Radiosynthesis of carbon‐11‐labelled GI181771, a new selective CCK‐A agonist

The novel CCK‐A agonist, (S)‐3‐(3‐{1‐[(isopropylphenylcarbamoyl)methyl]‐2,4‐dioxo‐5‐phenyl‐2,3,4,5‐tetrahydro‐1H‐benzo[b][1,4]diazepin‐3‐yl}ureido)benzoic acid, GI181771 ((S)‐ 1 ) has been isotopically labelled with carbon‐11 at its urea site using [¹¹C]phosgene in a one‐pot two‐step process, via the intermediate preparation of an [¹¹C]isocyanate derivative. Optimized conditions for the preparation of (S)‐[¹¹C]‐ 1 were the following: (1) Trapping of [¹¹C]phosgene (radiosynthesized from cyclotron‐produced [¹¹C]methane via [¹¹C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1–2 min in 300 µl of acetonitrile containing 0.6 µmol of the appropriate (structurally complex) chiral‐amine giving the corresponding [¹¹C]isocyanate followed by (2) addition of an excess of 3‐aminobenzoic acid (40 µmol in 100 µl of THF) as the second amine giving the desired urea derivative (S)‐[¹¹C]‐ 1 and (3) high‐performance liquid chromatography (HPLC) purification on a semi‐preparative Waters Symmetry® C18. Starting from a typical 1.2 Ci (44.4 GBq) batch of [¹¹C]methane, 25–35 mCi (0.92–1.29 GBq, 6.8–9.6% decay‐corrected yield based on starting [¹¹C] methane, n = 5) of (S)‐[¹¹C]‐ 1 could be obtained within 35 min of radiosynthesis (HPLC purification and formulation as an i.v. injectable solution using a home‐made Sep‐pak®Plus C18 device included) with specific radioactivities ranging from 500 to 1500 mCi/µmol (18.5–55.5 GBq/µmol). The radiotracer preparation was a clear and colourless solution and its pH was between 5 and 7. As demonstrated by HPLC analysis, the radiolabelled product was found to be >99% chemically and radiochemically pure and the preparation was shown to be free of non‐radioactive precursors (starting amines) and radiochemically stable for at least 60 min. Finally, enantiomeric purity was found to be >99% according to chiral HPLC, demonstrating the absence of racemization during the process. Copyright © 2005 John Wiley & Sons, Ltd.     

Highlighting the versatility of the Tracerlab synthesis modules. Part 2: fully automated production of [11C]‐labeled radiopharmaceuticals using a Tracerlab FXC‐Pro

The field of radiochemistry is moving toward exclusive use of automated synthesis modules for production of clinical radiopharmaceutical doses. Such a move not only comes with many advantages but also presents radiochemists with the challenge of re‐configuring synthesis modules for production of radiopharmaceuticals that require non‐conventional radiochemistry while maintaining full automation. Herein, we continue our series of articles showcasing the versatility of the Tracerlab FX synthesis modules by presenting straightforward, fully automated methods for preparing a range of carbon‐11 labeled radiopharmaceuticals using a Tracerlab FX_C‐Pro. Strategies for production of [¹¹C]acetate, [¹¹C]carfentanil, [¹¹C]choline, [¹¹C]3‐amino‐4‐[2‐[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile ([¹¹C]DASB), (+)‐a‐[¹¹C]dihydroterabenazine ([¹¹C]DTBZ), [¹¹C]flumazenil ([¹¹C]FMZ), meta‐hydroxyephedrine ([¹¹C]HED), [¹¹C]methionine, [¹¹C]PBR28, [¹¹C]Pittsburgh Compound B ([¹¹C]PiB), 1‐[¹¹C]methylpiperidin‐4‐yl propionate ([¹¹C]PMP), and [¹¹C]raclopride are presented. Copyright © 2011 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 [11C]atipamezole,a potential PET ligand for the α2‐adrenergic receptor in the brain

The α₂‐adrenergic receptor antagonist atipamezole has been labelled with carbon‐11 using [¹¹C]formaldehyde and 2‐ethyl‐2‐oxoacetylindane. Various routes are proposed for the synthesis of the latter: oxidation of 2‐acetyl‐2‐ethylindane, hydrolysis of 2‐diethoxy‐2‐indane and oxidation of 2‐diazoacetyl‐2‐ethylindane. The average radiochemical yield of [¹¹C]atipamezole was 24% based on [¹¹C]formaldehyde, and the synthesis time, including HPLC purification and formulation, was 45 min. Copyright © 2002 John Wiley & Sons, Ltd.     

