Fluorine‐18 labelling of PNAs functionalized at their pseudo‐peptidic backbone for imaging studies with PET

Peptide nucleic acids (PNAs) form a unique class of synthetic macromolecules, originally designed as ligands for the recognition of double‐stranded DNA, where the deoxyribose phosphate backbone of original DNA is replaced by a pseudo‐peptide N‐(2‐aminoethyl)glycyl backbone, while retaining the nucleobases of DNA. We have previously developed an original method to label oligonucleotide‐based macromolecules with the short‐lived positron‐emitter fluorine‐18 (t_1/2: 109.8 min) using the N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide reagent. Using this method, we herein report the fluorine‐18‐labelling of 13 decameric PNAs ( OLP_1‐13 ), of the same sequence (CTCATACTCT), but presenting selected modification of the pseudo‐peptidic backbone at two or three of the thymine residues (positions 2, 5 and 8). Structural characteristics of these backbone modifications include either an amino acid side chain (L ‐Lys, L ‐Glu, L ‐Leu and L ‐Arg) or a glycosyl moiety (mannose, galactose, fucose, N‐Ac‐galactosamine and N‐Ac‐glucosamine) attached via an appropriate spacer. N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide was synthesized in three radiochemical steps from 4‐cyano‐N,N,N‐trimethylanilinium trifluoromethanesulfonate and HPLC‐purified in 85–90 min (typical production: 3.7–4.8 GBq starting from a batch of 29.6–31.4 GBq of [¹⁸F]fluoride). Conjugation of the fluorine‐18‐labelled bromoacetamide reagent with the PNAs was performed in a mixture of acetonitrile and HEPES buffer (0.1 M, pH 7.9) for 10 min at 60°C and gave the corresponding pure labelled conjugated PNAs ([¹⁸F] c‐OLP_1‐13 ) after RP‐HPLC purification. The whole synthetic procedure, including the preparation of the fluorine‐18‐labelled reagent, provides up to 0.9 GBq (25 mCi) of HPLC‐purified [¹⁸F] c‐OLP_1‐13 in 160 min with a specific radioactivity of 45–65 GBq/µmol (1.2–1.7 Ci/µmol) at the end of synthesis starting from 29.6 to 31.4 GBq (800–850 mCi) of [¹⁸F]fluoride. Copyright © 2004 John Wiley & Sons, Ltd.     

Fluorine‐18 labelling of oligonucleotides: Prosthetic labelling at the 5′‐end using the N‐(4‐[18F]fluorobenzyl)‐2‐bromoacetamide reagent

Labelled oligonucleotides are new imaging tools to study gene expression at the nucleic acid and protein levels. We have previously developed a universal method to label oligonucleotides at their 3′‐end with radiohalogens and particularly with fluorine‐18, the most widely used positron‐emitter, t_1/2: 109.8 min. Using the same strategy, we herein report the fluorine‐18 labelling of oligonucleotides at their 5′‐end. A 18‐mer 2′O‐methyl modified oligoribonucleotide, bearing a phosphorothioate group at its 5′‐end, was conjugated to our fluorine‐18‐labelled reagent N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide. The whole synthetic procedure yielded up to 1 GBq of fluorine‐18‐labelled oligonucleotide with a specific radioactivity of 37–74 GBq/μmol in 160 min. Copyright © 2003 John Wiley & Sons, Ltd.     

Fluorine‐18 labelling of small interfering RNAs (siRNAs) for PET imaging

Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two single‐stranded ribonucleic acids of short sequences, have been labelled with the positron‐emitter fluorine‐18 (T_1/2: 109.8 min). The strategy involves (1) prosthetic conjugation of a single‐stranded oligonucleotide with [¹⁸F]FPyBrA (N‐[3‐(2‐[¹⁸F]fluoropyridin‐3‐yloxy)‐propyl]‐2‐bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [¹⁸F]siRNAs. Pure fluorine‐18‐labelled siRNAs (0.55–1.11 GBq, specific activity: 74–148 GBq/µmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [¹⁸F]fluoride (1.5–3.0%, non‐decay‐corrected isolated yields). Copyright © 2007 John Wiley & Sons, Ltd.     

