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.     

Radiosynthesis of [11C]SL25.1188 via [11C]CO2 fixation for imaging monoamine oxidase B

Carbon‐11‐labelled (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐[¹¹C]‐one ([¹¹C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one‐pot procedure directly from [¹¹C]CO₂, thereby precluding the use of [¹¹C]COCl₂. Formulated [¹¹C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [¹¹C]CO₂, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n = 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [¹¹C]SL25.1188 at ambient temperature and is suitable for human imaging studies.     

Synthesis of (±) 3‐(6‐nitro‐2‐quinolinyl)‐[9‐methyl‐11C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([11C‐methyl]NS 4194)

(±) 3‐(6‐Nitro‐2‐quinolinyl)‐[9‐methyl‐¹¹C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([¹¹C‐methyl]NS 4194), a selective serotonin reuptake inhibitor (SSRI), was synthesised within 35 min after end of bombardment with a radiochemical purity >98%. It had a decay‐corrected radiochemical yield of 7% after preparative HPLC, and a specific radioactivity around 37 GBq/μmol (EOS). A typical production starting with 40 GBq [¹¹C]CO₂ yielded 800 MBq of radiolabelled [¹¹C‐methyl]NS 4194 in a formulated solution. The synthesis of the precursor to [¹¹C‐methyl]NS 4194, (±) 9‐H‐3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane, as well as the unlabelled analogue (±) 9‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane (NS 4194), are also described. Copyright © 2002 John Wiley & Sons, Ltd.     

Facile and improved synthesis of [11C]Me‐QNB

[¹¹C]Me‐QNB is a muscarinic acetylcholinergic receptor antagonist that has been used for the assessment of myocardial muscarinic receptors density in different cardiovascular pathologies. In the current technical note, we report a facile, highly efficient and fully automated method for the preparation of this radiotracer. The radiosynthesis was performed by reaction of [¹¹C]CH₃I with the desmethylated precursor (QNB) at room temperature using the captive solvent method. Excellent radiochemical yield (91.1 ± 2.4%, decay‐corrected) and radiochemical purity (>99.5%), and good specific activity (137 ± 5 GBq/µmol) were obtained when the purification was performed by reverse phase HPLC in overall synthesis time <31 min. Purification using solid‐phase extraction offered lower radiochemical yield (27.6 ± 3.1%, decay‐corrected) and radiochemical purity (>95%) but higher specific activity (244 ± 18 GBq/µmol) in shorter reaction times (<21 min). These results, especially concerning radiochemical yield, significantly improve those previously reported in which the reaction was performed in a vial and the purification step was based on ionic chromatography.     

Improved synthesis and application of [11C]benzyl iodide in positron emission tomography radiotracer production

Positron emission tomography has increased the demand for new carbon‐11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [¹¹C]benzyl iodide ([¹¹C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [¹¹C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D₂ antagonist [¹¹C]clebopride as a proof of concept. [¹¹C]BnI was synthesized from [¹¹C]CO₂ via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one‐pot procedure, [¹¹C]BnI was synthesized in 11 min from [¹¹C]CO₂ with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [¹¹C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid‐phase intermediate purification. [¹¹C]Clebopride was synthesized within 28 min from [¹¹C]CO₂ in an isolated decay‐corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [¹¹C]BnI to product was 82 ± 11%. The reliable synthesis of [¹¹C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development. Copyright © 2015 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.     

Synthesis and evaluation of [11C]RU40555, a selective glucocorticoid receptor antagonist

We demonstrated the synthesis of carbon‐11 labeled 17‐α‐hydroxy‐11‐β‐/4‐/[methyl]‐[1‐methylethyl]‐aminophenyl/‐17α‐[prop‐1‐ynyl]esta‐4‐9‐diene‐3‐one (RU40555), a selective glucocorticoid receptor (GR) antagonist, and examined the in vivo profile of [¹¹C]RU40555. [¹¹C]RU40555 was synthesized by direct N‐methylation with [¹¹C]CH₃OTf at 60°C for 5 min and an injectable solution of [¹¹C]RU40555 was obtained in 31 min at the end of bombardment. The decay‐corrected radiochemical yield was 19%, the specific radioactivity was 57.5±14.0 GBq/µmol, and the radiochemical purity was more than 99% as determined by HPLC. In rat experiments, the effects of adrenalectomy (ADX) on brain accumulation of [¹¹C]RU40555 were examined. ADX significantly decreased plasma corticosterone levels, and significantly increased brain accumulation of [¹¹C]RU40555. We succeeded in developing a rapid automated synthesis method for [¹¹C]RU40555, a GR antagonist, and showed [¹¹C]RU40555 had a potential as a PET tracer for mapping GR. Copyright © 2005 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.     

