F]FP‐β‐CIT)

N‐(3‐[¹⁸F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane ([¹⁸F]FP‐β‐CIT) was synthesized in a two‐step reaction sequence. In the first reaction, 1‐bromo‐3‐(nitrobenzene‐4‐sulfonyloxy)‐propane was fluorinated with no‐carrier‐added fluorine‐18. The resulting product, 1‐bromo‐3‐[¹⁸F]‐fluoropropane, was distilled into a cooled reaction vessel containing 2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐nortropane, diisopropylethylamine and potassium iodide. After 30 min, the reaction mixture was subjected to a preparative HPLC purification. The product, [¹⁸F]FP‐β‐CIT, was isolated from the HPLC eluent with solid‐phase extraction and formulated to yield an isotonic, pyrogen‐free and sterile solution of [¹⁸F]FP‐β‐CIT. The overall decay‐corrected radiochemical yield was 25 ± 5%. Radiochemical purity was > 98% and the specific activity was 94 ± 50 GBq/µmol at the end of synthesis. Copyright © 2006 John Wiley & Sons, Ltd.     

Simplified synthesis of N‐(3‐[18F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane ([18F]β‐CFT‐FP) using [18F]fluoropropyl tosylate as the labelling reagent

A synthesis method has been developed for the labelling of N‐(3‐[¹⁸F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane ([¹⁸F]β‐CFT‐FP), a potential radioligand for visualization of the dopamine transporters by positron emission tomography. The two‐step synthesis includes preparation of [¹⁸F]fluoropropyl tosylate and its use without purification in the fluoroalkylation of 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane (nor‐β‐CFT). The final product is purified by HPLC. Optimization of the two synthesis steps resulted in a greater than 30% radiochemical yield of [¹⁸F]β‐CFT‐FP (decay corrected to end of bombardment). The synthesis time including HPLC‐purification was approximately 90 min. The radiochemical purity of the final product was higher than 99% and the specific radioactivity at the end of synthesis was typically 20 GBq/µmol. In comparison to alkylation by [¹⁸F]fluoropropyl bromide, the procedure described here results in an improved overall radiochemical yield of [¹⁸F]β‐CFT‐FP in a shorter time. Copyright © 2005 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.     

Comparison of synthesis yields of 3′‐deoxy‐3′‐[18F]fluorothymidine by nucleophilic fluorination in various alcohol solvents

[¹⁸F]Fluorothymidine ([¹⁸F]FLT) is synthesized with a high radiochemical yield by nucleophilic substitution in protic solvent. In this study, we compared [¹⁸F]fluorination yields of [¹⁸F]fluorothymidine ([¹⁸F]FLT) in various alcohol solvents: 3,3‐dimethyl‐1‐butanol, 2‐trifluoromethyl‐2‐propanol, t‐BuOH (2‐methyl‐2‐propanol), t‐amyl alcohol (2‐methyl‐2‐butanol), thexyl alcohol (2,3‐dimethyl‐2‐butanol) and 3,3‐dimethyl‐2‐butanol. We used 5′‐O‐DMTr‐2′‐deoxy‐3′‐O‐nosyl‐β‐D‐threopentofuranosyl)‐3‐N‐BOC‐thymine as a precursor for [¹⁸F]fluorination. [¹⁸F]F^? was eluted with TBAHCO₃ solution after trapping [¹⁸F]F^? on a PS‐HCO₃ cartridge. [¹⁸F]fluorination was performed at 100°C for 5–30 min using 20 mg of the precursor. [¹⁸F]fluorination and radiochemical yields of [¹⁸F]FLT were evaluated by radioTLC. [¹⁸F]fluorination yields were dependent on the solvent used. All tertiary alcohol solvents, except 2‐trifluoromethyl‐2‐propanol, showed >85% of [¹⁸F]fluorination yields, whereas primary and secondary alcohols showed 26.3–71.8%. The highest yield of 94.1±4.4% was obtained with thexyl alcohol after [¹⁸F]fluorination for 5 min. Automated synthesis with t‐amyl alcohol resulted in high synthetic yields of 64.6±6.1% after high‐performance liquid chromatography purification (n=43). The use of tertiary alcohol as a solvent provides high radiochemical yields of [¹⁸F]FLT. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [18F] 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression

To synthesize ¹⁸F‐labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting ¹⁸F into a target molecule are necessary. The ¹⁸F‐fluorobenzene moiety has been widely utilized in the synthesis of ¹⁸F‐labeled compounds. The present study utilized [¹⁸F]‐labeled aniline as intermediate in [¹⁸F]‐radiolabeling chemistry for the facile radiosynthesis of 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide ([¹⁸F]IDO5L) as indoleamine 2,3‐dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC₅₀. [¹⁸F]IDO5L was synthesized via coupling [¹⁸F]3‐chloro‐4‐fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [¹⁸F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/µmol at the end of synthesis within ~90 min, and the decay‐corrected radiochemical yield was 18.2 ± 2.1% (n = 4).     

