Highly efficient solid phase supported radiosynthesis of [11C]PiB using tC18 cartridge as a “3‐in‐1” production entity

Pittsburgh compound B ([¹¹C]PiB) is the gold standard positron emission tomography (PET) tracer for the in vivo imaging of amyloid plaques. Currently, it is synthesized by either solution chemistry or using a “dry loop” approach followed by HPLC purification within 30 minutes starting from [¹¹C]CO₂. Here, we report a novel, highly efficient solid phase supported carbon‐11 radiolabeling procedure using commercially available disposable tC18 cartridge as a “3‐in‐1” entity: reactor, purifier, and solvent replacement system. [¹¹C]PiB is synthesized by passing gaseous [¹¹C]CH₃OTf through a tC18 cartridge preloaded with a solution of precursor. Successive elution with aqueous ethanol solutions allows for nearly quantitative separation of the reaction mixture to provide chemically and radiochemically pure PET tracer. [¹¹C]PiB suitable for human injection is produced within 10 minutes starting from [¹¹C]CH₃OTf (20 min from [¹¹C]CO₂) in 22% isolated yield not corrected for decay and molar activity of 190 GBq/μmol using 0.2 mg of precursor. This technique reduces the amount of precursor and other supplies, avoids use of preparative HPLC and toxic solvents, and decreases the time between consecutive production batches. Solid phase supported technique can facilitate [¹¹C]PiB production compliant with Good Manufacturing Practice (GMP) and improve synthesis reliability.     

Efficient in‐loop synthesis of high specific radioactivity [11C]carfentanil

The synthesis of the precursor for [¹¹C]carfentanil and the precursor labelling with ¹¹C have both been improved. The problem ‘bottleneck’ step in the carfentanil precursor synthesis, due to low chemical yield (14%) of intermediates nitrile into amide conversion, has been solved. Application of a H₂O₂/K₂CO₃/DMSO reaction method significantly increased the yield of this chemical transformation (up to 84%). A simple and straight‐forward synthesis of [¹¹C]carfentanil was achieved by combining in‐loop methylation of the ammonia salt of the precursor by [¹¹C]CH₃I, using tetrabutylammonium hydroxide as a base, with a previously developed product purification procedure using a C2 extraction disc. A decay corrected yield with respect to [¹¹C]CH₃I of [¹¹C]carfentanil was 64±12% (n=6) with the synthesis time of 21 min. The radiochemical purity was >98%. Comparatively high specific radioactivity of [¹¹C]carfentanil [11.2±4.8 Ci/μmol (EOS, n=5)] was partially attributed to the use of [¹¹C]methane target gas for production of carbon‐11 methyl iodide. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of a 11C‐labelled taxane derivative by [1‐11C]acetylation

The ¹¹C‐labelling of the taxane derivative BAY 59‐8862 ( 1 ), a potent anticancer drug, was carried out as a module‐assisted automated multi‐step synthesis procedure. The radiotracer [¹¹C]1 was synthesized by reacting [1‐¹¹C]acetyl chloride ( 6 ) with the lithium salt of the secondary hydroxy group of precursor 3 followed by deprotection. After HPLC purification of the final product [¹¹C]1 , its solid‐phase extraction, formulation and sterile filtration, the decay‐corrected radiochemical yield of [¹¹C]1 was in the range between 12 and 23% (related to [¹¹C]CO₂; n=10). The total synthesis time was about 54 min after EOB. The radiochemical purity of [¹¹C]1 was greater than 96% and the chemical purity exceeded 80%. The specific radioactivity was 16.8±4.7 GBq/µmol (n=10) at EOS starting from 80 GBq of [¹¹C]CO₂. Copyright © 2006 John Wiley & Sons, Ltd.     

Nitroaldol reaction of nitro[11C]methane to form 2‐(hydroxymethyl)‐2‐nitro[2‐11C]propane‐1,3‐diol and [11C]Tris

The nitroaldol reaction of nitro[¹¹C]methane and formaldehyde, which yields 2‐(hydroxymethyl)‐2‐nitro[2‐¹¹C]propane‐1,3‐diol, is explored. The fluoride‐ion‐assisted nitroaldol reaction using (C₄H₉)₄NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay‐corrected) in 3 min at room temperature. Neither 2‐nitro[2‐¹¹C]ethanol nor 2‐nitro[2‐¹¹C]propane‐1,3‐diol was observed under the reaction conditions. The preparation of 2‐amino‐2‐(hydroxymethyl)‐[2‐¹¹C]propane‐1,3‐diol ([¹¹C]Tris) was described, which was followed by the nitro‐group reduction using NiCl₂ and NaBH₄ in aqueous MeOH. The decay‐corrected radiochemical conversion to [¹¹C]Tris was 68.0±6.5% in two steps. Copyright © 2010 John Wiley & Sons, Ltd.     

