Synthesis of NCA [carbonyl‐11C]amides by direct reaction of in situ generated [11C]carboxymagnesium halides with amines under microwave‐enhanced conditions

No‐carrier‐added (NCA) aromatic and aliphatic [carbonyl‐¹¹C]amides were rapidly (<5 min) synthesized in one pot in useful radiochemical yields (20–65%, decay‐corrected) by directly coupling amines with NCA [¹¹C]carboxyhyphenmagnesium halides generated in situ from Grignard reagents and cyclotron‐produced [¹¹C]carbon dioxide. In this system cyclohexylcarboxymagnesium chloride ( 1b ) is more reactive than 4‐fluorophenylcarboxymagnesium bromide ( 2b ) and primary amines (e.g. aniline, aminopyridines) far more reactive than secondary amines (e.g. 2‐(methylamino)pyridine). The scope of the reaction was widened considerably by the application of microwaves, which allowed reactions to be carried out at much higher temperature than the boiling point of the solvent (i.e. tetrahydrofuran, b.p. 67°C). Copyright © 2003 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.     

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.     

[carbonyl‐11C]Benzyl acetate: Automated radiosynthesis via Pd‐mediated [11C]carbon monoxide chemistry and PET measurement of brain uptake in monkey

[carbonyl‐¹¹C]Benzyl acetate ([¹¹C]1) has been proposed as a potential agent for imaging glial metabolism of acetate to glutamate and glutamine with positron emission tomography. [¹¹C]1 was synthesized from [¹¹C]carbon monoxide, iodomethane and benzyl alcohol via palladium‐mediated chemistry. The radiosynthesis was automated with a modified Synthia platform controlled with in‐house developed Labview software. Under production conditions, [¹¹C]1 was obtained in 10% (n=6) decay‐corrected radiochemical yield from [¹¹C]carbon monoxide in >96% radiochemical purity and with an average specific radioactivity of 2415 mCi/µmol. The total radiosynthesis time was about 45 min. Peak uptake of radioactivity in monkey brain (SUV=3.1) was relatively high and may be amenable to measuring uptake and metabolism of acetate in glial cells of the brain. Published in 2010 by 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 [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.     

[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 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.     

Development of a fully automated low-pressure [11C]CO carbonylation apparatus

[¹¹C]carbon monoxide ([¹¹C]CO) is a versatile synthon for radiolabeling of drug-like molecules for imaging studies with positron emission tomography (PET). We here report the development of a novel, user-friendly, fully automated, and good manufacturing practice (GMP) compliant low-pressure synthesis module for ¹¹C-carbonylation reactions using [¹¹C]CO. In this synthesis module, [¹¹C]CO was reliably prepared from cyclotron-produced [¹¹C]carbon dioxide ([¹¹C]CO₂) by reduction over heated molybdenum and delivered to the reaction vessel within 7 min after end of bombardment, with an overall radiochemical yield (RCY) of 71%. [¹¹C]AZ13198083, a histamine type-3 receptor ligand, was used as a model compound to assess the functionality of the radiochemistry module. At full batch production conditions (55 μA, 30 min), our newly developed low-pressure ¹¹C-carbonylation apparatus enabled us to prepare [¹¹C]AZ13198083 in an isolated radioactivity of 8540 ± 1400 MBq (n = 3). The radiochemical purity of each of the final formulated batches exceeded 99%, and all other quality control tests results conformed with specifications typically set for carbon-11 labeled radiopharmaceuticals. In conclusion, this novel radiochemistry system offers a convenient GMP compliant production drugs and radioligands for imaging studies in human subjects.     

Preparation of [11C]formaldehyde using a silver‐containing ceramic catalyst

A ceramic material, prepared from kaolin doped with silver ions in various concentrations, was evaluated as a catalyst for the conversion of [¹¹C] methanol into [¹¹C]formaldehyde in a gas flow system. Employment of [¹¹C] methanol with a minimized water content, 300 mg of catalyst (20% of silver) at 500°C and a carrier gas flow rate of 40 mL/min resulted in a radiochemical decay‐corrected [¹¹C]formaldehyde yield of 67% relative to [¹¹C]methanol. Wet [¹¹C]methanol under the same conditions gave 54% of [¹¹C] formaldehyde. Copyright © 2003 John Wiley & Sons, Ltd.     

