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 [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.     

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 substituted [11C]ureas and [11C]sulphonylureas by Rh(I)‐mediated carbonylation

The urea moiety is present in many biologically active compounds and thus an attractive target for ¹¹C‐labelling. To extend the scope of the rhodium(I)‐mediated carbonylative cross‐coupling reaction between an azide and an amine and investigate its tolerance for functional groups, we have synthesized eight ureas and two sulphonylureas that were ¹¹C‐labelled in the carbonyl position. The decay‐corrected analytical radiochemical yields were in the range of 14–96% (from [¹¹C]carbon monoxide). For example: starting from 1.33 GBq [¹¹C]carbon monoxide, 0.237 GBq (66%) of the cytotoxic sulphonylurea [¹¹C]LY‐181984 11 was isolated within 60 min from end of bombardment. The mild reaction conditions and generality regarding functional groups of this method make it an attractive alternative to the [¹¹C]phosgene method for the synthesis of ¹¹C‐labelled ureas. Copyright © 2010 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 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.     

[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.     

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 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.     

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.     

Rhodium‐mediated [11C]carbonylation: a library of N‐phenyl‐N′‐{4‐(4‐quinolyloxy)‐phenyl}‐[11C]‐urea derivatives as potential PET angiogenic probes

As part of our ongoing investigation into the imaging of angiogenic processes, a small library of eight vascular endothelial growth factor receptor‐2 (VEGFR‐2)/platelet‐derived growth factor receptor β dual inhibitors based on the N‐phenyl‐N′‐4‐(4‐quinolyloxy)‐phenyl‐urea was labelled with ¹¹C (β⁺, t_1/2=20.4 min) in the urea carbonyl position via rhodium‐mediated carbonylative cross‐coupling of an aryl azide and different anilines. The decay‐corrected radiochemical yields of the isolated products were in the range of 38–81% calculated from [¹¹C]carbon monoxide. Starting with 10.7±0.5 GBq of [¹¹C]carbon monoxide, 1‐[4‐(6,7‐dimethoxy‐quinolin‐4‐yloxy)‐3‐fluoro‐phenyl]‐3‐(4‐fluoro‐phenyl)‐[¹¹C]‐urea (2.1 GBq) was isolated after total reaction time of 45 min with a specific activity of 92±4 GBq µmol^?1. Copyright © 2009 John Wiley & Sons, Ltd.     

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 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.     

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.     

Rapid preparation of [11C]flumazenil: captive solvent synthesis combined with purification by analytical sized columns

To produce the radioligand [N‐methyl‐¹¹C]flumazenil at very high specific radioactivity for our small animal imaging studies we have developed procedures for its rapid synthesis, purification and analysis. We have developed ‘micro‐reactor’ apparatus which are assembled from analytical HPLC guard columns packed with stainless steel powder for performing the carbon‐11 methylation reactions. These highly efficient reaction columns enable high radiochemical yields to be obtained with very small amounts of precursor (20–40 µg). The very small amount of reactants used enables the use of small analytical‐sized HPLC columns for the rapid purification of the radioligand. Combining these techniques has enabled us to consistently prepare [N‐methyl‐¹¹C]flumazenil from [¹¹C]iodomethane with radiochemical yields of 80% (decay corrected). This results in 8–10 GBq of [N‐methyl‐¹¹C]flumazenil at very high specific radioactivities of 520–600 GBq/µmol at the end‐of‐synthesis. The total preparation time from end‐of‐bombardment of cyclotron‐produced [¹¹C]carbon dioxide to end‐of‐synthesis is 20 min. A quality control method based on very rapid HPLC analysis (completed within 2 min) on a micro‐analytical HPLC column has also being developed to reduce the time from the end‐of‐synthesis to injection for imaging. Copyright © 2007 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.     

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.