The automated radiosynthesis and purification of the opioid receptor antagonist, [6‐O‐methyl‐11C]diprenorphine on the GE TRACERlab FXFE radiochemistry module

[6‐O‐Methyl‐¹¹C]diprenorphine ([¹¹C]diprenorphine) is a positron emission tomography ligand used to probe the endogenous opioid system in vivo. Diprenorphine acts as an antagonist at all of the opioid receptor subtypes, that is, μ (mu), κ (kappa) and δ (delta). The radiosynthesis of [¹¹C]diprenorphine using [¹¹C]methyl iodide produced via the ‘wet’ method on a home‐built automated radiosynthesis set‐up has been described previously. Here, we describe a modified synthetic method to [¹¹C]diprenorphine performed using [¹¹C]methyl iodide produced via the gas phase method on a GE TRACERlab FX_FE radiochemistry module. Also described is the use of [¹¹C]methyl triflate as the carbon‐11 methylating agent for the [¹¹C]diprenorphine syntheses. [¹¹C]Diprenorphine was produced to good manufacturing practice standards for use in a clinical setting. In comparison to previously reported [¹¹C]diprenorphine radiosyntheisis, the method described herein gives a higher specific activity product which is advantageous for receptor occupancy studies. The radiochemical purity of [¹¹C]diprenorphine is similar to what has been reported previously, although the radiochemical yield produced in the method described herein is reduced, an issue that is inherent in the gas phase radiosynthesis of [¹¹C]methyl iodide. The yields of [¹¹C]diprenorphine are nonetheless sufficient for clinical research applications. Other advantages of the method described herein are an improvement to both reproducibility and reliability of the production as well as simplification of the purification and formulation steps. We suggest that our automated radiochemistry route to [¹¹C]diprenorphine should be the method of choice for routine [¹¹C]diprenorphine productions for positron emission tomography studies, and the production process could easily be transferred to other radiochemistry modules such as the TRACERlab FX C pro. © 2014 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals Published by John Wiley & Sons Ltd.     

Radiosynthesis of 7‐chloro‐N,N‐dimethyl‐5‐[11C]methyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide, [11C]SSR180575, a novel radioligand for imaging the TSPO (peripheral benzodiazepine receptor) with PET

SSR180575 (7‐chloro‐N,N,5‐trimethyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide) is the lead compound of an original pyridazinoindole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short‐lived positron‐emitter carbon‐11 (T_1/2: 20.38 min) at its 5‐methylpyridazino[4,5‐b]indole moiety as well as at its N,N‐dimethylacetamide function by methylation of the corresponding nor‐analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole‐N‐methyl‐¹¹C]SSR180575, where routine production batches of 4.5–5.0 GBq of radiochemically pure (>99%) i.v. injectable solutions (specific radioactivities: 50–90 GBq/ µ mol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [¹¹C]CO₂ cyclotron production batch (non‐decay‐corrected overall radiochemical yields: 8–9%). The process comprises (1) trapping at ?10°C of [¹¹C]methyl triflate in DMF (300 µ l) containing 0.2–0.3 mg of the indole precursor for labeling and 4 mg of K₂CO₃ (excess); (2) heating at 120°C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi‐preparative reversed‐phase HPLC (Zorbax^® SB‐C‐18). In vivo pharmacological properties of [indole‐N‐methyl‐¹¹C]SSR180575 as a candidate for imaging neuroinflammation with positron emission tomography are currently evaluated. Copyright © 2010 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 and PET evaluation of (R)‐[S‐methyl‐11C]thionisoxetine,a candidate radioligand for imaging brain norepinephrine transporters