Transition metal mediated synthesis using [11C]CO at low pressure – a simplified method for 11C‐carbonylation

Transition metal mediated carbonylation with [¹¹C]CO has proven a useful method to label a wide array of compounds in the carbonyl position. However, the general use in radiopharmaceutical synthesis has been hampered by the low solubility of carbon monoxide in most solvents and the resulting challenge to confine [¹¹C]CO in low volume reaction vessels. This paper introduces a method that utilises xenon to transfer pre‐concentrated [¹¹C]CO to a sealed disposable glass vial containing carbonylation reagents. The high solubility of xenon in the organic solvent made it possible to confine the [¹¹C]CO without utilising a pressure autoclave or chemical trapping additives. The utility of the method in ¹¹C‐carbonylation was investigated by conducting three model reactions, where [¹¹C‐carbonyl]N‐benzylbenzamide, [¹¹C‐carbonyl]triclocarban and [¹¹C‐carbonyl]methyl nicotinate were afforded in decay corrected radiochemical yields of 71 ± 6%, 42 ± 15% and 29 ± 10%, respectively. These promising results and the straight forward technical implementation suggest that ¹¹C‐cabonylation can become a viable mean to provide labelled carbonyl functionalities in routine radiopharmaceutical synthesis. Compounds labelled with short lived positron emitters are used in Positron Emission Tomography, a molecular imaging technology with applications in clinical diagnostics, clinical research and basic biomedical research.     

Synthesis and biological evaluation of [carboxyl‐11C]eprosartan

Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT₁ receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT₁ receptor antagonist [carboxyl‐¹¹C]eprosartan 10, 4‐[2‐butyl‐5‐((E)‐2‐carboxy‐3‐thiophen‐2‐yl‐propenyl)‐imidazol‐1‐ylmethyl]‐[carboxyl‐¹¹C]benzoic acid, and its precursor (E)‐3‐[2‐butyl‐3‐(4‐iodo‐benzyl)‐3H‐imidazol‐4‐yl]‐2‐thiophen‐2‐ylmethyl‐acrylic acid 9. ¹¹C‐carboxylation of the iodobenzyl moiety was performed using a palladium‐mediated reaction with [¹¹C]carbon monoxide in the presence of tetra‐n‐butyl‐ammonium hydroxide in a micro‐autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl‐¹¹C]eprosartan 10 was obtained in 37–54% decay‐corrected radiochemical yield (from [¹¹C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5‐µAh bombardment gave 2.04 GBq of 10 (50% rcy from [¹¹C]carbon monoxide) with a specific activity of 160 GBq µmol^?1 at 34 min after EOB. Frozen‐section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall. Copyright © 2009 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.     

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.     

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.     

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.     

Synthesis of a mGluR5 antagonist using [11C]copper(I) cyanide

5‐(2‐Phenylethynyl)pyridine‐3‐[¹¹C]carbonitrile ([¹¹C]LY2232645), a metabotropic glutamate 5 receptor (mGluR5) antagonist, was synthesized by a no‐carrier‐added nucleophilic halogen displacement with [¹¹C]copper(I) cyanide. The average radiochemical yield was 2.5%, and the average specific activity was 1365 mCi/µmol at end‐of‐synthesis. The total time of synthesis, purification, and formulation was 26 min. Copyright © 2006 John Wiley & Sons, Ltd.     

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

Toluene derivatives are often found in drug‐like molecules, and are therefore desirable as radiolabelled moieties. The desire for an alternate to the Stille coupling led us to investigate the feasibility of the Suzuki coupling. We have found the Suzuki coupling route to be a robust alternative to the Stille coupling for the synthesis of functionalized [¹¹C]toluene derivatives from [¹¹C]methyl iodide. The avoidance of potentially toxic tin‐containing by‐products is an added advantage. The products synthesized via Suzuki coupling with [¹¹C]methyl iodide were isolated in generally high yields (56–92%), with high radiochemical purity (>95%) and specific radioactivity (>4000 Ci/mmol) in less than 20 min following production of [¹¹C]methyl iodide. Copyright © 2005 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.     

An evaluation of a high‐pressure 11CO carbonylation apparatus

[¹¹C]Carbon monoxide (¹¹CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping ¹¹CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high‐pressure synthesizer prototype for the use in ¹¹C‐carbonylation reactions. [¹¹C]Carbon monoxide was easily prepared by online reduction of [¹¹C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of ¹¹CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 ¹¹CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the ¹¹CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the ¹¹CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high‐pressure synthesizer using [¹¹C]carbon monoxide as the labeling precursor is easy to operate allowing for ¹¹C‐carbonylation reactions to be performed in a high yield and in a routinely fashion.