N‐heterocyclic carbenes as ligands in palladium‐mediated [11C]radiolabelling of [11C]amides for positron emission tomography

A model palladium‐mediated carbonylation reaction synthesizing N‐benzylbenzamide from iodobenzene and benzylamine was used to investigate the potential of four N‐heterocyclic carbenes (N,N′‐bis(diisopropylphenyl)‐4,5‐dihydroimidazolinium chloride ( I ), N,N′‐bis(1‐mesityl)‐4,5‐dihydroimidazolinium chloride ( II ), N,N′‐bis(1‐mesityl)imidazolium chloride ( III ) and N,N′‐bis(1‐adamantyl)imidazolium chloride ( IV )) to act as supporting ligands in combination with Pd₂(dba)₃. Their activities were compared with other Pd‐diphosphine complexes after reaction times of 10 and 120 min. Pd₂(dba)₃ and III were the best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [¹¹C]N‐benzylbenzamide in good radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically unreactive and insoluble [¹¹C]CO which was then released and reacted via the Pd‐mediated carbonylation process. Potentially useful side products [¹¹C]N,N′‐dibenzylurea and [¹¹C]benzoic acid were also observed. Increased amounts of [¹¹C]N,N′‐dibenzylurea were yielded when PdCl₂ was the Pd precursor. Reduced yields of [¹¹C]benzoic acid and therefore improved RCP were seen for III /Pd₂(dba)₃ over commonly used dppp/Pd₂(dba)₃ making it more favourable in this case. Copyright © 2010 John Wiley & Sons, Ltd.     

Preparation of [11C]methyl nona‐fluorobutyl‐1‐sulfonate ([11C]MeONf) and its use in the synthesis of [11C]‐6‐OH‐BTA‐1

The rapid, simple and high‐yield synthesis of the extraordinarily reactive ¹¹C‐methylating agent, [¹¹C]methyl nona‐fluorobutyl‐1‐sulfonate ([¹¹C]MeONf), and its use in the synthesis of the promising β‐amyloid imaging agent, [¹¹C]‐6‐OH‐BTA‐1, is reported. In terms of radioactive methylation yields, [¹¹C]MeONf seems to surpass [¹¹C]methyl trifluoromethansulfonate ([¹¹C]MeOTf) as a methylating agent in this particular case giving the ¹¹C‐labelled compound in high‐preparative radiochemical yields between 27 and 29% EOS with a minimum formation of radioactive by‐products. Copyright © 2007 John Wiley & Sons, Ltd.     

Simple synthesis of [1‐11C]acetate

[1‐¹¹C]Acetate is prepared by carboxylation of a Grignard reagent, CH₃MgBr, on a simple polyethylene loop with cyclotron‐produced [¹¹C]carbon dioxide, followed by hydrolysis and purification on solid‐phase extraction cartridges. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiolabeling of two 11C‐labeled formylating agents and their application in the preparation of [11C]benzimidazole

The radiolabeling of formyl groups with carbon‐11 has so far been awarded little attention in the literature. We report here the preparation of the methyl and trifluoroethyl esters of [¹¹C]formic acid and their use as ¹¹C‐formylating agents in the preparation of [¹¹C]benzimidazole. Methyl‐ethyl and trifluoroethyl [¹¹C]formates were obtained in 36–45% radiochemical yield using a two‐step two‐pot process starting from [¹¹C]carbon dioxide. The analytical radiochemical yield of [¹¹C]benzimidazole using each of these two ¹¹C‐formylating agents exceeded 96%. Given the high yields of the ¹¹C‐formylating agents as well as the high yield of [¹¹C]benzimidazole following their application, we expect these agents to find utility for a wider range of substrates.     

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.     