Introduction: (R)‐3‐(2‐(methylthio)phenoxy)‐N‐methyl‐3‐phenylpropan‐1‐amine [(R)–thionisoxetine; 1 ] is a potent inhibitor of the norepinephrine transporter (NET). We aimed to label 1 with carbon‐11 (t_1/2 = 20.4 min) for evaluation as a radioligand for imaging NET in living brain with positron emission tomography (PET). Methods: Methyl 3‐(2‐((R)‐3‐(methylamino)‐1‐phenylpropoxy)phenylthio)‐propanoate (MPPP) and 1 were each prepared from o‐hydroxythiophenol in three steps. Treatment of MPPP with potassium t‐butoxide and [¹¹C]methyl iodide in tetrahydrofuran gave [S‐methyl‐¹¹C]thionisoxetine ([¹¹C] 1 ), which was purified with HPLC. The distribution of radioactivity in brain after intravenous injection of [¹¹C] 1 into cynomolgus monkey was followed with PET and the appearance of radiometabolites in plasma monitored with radio‐HPLC. Results: [¹¹C] 1 was obtained in high yield from [¹¹C]methyl iodide. Of the radioactivity injected into monkey, 2.4% entered brain. Ratios of radioactivity in thalamus, mesencephalon, occipital cortex and caudate to that in cerebellum at 93 min were 1.3, 1.2, 1.2 and 1.1, respectively. The radioactivity in plasma corresponding to unchanged radioligand decreased to 53% at 45 min, with the remainder represented by hydrophilic radiometabolites. Conclusions: MPPP is an effective precursor for ¹¹C‐methylation to [¹¹C] 1 , suggesting that the S‐γ‐propionic acid methyl ester protecting group may have wider value in the ¹¹C‐labeling of aryl methyl sulfides. However, the relatively low ratios of radioactivity to the cerebellum together with an unexpected accumulation of radioactivity in the caudate, makes [¹¹C] 1 an unpromising NET radioligand. Copyright © 2006 John Wiley & Sons, Ltd.     

The use of tetrabutylammonium fluoride to promote N‐ and O‐11C‐methylation reactions with iodo[11C]methane in dimethyl sulfoxide

The N‐ or O‐methylation reactions of compounds bearing amide, aniline, or phenol moieties using iodo[¹¹C]methane (1) with the aid of a base are frequently applied to the preparation of ¹¹C‐labeled radiopharmaceuticals. Although sodium hydride and alkaline metal hydroxides are commonly employed as bases in these reactions, their poor solubility properties in organic solvents and hydrolytic activities have sometimes limited their application and made the associated ¹¹C‐methylation reactions difficult. In contrast to these bases, tetrabutylammonium fluoride (TBAF) is moderately basic, highly soluble in organic solvents, and weakly nucleophilic. Although it was envisaged that TBAF could be used as the preferred base for ¹¹C‐methylation reactions using 1, studies concerning the use of TBAF to promote ¹¹C‐methylation reactions are scarce. Herein, we have evaluated the efficiency of the ¹¹C‐methylation reactions of 13 model compounds using TBAF and 1. In most cases, the N‐¹¹C‐methylations were efficiently promoted by TBAF in dimethyl sulfoxide at ambient temperature, whereas the O‐¹¹C‐methylations required heating in some cases. Comparison studies revealed that the efficiencies of the ¹¹C‐methylation reactions with TBAF were comparable or sometimes greater than those conducted with sodium hydride. Based on these results, TBAF should be considered as the preferred base for ¹¹C‐methylation reactions using 1.     

