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.     

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.     

High-yielding,automated radiosynthesis of [11C]martinostat using [11C]methyl triflate

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [¹¹C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug–occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [¹¹C]martinostat using [¹¹C]methyl triflate in ethanol, as opposed to the originally described synthesis using [¹¹C]methyl iodide and DMSO. [¹¹C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5–1.8 GBq (41–48 mCi; n = 3) of formulated [¹¹C]martinostat was obtained from solid-phase extraction using a hydrophilic–lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [¹¹C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [¹¹C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.     

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.     

Efficient syntheses of [11C]zidovudine and its analogs by convenient one‐pot palladium(0)–copper(I) co‐mediated rapid C‐[11C]methylation

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one‐pot method for Pd(0)–Cu(I) co‐mediated rapid C–C coupling of [¹¹C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [¹¹C]zidovudine, [¹¹C]stavudine, and [¹¹C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4–7.0 GBq) and specific radioactivity (74–147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one‐pot Pd(0)–Cu(I) co‐mediated rapid C‐[¹¹C]methylation also worked well for syntheses of [methyl‐¹¹C]thymidine and [methyl‐¹¹C]4′‐thiothymidine, resulting twice the radioactivity of those prepared by a previous two‐pot method. The mechanism of one‐pot Pd(0)–Cu(I) co‐mediated rapid C‐[¹¹C]methylation was also discussed.     

Synthesis of 1,1′ [11C]‐methylene‐di‐(2‐naphthol) ([11C]ST1859) for PET studies in humans

1,1′‐Methylene‐di‐(2‐naphthol) (ST1859), a candidate drug for the treatment of Alzheimer's disease, was radiolabelled with carbon‐11 with the aim to perform PET microdosing studies in humans. The radiosynthesis was automated in a commercial synthesis module (Nuclear Interface PET tracer synthesizer) and proceeded via reaction of [¹¹C]formaldehyde with 2‐naphthol. [¹¹C]formaldehyde was prepared by catalytic dehydrogenation of [¹¹C]methanol (conversion yield: 48±11% (n = 19)) employing a recently developed silver‐containing ceramic catalyst. Starting from 69±3 GBq of [¹¹C]carbon dioxide (n = 19), 4±1 GBq of [¹¹C]ST1859 (decay‐corrected to the end of bombardment), readily formulated for intravenous administration, could be obtained in an average synthesis time of 38 min. The specific radioactivity of [¹¹C]ST1859 at the end of synthesis exceeded 32 GBq/µmol. Copyright © 2005 John Wiley & Sons, Ltd.     

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 diethyl [carbonyl‐11C]malonate from [11C]carbon monoxide by rhodium‐promoted carbonylation and its application as a reaction intermediate

Rhodium‐mediated carbonylation reaction was applied to synthesize diethyl [carbonyl‐¹¹C]malonate using [¹¹C]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol 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), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [¹¹C]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/µmol (7.28 nmol total mass) after 8 µAh bombardment and 35 min synthesis. The corresponding ¹³C‐labelled compound was synthesized using (¹³C)carbon monoxide to confirm the position of the carbonyl‐labelled atom by ¹³C‐NMR. Diethyl [carbonyl‐¹¹C]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl‐¹¹C]malonate in 50% analytical radiochemical yield. Copyright © 2006 John Wiley & Sons, Ltd.     

Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide

We aimed to label tubastatin A (1) with carbon‐11 (t_1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one‐pot Pd‐mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [¹¹C]1. Labeling was achieved in useful radiochemical yields (16.1 ± 5.6%, n = 4) through a two‐step process based on Pd‐mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and p‐nitrophenol to give the [¹¹C]p‐nitrophenyl ester ([¹¹C]5), followed by ultrasound‐assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P₁‐t‐Bu. However, success in labeling the hydroxamic acid group of [¹¹C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids.     

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.     

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.     

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.     

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 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 (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene

In this paper, we describe the radiosynthesis of the compound (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene, a potential, universal tumour positron emission tomography imaging agent. The production of (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was carried out via ¹¹C‐methylation of (E)‐2‐(hydroxy)‐3′,4,5′‐trimethoxystilbene by using [¹¹C]methyl trifluoromethanesulfonate ([¹¹C]methyl triflate). (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was obtained with a radiochemical purity greater than 95% in a 20 ± 2% decay‐corrected radiochemical yield, based upon [¹¹C]carbon dioxide. Synthesis, purification and formulation were completed on an average of 30 min following the end of bombardment (EOB). The specific radioactivity obtained was 1.9 ± 0.6 GBq/µmol at EOB. Copyright © 2007 John Wiley & Sons, Ltd.     

Radiosynthesis of a 2‐substituted 4,5‐dihydro‐1H‐[2‐11C] imidazole: the I2 imidazoline receptor ligand [11C] benazoline

Benazoline (2‐naphthalen‐2‐yl‐4,5‐dihydro‐1H‐imidazole) is a selective high‐affinity ligand for the imidazoline I₂ receptor. This compound was labelled with carbon‐11 (T_1/2=20.4 min) at the number two carbon atom of its 2‐imidazoline ring. Cyclotron‐produced [¹¹C]carbon dioxide reacted with 2‐naphthylmagnesium bromide to give 2‐[carboxyl‐¹¹C]naphthoic acid in 60% radiochemical yield. The latter was heated with a mixture of ethylenediamine and its dihydrochloride at 300°C to give [¹¹C]benazoline in 16% overall yield, relative to [¹¹C]carbon dioxide and with a specific radioactivity of 54 GBq/μmol, decay corrected for end of irradiation. The procedure requires about 45 min from end of cyclotron irradiation. This method should be extendable to other imidazolines. Copyright © 2003 John Wiley & Sons, Ltd.     

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.     

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.     

[11C]Methanol production by a fast and mild aqueous‐phase reduction of [11C]formic acid with samarium diiodide

The reduction of [¹¹C]carbon dioxide to [¹¹C]methanol with lithium aluminium hydride (LiAlH₄) and subsequent conversion into [¹¹C]methyl iodide is a standard way of producing the latter precursor for radiolabelling. However, it suffers from appreciable losses by incomplete reduction giving [¹¹C]formate. We show that samarium diiodide (SmI₂) can be used to improve the yield of [¹¹C]methanol by its ability to efficiently reduce [¹¹C]formate to [¹¹C]methanol. This can be done either by making [¹¹C]formate intentionally and treating it with SmI₂ or by treating the LiAlH₄‐reduced [¹¹C]CO₂ with SmI₂. In the latter approach, sodium thiosulphate has a similar effect as SmI₂. Hydriodic acid was also shown to exert some reducing action on [¹¹C]formate too. [¹¹C]Carbonate is reduced to a small extent by SmI₂ under the mild conditions employed. In contrast to the very easy [¹¹C]formate reduction, SmI₂ had little effect on [¹¹C]acetate and practically no [¹¹C]ethanol could be produced. Copyright © 2006 John Wiley & Sons, Ltd.