Automated radiosynthesis of [11C]MTP38—a phosphodiesterase 7 imaging tracer—using [11C]hydrogen cyanide for clinical applications

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[¹¹C]carbonitrile ([¹¹C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [¹¹C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [¹¹C]MTP38 using [¹¹C]hydrogen cyanide ([¹¹C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [¹¹C]MTP38 was performed using an automated ¹¹C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [¹¹C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [¹¹C]CO₂ at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [¹¹C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [¹¹C]MTP38 for clinical applications using an ¹¹C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [¹¹C]MTP38 suitable for clinical applications.     

Radiosynthesis of [11C]paclitaxel

[¹¹C]paclitaxel, a potential solid tumor imaging agent, was synthesized by reacting [α‐¹¹C]benzoyl chloride with the primary amine precursor of paclitaxel. The time for synthesis, purification, and formulation was 38 min from end of bombardment with an average specific radioactivity of 49.9 GBq/μmol (1349 mCi/μmol) at end of synthesis. The average decay corrected radiochemical yield was 7% with greater than 99% radiochemical purity. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [11C]gefitinib for imaging epidermal growth factor receptor tyrosine kinase with positron emission tomography

We have synthesized N‐(3‐chloro‐4‐fluorophenyl)‐7‐[¹¹C]methoxy‐6‐[3‐(morpholin‐4‐yl)propoxy]quinazolin‐4‐amine, [¹¹C]gefitinib ([¹¹C]Iressa), a high affinity (IC₅₀ = 2 nM) inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR‐TK), in solution and in a semi‐automated stainless loop methylation system using [¹¹C]methyl triflate. The trapping efficiency for [¹¹C]methyl triflate in solution was higher than in the solvent film generated in the loop system, thus the overall radiochemical yield was considerably higher for the synthesis in solution. The average radiochemical yield for the solution chemistry was 15% with an average specific radioactivity of approximately 9000 mCi/µmole at EOS in one step from its corresponding desmethyl phenol precursor. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of [N‐methyl‐11C]methylene blue

In this paper we present the radiochemical synthesis of the novel compound [N‐methyl‐¹¹C]methylene blue. The synthesis of [N‐methyl‐¹¹C]methylene blue was accomplished by means of ¹¹C‐methylation of commercially available Azure B using [¹¹C]methyl trifluoromethanesulfonate ([¹¹C]methyl triflate). Following purification [N‐methyl‐¹¹C]methylene blue was obtained with a radiochemical purity greater than 97% in a 4–6% decay corrected radiochemical yield. The synthesis was completed in an average of 35 min following the end of bombardment. Copyright © 2003 John Wiley & Sons, Ltd.     

Reduction of [11C]CO2 to [11C]CO using solid supported zinc

A new method for the reduction of no‐carrier‐added [¹¹C]carbon dioxide into [¹¹C]carbon monoxide ([¹¹C]CO) is described, in which the reductant (zinc) is supported on fused silica particles. Using this setup, which allows for a reduction temperature (485°C) well above the melting point for zinc (420°C), radiochemical yields of up to 96% (decay‐corrected) were obtained. A slight decrease in radiochemical yield was observed upon repeated [¹¹C]CO productions (93 ± 3%, n  = 20). The methodology is convenient and efficient and provides a straightforward path to no‐carrier‐added production of [¹¹C]CO.     

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.     