Critical evaluation of the chemical standardization procedure for measuring gastric emptying of solids

The purpose of this study was to evaluate the baking process of yolk spiked with octanoate to measure gastric emptying rate of solids. [1‐¹¹C]octanoate was produced by the reaction of [¹¹C]CO₂ with heptyl magnesium bromide in tetrahydrofuran (THF), followed by purification with HPLC. The decay corrected radiochemical yield ranged from 24 to 38% (5.9–9.8 GBq EOS, synthesis time: 25 min; specific radioactivity ～90 GBq μmol^?1). To check the evaporation of [1‐¹¹C]octanoate during the baking process of yolk, [1‐¹¹C]octanoate or potassium [1‐¹¹C]octanoate, respectively, was added. An important fraction of the acid evaporated while for the potassium [1‐¹¹C]octanoate <10% disappeared. Conclusion: potassium (1‐¹³C)octanoate is a better tracer than (1‐¹³C) octanoate to study gastroenterological phenomena. Copyright © 2002 John Wiley & Sons, Ltd.     

Novel probes for imaging amyloid‐β: F‐18 and C‐11 labeling of 2‐(4‐aminostyryl)benzoxazole derivatives

2‐(4‐Methylaminostyryl)‐6‐(2‐[¹⁸F]fluoroethoxy)benzoxazole ([¹⁸F]BF‐168) was prepared and found to be a potential probe for imaging amyloid‐β. The precursor, a 6‐(2‐tosyloxyethoxy)benzoxazole derivative, was fluorinated with [¹⁸F]KF and Kryptofix 222 in acetonitrile, and the crude product purified by semi‐preparative HPLC to give [¹⁸F]BF‐168. The radiochemical purity was >95% and the maximum specific activity was 106 TBq/mmol at the end of synthesis. The synthesis time was 110 min from the end of bombardment. 2‐(4‐[N‐methyl‐¹¹C]methylaminostyryl)‐5‐fluorobenzoxazole ([¹¹C]BF‐145) was also prepared from 2‐(4‐aminostyryl)‐5‐fluorobenzoxazole, [¹¹C]MeI and 5 N NaOH in DMSO, and purified by semi‐preparative HPLC. The radiochemical purity was >95% and the specific activity was 40–70 TBq/mmol at the end of synthesis. The synthesis time was 45 min from the end of bombardment. Copyright © 2004 John Wiley & Sons, Ltd.     

Reductive N‐alkylation of secondary amines with [2‐11C]acetone

The development of a labeling method for secondary amines with [2‐¹¹C]acetone is described since the R₂N‐isopropyl moiety is present in many biologically active compounds. The influence of a variety of parameters (e.g. reagents, solvents, temperature, and time) on the reaction outcome is discussed. Under the optimal reaction conditions, [¹¹C]1‐isopropyl‐4‐phenylpiperazine ([¹¹C]iPPP) was synthesized from [2‐¹¹C]acetone and 1‐phenylpiperazine in a decay‐corrected radiochemical yield of 72%. The overall synthesis time, from EOB to HPLC analysis of [¹¹C]iPPP, was 20 min. Specific activity was 142–208 GBq/μmol at the end of synthesis. Copyright © 2003 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.     

Radiosynthesis and in vivo evaluation of [11C]Ro‐647312: a novel NR1/2B subtype selective NMDA receptor radioligand

[2‐(3,4‐Dihydro‐1H‐isoquinolin‐2‐yl)‐pyridin‐4‐yl]‐dimethylamine, Ro‐647312 ( 1 ) represents a new novel class of NR1/2B subtype selective NMDA ligand. Ro‐647312 has been radiolabelled with carbon‐11 using [¹¹C]methyl triflate from the nor‐methyl compound 2 . The reaction was performed in acetone as solvent using aqueous NaOH as base. Following HPLC purification [¹¹C]Ro‐647312 ([¹¹C]‐ 1 ) was obtained in 6.9–9.2% (n = 3) radiochemical yield decay‐corrected based on starting [¹¹C]CO₂, with specific radioactivity measured at the end of the radiosynthesis ranging from 1.0 to 3.5 Ci/µmol (37–129 GBq/µmol). Radiochemical and chemical purities were assessed as >99 and >95%, respectively. Following i.v. injection of [¹¹C]‐ 1 in rat, the distribution of radioactivity was homogeneous in all brain structures and did not correlate with the known distribution of NR2B subunits. The radioactivity observed in plasma was also higher than any brain structure throughout the time course of the experiment. [¹¹C]‐ 1 does not possess the required properties for imaging NMDA receptors using positron emission tomography. Copyright © 2004 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.     