Synthesis of [11C‐carbonyl]hydroxyureas by a rhodium‐mediated carbonylation reaction using [11C]carbon monoxide

[¹¹C]Hydroxyurea has been successfully labelled using [¹¹C]carbon monoxide at low concentration. The decay‐corrected radiochemical yield was 38±3%, and the trapping efficiency of [¹¹C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium‐mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5‐cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]₂) and 1,2‐bis(diphenylphosphino)ethane (dppe). (¹³C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by ¹³C‐NMR. In order to perform accurate LC–MS identification, the derivative 1‐hydroxy‐3‐phenyl[¹¹C]urea was synthesized in a 35±4% decay‐corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1‐hydroxy‐3‐phenyl[¹¹C]urea was collected starting from 6.75 GBq of [¹¹C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [¹¹C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients. Copyright © 2006 John Wiley & Sons, Ltd.     

An improved synthesis of [11C]MENET via Suzuki coupling with [11C]methyl iodide

[¹¹C]MENET, a promising norepinephrine transporter imaging agent, was prepared by Suzuki cross coupling of 1 mg N‐t‐Boc pinacolborate precursor with [¹¹C]CH₃I in DMF using palladium complex generated in situ from Pd₂(dba)₃ and (o‐CH₃C₆H₄)₃P together with K₂CO₃ as the co‐catalyst, followed by deprotection with trifluoroacetic acid. This improved radiolabeling method provided [¹¹C]MENET in high radiochemical yield at end of synthesis (EOS, 51 ± 3%, decay‐corrected from end of ¹¹CH₃I synthesis, n = 6), moderate specific activity (1.5–1.9 Ci/µmol at EOS), and high radiochemical (>98%) and chemical purity (>98%) in a synthesis time of 60 ± 5 min from the end of bombardment. Copyright © 2013 John Wiley & Sons, Ltd.     

An updated synthesis of [11C]carfentanil for positron emission tomography (PET) imaging of the μ‐opioid receptor

[¹¹C]Carfentanil ([¹¹C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ‐opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [¹¹C]MeOTf, and purified using a C2 solid‐phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [¹¹C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [¹¹C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.     

Novel synthesis of [1‐11C]γ‐vinyl‐γ‐aminobutyric acid ([1–11C]GVG) for pharmacokinetic studies of addiction treatment

γ‐Vinyl‐γ‐aminobutyric acid (GVG, Vigabatrin^®), a suicide inhibitor of GABA‐transaminase (GABA‐T), has been suggested as a new drug for the treatment of substance abuse. In order to better understand its pharmacokinetics and potential side effects, we have developed a radiosynthesis of carbon‐11 (t_1/2=20 min) labeled GVG for positron emission tomographic (PET) studies. We report here a novel synthetic strategy to prepare the precursor and to efficiently label GVG with C‐11. 5‐Bromo‐3‐(carbobenzyloxy)amino‐1‐pentene was synthesized in five steps from homoserine lactone, including reduction and methylenation. This was used in a one‐pot, two‐step radiosynthesis. Displacement of bromide with no‐carrier‐added [¹¹C]cyanide followed by acid hydrolysis afforded [1‐¹¹C]GVG with decay corrected radiochemical yields of 27±9% (n=6, not optimized) with respect to [¹¹C]cyanide in a synthesis time of 45 min. Copyright © 2002 John Wiley & Sons, Ltd.     

Radiosynthesis of [11C]ximelagatran via palladium catalyzed [11C]cyanation

N‐hydroxyamidines (amidoximes) may be used in prodrug technology in improving oral bioavailability of drugs containing amidino functional groups. In the body, amidoximes are reduced quickly to amidines by enzymes that are present in several organs. Ximelagatran is a benzamidoxime and ethyl ester prodrug of melagatran, which is a thrombin inhibitor. Our aim was to develop a fast and efficient labeling route for the synthesis of [¹¹C]ximelagatran ([¹¹C]3) with a label in a metabolically stable position. [¹¹C]3 was synthesized via a two‐step synthesis sequence, starting from palladium catalyzed [¹¹C]cyanation of its corresponding bromide precursor (2‐[2‐(4‐bromo‐benzylcarbamoyl)‐azetidin‐1‐yl]‐1‐cyclohexyl‐2‐oxo‐ethyl amino‐acetic acid ethyl ester) (1), followed by a reaction with hydroxylamine. [¹¹C]3 was synthesized with 27±17% total overall decay corrected yield (specific radioactivity of 2360±165 Ci/mmol at EOS), with a total synthesis time of 45 min. A fast and efficient labeling route for the synthesis of [¹¹C]3 was developed. Copyright © 2008 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.     