The first synthesis of [11C]oseltamivir: a tool for elucidating the relationship between Tamiflu and its adverse effects on the central nervous system

Oseltamivir phosphate (Tamiflu ^® ) is an anti‐influenza drug approved in many countries. Recently, in Japan, adverse effects on the central nervous system have been reported in younger patients administrated with Tamiflu. As a tool for elucidating the relationship between Tamiflu and its adverse effects, ¹¹C‐labeled oseltamivir was synthesized through a two‐step reaction involving [¹¹C]acetylation with [1‐¹¹C]acetyl chloride. Starting from approximately 37.0 GBq of [¹¹C]CO₂, 1.2–1.8 GBq (n=5) of [¹¹C]oseltamivir was obtained at the end of synthesis (EOS) 36–39 min after the end of bombardment. Radiochemical purity and specific activity were greater than 98% and 2.7–6.3 GBq/µmol at EOS, respectively. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis of the diastereomerically pure (E)‐[11C]ABP688

We report an efficient protocol for the radiosynthesis of diastereomerically pure (E)‐[¹¹C]ABP688, a positron emission tomography (PET) tracer for metabotropic glutamate type 5 (mGlu5) receptor imaging. The protocol reliably provides sterile and pyrogen‐free formulation of (E)‐[¹¹C]ABP688 suitable for preclinical and clinical PET imaging with >99% diastereomeric excess (d.e.), >99% overall radiochemical purity (RCP), 14.9 ± 4.3% decay‐corrected radiochemical yield (RCY), and 148.86 ± 79.8 GBq/μmol molar activity in 40 minutes from the end of bombardment.     

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 of [1‐11C]propyl and [1‐11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions

A method to prepare [1‐¹¹C]propyl iodide and [1‐¹¹C]butyl iodide from [¹¹C]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [¹¹C]carbon monoxide and hydrogen gave [1‐¹¹C]propionaldehyde and [1‐¹¹C]propionic acid. The carbonylation products were reduced and subsequently converted to [1‐¹¹C]propyl iodide. Labelled propyl iodide was obtained in 58±4% decay corrected radiochemical yield and with a specific radioactivity of 270±33 GBq/µmol within 15 min from approximately 12 GBq of [¹¹C]carbon monoxide. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [¹¹C]carbon monoxide, in 34±2% decay corrected radiochemical yield and with a specific radioactivity of 146±20 GBq/µmol. The alkyl iodides were used in model reactions to synthesize [O‐propyl‐1‐¹¹C]propyl and [O‐butyl‐1‐¹¹C]butyl benzoate. Propyl and butyl analogues of etomidate, a β‐11‐hydroxylase inhibitor, were also synthesized. Copyright © 2006 John Wiley & Sons, Ltd.     

[11C]methyl iodide from [11C]methane and iodine using a non‐thermal plasma method

A method and an apparatus for preparing [¹¹C]methyl iodide from [¹¹C]methane and iodine in a single pass through a non‐thermal plasma reactor has been developed. The plasma was created by applying high voltage (400 V/31 kHz) to electrodes in a stream of helium gas at reduced pressure. The [¹¹C]methane used in the experiments was produced from [¹¹C]carbon dioxide via reduction with hydrogen over nickel. [¹¹C]methyl iodide was obtained with a specific radioactivity of 412 ± 32 GBq/µmol within 6 min from approximately 24 GBq of [¹¹C]carbon dioxide. The decay corrected radiochemical yield was 13 ± 3% based on [¹¹C]carbon dioxide at start of synthesis. [¹¹C]Flumazenil was synthesized via a N‐alkylation with the prepared [¹¹C]methyl iodide. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [1‐11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions

A method is presented for preparing [1‐¹¹C]ethyl iodide from [¹¹C]carbon monoxide. The method utilizes methyl iodide and [¹¹C]carbon monoxide in a palladium‐mediated carbonylation reaction to form a mixture of [1‐¹¹C]acetic acid and [1‐¹¹C]methyl acetate. The acetates are reduced to [1‐¹¹C]ethanol and subsequently converted to [1‐¹¹C]ethyl iodide. The synthesis time was 20 min and the decay‐corrected radiochemical yield of [1‐¹¹C]ethyl iodide was 55 ± 5%. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Ethyl iodide was used in two model reactions, an O‐alkylation and an N‐alkylation. Starting with approximately 2.5 GBq of [¹¹C]carbon monoxide, the isolated decay‐corrected radiochemical yields for the ester and the amine derivatives were 45 ± 0.5% and 25 ± 2%, respectively, based on [¹¹C]carbon monoxide. Starting with 10 GBq of [¹¹C]carbon monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific radioactivity of 36 GBq/µmol. Copyright © 2004 John Wiley & Sons, Ltd.