Radiosynthesis of 2‐exo‐(2′‐[18F]Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine‐based radioligand for nicotinic acetylcholine receptor PET imaging

2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F₂PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [¹⁸F]F₂PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[¹⁸F]F‐Kryptofix^®₂₂₂ complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [¹⁸F]F₂PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry^® C18, eluent aqueous 0.05 M NaH₂PO₄ CH₃CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [¹⁸F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd.     

The first enzymatic method for C–18F bond formation: the synthesis of 5′‐[18F]‐fluoro‐5′‐deoxyadenosine for imaging with PET

The use of the key enzyme involved in carbon–fluorine bond formation in Streptomyces cattleya catalysing the formation of 5′‐fluoro‐5′‐deoxyadenosine (5′‐FDA) from fluoride ion and S‐adenosyl‐l‐methionine (SAM) was explored for its potential application in fluorine‐18 labelling of the adenosine derivative. Enzymatic radiolabelling of [¹⁸F]‐5′‐FDA was successfully carried out starting from SAM and [¹⁸F]HF when the concentration of the enzyme preparation was increased from sub‐mg/ml values to mg/ml values. The purity of the enzyme had no measurable effect on the radiochemical yield of the reaction and the radiochemical purity of [¹⁸F]‐5′‐FDA. Copyright © 2003 John Wiley & Sons, Ltd.     

Facile synthesis of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB) for protein labeling

An efficient preparation of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) based on a convenient three‐step, one‐pot procedure is described. [¹⁸F]Fluorination of the precursor ethyl 4‐(trimethylammonium triflate)benzoate gave ethyl 4‐[¹⁸F]fluorobenzoate. Saponification of the ethyl 4‐[¹⁸F]fluorobenzoate with aqueous tetrapropylammonium hydroxide yielded the corresponding 4‐[¹⁸F]fluorobenzoate salt ([¹⁸F]FBA), which was then treated with N,N,N,N′‐tetramethyl‐O‐(N‐succinimidyl)uronium hexafluorophosphate. The purified [¹⁸F]SFB was used for the labeling of Avastin^? (Bevacizumab) through [¹⁸F]fluorobenzoylation of the Avastin's α‐amino groups. The decay‐corrected radiochemical yields of [¹⁸F]SFB were as high as 44% (based on [¹⁸F]fluoride (n=10) with a synthesis time of less than 60 min. [¹⁸F]Avastin was produced in decay‐corrected radiochemical yields of up to 42% (n=5) within 30 min (based on [¹⁸F]SFB). The radiochemical purities of [¹⁸F]SFB and [¹⁸F]Avastin were greater than 95%. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [18F]FETO,a novel potential 11‐β hydroxylase inhibitor

Recent publications reported high uptake of the carbon‐11 labelled 11β‐hydroxylase inhibitors (R)–[O–methyl‐¹¹C]metomidate ([¹¹C]MTO) and (R)–[O–ethyl‐¹¹C]etomidate ([¹¹C]ETO) in adrenocortical incidentalomas with excellent selectivity for positron emission tomography (PET). In our studies [¹⁸F]FETO, (the [¹⁸F]fluoroethyl ester of etomidate, (R)‐1‐(1‐phenylethyl)‐1H‐imidazole‐5‐carboxylic acid, 2′‐[¹⁸F]fluoroethyl ester), an analogue of [¹¹C]MTO and [¹¹C]ETO was chosen due to the suspected similarity of the pharmacokinetic and pharmacodynamic properties, and was prepared in the following two step procedure: 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, [¹⁸F]BFE was reacted with the tetrabutylammonium salt of (R)‐1‐(1‐phenylethyl)‐1H‐imidazole‐5‐carboxylic acid to yield [¹⁸F]FETO, a novel inhibitor of the 11β‐hydroxylase. The proposed synthesis of [¹⁸F]FETO allows the production of sufficient amounts of this new PET‐tracer to serve 1–2 patients with an overall synthesis time of less than 80 min. 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.