Synthesis of the phytohormone [11C]methyl jasmonate via methylation on a C18 Sep Pak™ cartridge

[¹¹C]labeled (±)‐methyl jasmonate was synthesized using a C₁₈ Sep Pak? at ～100°C to sustain a solid‐supported ¹¹C‐methylation reaction of sodium (±)‐jasmonate using [¹¹C]methyl iodide. After reaction, the Sep Pak was rinsed with acetone to elute the labeled product, and the solvent evaporated rendering [¹¹C]‐(±)‐methyl jasmonate at 96% radiochemical purity. The substrate, (±)‐jasmonic acid, was retained on the Sep Pak so further chromatography was unnecessary. Total synthesis time was 25 min from the end of bombardment (EOB) which included 15 min to generate [¹¹C]methyl iodide using the GE Medical Systems PET Trace MeI system, 5 min for reaction and extraction from the cartridge, and 5 min to reformulate the product for plant administration. An overall radiochemical yield (at EOB) of 17±4.3% was obtained by this process, typically producing 10 mCi of purified radiotracer. A specific activity of 0.5 Ci/µmol was achieved using a short 3 min cyclotron beam to produce the starting ¹¹C. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and preliminary PET study of the 5‐HT7 receptor antagonist [11C]DR4446

DR4446 (1‐methyl‐2a‐[4‐(4,5,6,7‐tetrahydrothieno[3,2‐c]pyridin‐5‐yl)butyl]‐2a,3,4,5‐tetrahydro‐1H‐benz[cd]indole‐2‐one) is a potent 5‐HT₇ receptor antagonist (K_i=9.7 nM) with a high selectivity over other 5‐HT family receptors (K_i for 5‐HT_1A: 770 nM; for other 5‐HT receptors: >1000 nM). As a positron emission tomography (PET) tracer for the 5‐HT₇ receptor, [¹¹C]DR4446 was synthesized at high radiochemical purity ( >98%) with specific activity of 73–120 GBq/μmol at the end of synthesis by the alkylation of the desmethyl precursor (1) with [¹¹C]CH₃I in the presence of NaH. A PET study in monkey demonstrated that [¹¹C]DR4446 had good permeability into the brain, and had a specific binding component in the brain regions including the thalamus, possibly an area in the 5‐HT₇ receptors. Metabolite analysis showed that [¹¹C]DR4446 was relatively stable and low percentages of two radio‐labeled metabolites were detected in the plasma of monkey using HPLC. Copyright © 2002 John Wiley & Sons, Ltd.     

A convenient synthesis of [11C]paraquat and other [N‐methyl‐11C]bisquaternary ammonium compounds

[¹¹C]Paraquat was synthesized by the reaction of [¹¹C]methyl triflate with the mono‐triflate salt of 1‐methyl‐[4,4′]bipyridinyl. The product was selectively separated from the precursor by a microcolumn of Chelex 100 ion exchange resin. The method was applied to the synthesis of a variety of [N‐methyl‐¹¹C]bisquaternary ammonium compounds. This is the first reported use of a chelating cation exchange resin for the selective purification of organic dications. Copyright © 2002 John Wiley & Sons, Ltd.     

A combined loop‐SPE method for the automated preparation of [11C]doxepin

A simple and versatile loop‐solid phase extraction (SPE) method was developed for the automated preparation of [¹¹C]doxepin, a histamine H₁ receptor antagonist, from [¹¹C]methyl triflate ([¹¹C]MeOTf). This labeling agent was passed through a Teflon or Tefzel loop coated internally with a film of the precursor solution. The reaction products were then flushed from the loop to a short SPE column, where they were concentrated and then injected onto a semi‐preparative HPLC column simply by switching an injection valve. By applying this combined loop‐SPE technique the whole procedure turned out to be easily automated. The formation of [¹¹C]methylated doxepin ([¹¹C]methyldoxepin) was observed and the ratio of doxepin to methyldoxepin was found to be clearly correlated with the mass ratio of nordoxepin to MeOTf. This observation highlights the importance of [¹¹C]MeOTf specific activity in the [¹¹C]methylation of secondary amines. Using this method, [¹¹C]Doxepin was prepared in over 40% radiochemical yield from high specific activity [¹¹C]MeOTf. Copyright © 2002 John Wiley & Sons, Ltd.