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.     

Radiosynthesis of [18F]DPA‐714, a selective radioligand for imaging the translocator protein (18 kDa) with PET

Recently, a novel series of 2‐phenylpyrazolo[1,5‐a]pyrimidineacetamides has been reported as selective ligands of the translocator protein (18 kDa). Within this series, DPA‐714 (N,N‐diethyl‐2‐(2‐(4‐(2‐fluoroethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide, K_i=7.0 nM) is a compound, which had been designed with a fluorine atom in its structure, allowing labelling with fluorine‐18 (half‐life: 109.8 min) and in vivo imaging using positron emission tomography. DPA‐714 and its tosyloxy derivative (N,N‐diethyl‐2‐(2‐(4‐(2‐toluenesulfonyloxyethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) as precursor for the labelling with fluorine‐18 were synthesized in two steps from DPA‐713 (N,N‐diethyl‐2‐(2‐(4‐methoxyphenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) and obtained in 32 and 42% yields, respectively. [¹⁸F]DPA‐714 was synthesized using a simple one‐step process (a tosyloxy‐for‐fluorine nucleophilic aliphatic substitution), which has been fully automated on our Zymate‐XP robotic system. It involves: (A) reaction of K[¹⁸F]F‐Kryptofix^®222 with the tosyloxy precursor (4.5–5.0 mg, 8.2–9.1 µmol) at 165°C for 5 min in dimethyl sufloxide (0.6 mL) followed by (B) C18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative high‐performance liquid chromatography (HPLC) purification on a Waters X‐Terra? RP18. Typically, 5.6–7.4 GBq of [¹⁸F]DPA‐714 (>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 SepPak^®‐based formulation included), starting from a 37 GBq [¹⁸F]fluoride batch (overall non‐decay‐corrected and isolated radiochemical yield: 15–20%). Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐1‐β‐D‐xylofuranosyluracil ([18F]‐FMXU) for PET

The synthesis of a pyrimidine analog, 3′‐deoxy‐3′‐[¹⁸F]‐fluoro‐1‐β‐D ‐xylofuranosyluracil ([¹⁸F]‐FMXU) is reported. 5‐Methyluridine 1 was converted to its di‐methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′,5′‐di‐methoxytrityluridine 2 was converted to its 3′‐triflate 4 followed by derivatization to the respective N³‐t‐Boc product 5 . The triflate 5 was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6 , which by acid hydrolysis yielded compound 7 . The crude preparation was purified by HPLC to obtain the desired product [¹⁸F]‐FMXU. The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33% in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of [18F]PBR111, a selective radioligand for imaging the translocator protein (18 kDa) with PET

PBR111 (2‐(6‐chloro‐2‐(4‐(3‐fluoropropoxy)phenyl)imidazo[1,2‐a]pyridin‐3‐yl)‐N,N‐diethylacetamide) is a novel, reported, high‐affinity and selective ligand for the translocator protein (18 kDa). PBR111 has been labelled with fluorine‐18 (half‐life: 109.8 min) using our Zymate‐XP robotic system. The process involves (A) a simple one‐step tosyloxy‐for‐fluorine nucleophilic aliphatic substitution (performed at 165°C for 5 min in DMSO using K[¹⁸F]F‐Kryptofix^®222 and 6.8–7.6 µmol of the corresponding tosylate as precursor for labelling) followed by (B) C‐18 PrepSep cartridge pre‐purification and (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Up to 4.8 GBq (130 mCi) of [¹⁸F]PBR111 could be obtained with specific radioactivities ranging from 74 to 148 GBq/µmol (2–4 Ci/µmol) in 75–80 min (HPLC purification and SepPak^®‐based formulation included), starting from a 37.0 GBq (1.0 Ci) [¹⁸F]fluoride batch. Overall non‐decay‐corrected isolated yields were 8–13% (13–21% decay‐corrected). Copyright © 2008 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.     

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.     

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.     

