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.     

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 1‐iodo‐2‐[11C]methylpropane and 2‐methyl‐1‐[11C]propanol and its application for alkylation reactions and C―C bond formation

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2‐Methyl‐1‐[¹¹C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 μmol) were needed. 1‐Iodo‐2‐[¹¹C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1‐iodo‐2‐[¹¹C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [¹¹C]2‐methyl‐1‐propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/μmol at the end of synthesis. Altogether, the syntheses of 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol were achieved and applied as proof of their applicability.     

Nitroaldol reaction of nitro[11C]methane to form 2‐(hydroxymethyl)‐2‐nitro[2‐11C]propane‐1,3‐diol and [11C]Tris

The nitroaldol reaction of nitro[¹¹C]methane and formaldehyde, which yields 2‐(hydroxymethyl)‐2‐nitro[2‐¹¹C]propane‐1,3‐diol, is explored. The fluoride‐ion‐assisted nitroaldol reaction using (C₄H₉)₄NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay‐corrected) in 3 min at room temperature. Neither 2‐nitro[2‐¹¹C]ethanol nor 2‐nitro[2‐¹¹C]propane‐1,3‐diol was observed under the reaction conditions. The preparation of 2‐amino‐2‐(hydroxymethyl)‐[2‐¹¹C]propane‐1,3‐diol ([¹¹C]Tris) was described, which was followed by the nitro‐group reduction using NiCl₂ and NaBH₄ in aqueous MeOH. The decay‐corrected radiochemical conversion to [¹¹C]Tris was 68.0±6.5% in two steps. Copyright © 2010 John Wiley & Sons, Ltd.     

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

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

Synthesis of 1‐(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.     

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

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

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.     

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 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.     

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 (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.     

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.     

Radiolabeling of two 11C‐labeled formylating agents and their application in the preparation of [11C]benzimidazole

The radiolabeling of formyl groups with carbon‐11 has so far been awarded little attention in the literature. We report here the preparation of the methyl and trifluoroethyl esters of [¹¹C]formic acid and their use as ¹¹C‐formylating agents in the preparation of [¹¹C]benzimidazole. Methyl‐ethyl and trifluoroethyl [¹¹C]formates were obtained in 36–45% radiochemical yield using a two‐step two‐pot process starting from [¹¹C]carbon dioxide. The analytical radiochemical yield of [¹¹C]benzimidazole using each of these two ¹¹C‐formylating agents exceeded 96%. Given the high yields of the ¹¹C‐formylating agents as well as the high yield of [¹¹C]benzimidazole following their application, we expect these agents to find utility for a wider range of substrates.     

Synthesis and characterization of N‐(2‐chloro‐5‐methylthiophenyl)‐N′‐(3‐methylthiophenyl)‐N′‐[11C]methylguanidine [11C]CNS 5161, a candidate PET tracer for functional imaging of NMDA receptors

N‐methyl‐D ‐aspartate (NMDA) receptors play a key role in excitatory neurotransmission and are linked to a variety of acute and chronic neurodegenerative diseases including epilepsy, schizophrenia, Parkinson's disease and drug abuse. N‐(2‐chloro‐5‐methylthiophenyl)‐N′‐(3‐methylthiophenyl)‐N′‐methylguanidine (CNS 5161) is a high affinity ligand (Ki=1.87±0.25 nM) for the NMDA PCP site, which potentially can be used for functional imaging of this receptor. Herein we report the synthesis of the corresponding positron emission tomography (PET) tracer [¹¹C]CNS 5161 by means of [¹¹C]methylation of the desmethyl guanidine precursor. [¹¹C]CNS 5161 was synthesized with a decay corrected radiochemical yield of 10% within 45 min after end of bombardment (EOB). The final product was prepared in a sterile saline solution suitable for clinical studies with a radiochemical purity of >96% and a specific activity of 41 GBq/mmol at time of injection. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of the α4β2 nicotinic acetylcholine receptor ligand: 5‐((1‐[11C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)vinyl)pyridine

5‐((1‐[¹¹C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)‐vinyl)pyridine ([¹¹C]‐FPVC) was synthesized from [¹¹C]‐methyl iodide and the corresponding normethyl precursor. The average time of synthesis, purification, and formulation was 42 min with an average non‐decay‐corrected radiochemical yield of 19%. The average specific radioactivity was 359 GBq/µmol (9691 mCi/µmole) at end of synthesis (EOS). Copyright © 2006 John Wiley & Sons, Ltd.     

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.     

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.     

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.