Methylation of the thiophene ring using Carbon‐11‐labelled methyl iodide: formation of 3‐[11C]methylthiophene

This paper describes the radiosynthesis of 3‐[¹¹C]methylthiophene, chosen as a model reaction for the preparation of heteroaromatic methylthienyl compounds. Labelling was performed from the corresponding lithiothiophene derivative and [¹¹C]methyl iodide as the alkylating agent in THF at ?78°C. The conditions used were the following: (1) trapping for 2–3 min at ?78°C of the [¹¹C]methyl iodide in the THF solution containing the freshly prepared 3‐lithiothiophene; (2) Hydrolysis of the reaction mixture by adding 0.5 ml of the HPLC mobile phase and (3) HPLC purification. 3‐[¹¹C]Methylthiophene ([¹¹C]‐ 1 ) was collected in high yield as the unique peak of the HPLC radiochromatogram. Non‐reacted [¹¹C]methyl iodide was not present. Typically, 50–60 mCi (1.85–2.22 GBq) of 3‐[¹¹C]methylthiophene ([¹¹C]‐ 1 ) were obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 0.6 to 1.0 Ci/μmol (22.2–37.0 GBq/μmol) starting from 180 to 200 mCi (6.66–7.40 GBq) of [¹¹C]CO₂ (10 μA, 10 min (6000 μC) irradiation). Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

BF3 etherate catalysed formation of [11C]methyl esters: a novel radiolabelling technique

A novel way of preparing ¹¹C labelled methyl esters using [¹¹C]methanol and either BF₃ etherate or trimethylsilyl chloride as catalyst was investigated. Radiochemical yields with BF₃ etherate were between 30 and 33% for [¹¹C]methyl benzoate and less than 1% for [¹¹C]methyl thio salicylate. No [¹¹C]methyl ester formation could be observed with trimethylsilyl chloride for all compounds investigated. This method is an alternative to using [¹¹C]methyl iodide in the presence of a base. It is particularly suited for carboxylic acids bearing functional groups which would compete for [¹¹C]methyl iodide, thus eliminating the need to introduce protecting groups. However, o‐anisic acid formed [¹¹C]methyl salicylate in 33–30% decay corrected radiochemical yield due to hydrolytic cleavage of the methyl ether, and none of the desired [¹¹C]methyl 2‐methoxy benzoate could be obtained. When salicylic acid was used as starting material, [¹¹C]methyl salicylate could only be obtained in 5–8% decay corrected radiochemical yield. Copyright © 2004 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.     

Radiosynthesis of N‐[4‐(4‐fluorobenzyl)piperidin‐1‐yl]‐N′‐(2‐[11C]oxo‐1,3‐dihydrobenzimidazol‐5‐yl)oxamide,a NR2B‐selective NMDA receptor antagonist

In order to perform in vivo imaging of the NR2B NMDA receptor system by positron emission tomography, a NR2B selective NMDA receptor antagonist has been labelled with carbon‐11 (half‐life: 20 min). N‐[4‐(4‐fluorobenzyl)piperidin‐1‐yl]‐N′‐(2‐oxo‐1,3‐dihydrobenzimidazol‐5‐yl)oxamide has been described demonstrating high affinity and selectivity for the NR2B receptors (IC₅₀ of 5 nM in [³H]Ro‐25,6981 binding assay). The labelling precursor and the reference compound were synthesized by coupling the 4‐(4‐fluorobenzyl)piperidine with the corresponding oxalamic acid. The reaction of [¹¹C]phosgene with phenylenediamine precursor led the formation of the [¹¹C]benzimidazolone ring present on the ligand. The labelling occurred in THF or acetonitrile and the decay corrected radiochemical yield was 30–40% from the produced [¹¹C]methane. HPLC purification and formulation led to 2.6–3.7 GBq (70–100 mCi) of radioligand within 30–35 min. The specific radioactivity was 72–127 GBq/µmol (2–3.4 Ci/µmol) at the end of synthesis. Copyright © 2009 John Wiley & Sons, Ltd.