Synthesis of 1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐[Methyl‐11C]thymine ([11C]FMAU) via a Stille cross‐coupling reaction with [11C]methyl iodide

1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐[methyl‐¹¹C]thymine ([¹¹C]FMAU) [¹¹C]‐ 1 was synthesised via a palladium‐mediated Stille coupling reaction of 1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐5‐(trimethylstannyl)uracil 2 with [¹¹C]methyl iodide in a one‐pot procedure. The reaction conditions were optimized by screening various catalysts and solvents, and by altering concentrations and reaction temperatures. The highest yield was obtained using Pd₂(dba)₃ and P(o‐tolyl)₃ in DMF at 130°C for 5 min. Under these conditions the title compound [¹¹C]‐ 1 was obtained in 28±5% decay‐corrected radiochemical yield calculated from [¹¹C]methyl iodide (number of experiments=7). The radiochemical purity was >99% and the specific radioactivity was 0.1 GBq/μmol at 25 min after end of bombardment. In a typical experiment 700–800 MBq of [¹¹C]FMAU [¹¹C]‐ 1 was obtained starting from 6–7 GBq of [¹¹C]methyl iodide. A mixed ¹¹C/¹³C synthesis to yield [¹¹C]‐ 1 /(¹³C)‐ 1 followed by ¹³C‐NMR analysis was used to confirm the labelling position. The labelling procedure was found to be suitable for automation. Copyright © 2002 John Wiley & Sons, Ltd.     

18F‐labelling of a potent nonpeptide CCR1 antagonist: synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[18F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea in an automated module

The synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[¹⁸F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea ( [¹⁸F]4 ), a potent nonpeptide CCR1 antagonist, is described as a module‐assisted two‐step one‐pot procedure. The final product was obtained utilizing the reductive amination of the formed 4‐[¹⁸F]fluorobenzaldehyde ( 2 ) with a piperazine derivative 3 and sodium cyanoborohydride. After HPLC purification of the final product [¹⁸F]4 , its solid phase extraction, formulation and sterile filtration, the isolated (not decay‐corrected) radiochemical yields of [¹⁸F]4 were between 7 and 13% (n=28). The time of the entire manufacturing process did not exceed 95 min. The radiochemical purity of [¹⁸F]4 was higher than 95%, the chemical purity ?60% and the enantiomeric purity >99.5%. The specific radioactivity was in the range of 59–226 GBq/µmol at starting radioactivities of 23.6–65.0 GBq [¹⁸F]fluoride. 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.     

Radiosynthesis of 7‐chloro‐N,N‐dimethyl‐5‐[11C]methyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide, [11C]SSR180575, a novel radioligand for imaging the TSPO (peripheral benzodiazepine receptor) with PET

SSR180575 (7‐chloro‐N,N,5‐trimethyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide) is the lead compound of an original pyridazinoindole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short‐lived positron‐emitter carbon‐11 (T_1/2: 20.38 min) at its 5‐methylpyridazino[4,5‐b]indole moiety as well as at its N,N‐dimethylacetamide function by methylation of the corresponding nor‐analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole‐N‐methyl‐¹¹C]SSR180575, where routine production batches of 4.5–5.0 GBq of radiochemically pure (>99%) i.v. injectable solutions (specific radioactivities: 50–90 GBq/ µ mol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [¹¹C]CO₂ cyclotron production batch (non‐decay‐corrected overall radiochemical yields: 8–9%). The process comprises (1) trapping at ?10°C of [¹¹C]methyl triflate in DMF (300 µ l) containing 0.2–0.3 mg of the indole precursor for labeling and 4 mg of K₂CO₃ (excess); (2) heating at 120°C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi‐preparative reversed‐phase HPLC (Zorbax^® SB‐C‐18). In vivo pharmacological properties of [indole‐N‐methyl‐¹¹C]SSR180575 as a candidate for imaging neuroinflammation with positron emission tomography are currently evaluated. Copyright © 2010 John Wiley & Sons, Ltd.     

Automated radiosynthesis of N‐(4‐[18F]fluorobenzyl)‐2‐bromoacetamide: an F‐18‐labeled reagent for the prosthetic radiolabeling of oligonucleotides

The potential for radiolabeled antisense oligonucleotides to image gene expression combined with the enhanced resolution of positron‐emission tomography justifies the continued interest in the development of oligonucleotides tagged with positron‐emitting radionuclides. The radiolabeling of oligonucleotides is a multi‐step process and may require handling large amounts of radioactivity initially. A previously reported method for radiolabeling oligonucleotides with N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide was adapted for use in a commercially available automated synthesis unit by linking two reaction trains. The yield of N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide ranged from 3 to 18% and the synthesis was completed within 1 h. Challenges in using this unit included the maintenance of anhydrous conditions for the effective reduction of 4‐[¹⁸F]fluorobenzonitrile. Preliminary results indicated that a mean yield of 36% could be obtained upon incubation of an oligonucleotide with N–(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide. The entire synthesis could be performed within 3 h. 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.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.     

Radiosynthesis of (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl] oxazolidin‐2‐[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase‐B with PET

Within a novel series of 2‐oxazolidinones developed in the past by Sanofi‐Synthélabo, SL25.1188 ((S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐one), a compound that inhibits selectively and competitively MAO‐B in human and rat brain (Ki values of 2.9 and 8.5 nM for MAO‐B, respectively, and ED_{50 (rat)}: 0.6 mg/kg p.o.), was considered an appropriate candidate for imaging this enzyme with positron emission tomography. SL25.1188 was labelled with carbon‐11 (T_1/2: 20.38 min) in one chemical step using the following process: (i) reaction of [¹¹C]phosgene with the corresponding ring‐opened precursor (1.2–2.5 mg) at 100°C for 2 min in dichloromethane (0.5 mL) followed by (ii) concentration to dryness of the reaction mixture and finally (iii) semi‐preparative HPLC purification on a Waters Symmetry^® C18. A total of 300–500 MBq of [¹¹C]SL25.1188 (>95% chemically and radiochemically pure) could be obtained within 30–32 min (Sep‐pak‐based formulation included) with specific radioactivities ranging from 50 to 70 GBq/µmol (3.5–7% decay‐corrected radiochemical yield, based on starting [¹¹C]CH₄). 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.     

(R)‐N‐Methyl‐3‐(3′‐[18F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (18F‐MFP3) as a potential PET imaging agent for norepinephrine transporter

A decline of norepinephrine transporter (NET) level is associated with several psychiatric and neurological disorders. Therefore positron emission tomography (PET) imaging agents are greatly desired to study the NET pathway. We have developed a C‐fluoropropyl analog of nisoxetine: (R)‐N‐methyl‐3‐(3′‐[¹⁸F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (¹⁸F‐MFP3) as a new potential PET radiotracer for NET with the advantage of the longer half‐life of fluorine‐18 (110 min compared with carbon‐11 (20 min). Synthesis of (R)‐N‐methyl‐3‐(3′‐fluoropropyl)phenoxy)‐3‐phenylpropanamine (MFP3) was achieved in five steps starting from (S)‐N‐methyl‐3‐ol‐3‐phenylpropanamine in approx. 3–5% overall yields. In vitro binding affinity of nisoxetine and MFP3 in rat brain homogenates labeled with ³H‐nisoxetine gave Ki values of 8.02 nM and 23 nM, respectively. For radiosynthesis of ¹⁸F‐MFP3, fluorine‐18 was incorporated into a tosylate precursor, followed by the deprotection of the N‐BOC‐protected amine group with a 15% decay corrected yield in 2.5 h. Reverse‐phase chromatographic purification provided ¹⁸F‐MFP3 in specific activities of >2000 Ci/mmol. Fluorine‐18 labeled ¹⁸F‐MFP3 has been produced in modest radiochemical yields and in high specific activities. Evaluation of ¹⁸F‐MFP3 in animal imaging studies is in progress in order to validate this new fluorine‐18 radiotracer for PET imaging of NET. Copyright © 2010 John Wiley & Sons, Ltd.