Synthesis of N‐(2‐chloro‐5‐methylthiophenyl)‐ N′‐(3‐methyl‐thiophenyl)‐ N′‐[3H3]methylguanidine, {[3H3]CNS‐5161}

The preparation of the title compound, [³H₃]CNS‐5161, was accomplished in three steps starting with the production of [³H₃]iodomethane (CT₃I). The intermediate N‐[³H₃]methyl‐3‐(thiomethylphenyl)cyanamide was prepared in 77% yield by the addition of CT₃I to 3‐(thiomethylphenyl)cyanamide, previously treated with sodium hydride. Reaction of this tritiated intermediate with 2‐chloro‐5‐thiomethylaniline hydrochloride formed the guanidine compound [³H₃]CNS‐5161. Purification by HPLC gave the desired labeled product in an overall yield of 9% with >96% radiochemical purity and a final specific activity of 66 Ci mmol^?1. Copyright © 2002 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.     

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.     

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 [11C] N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐methoxyphenyl)‐N′‐methylguanidine ([11C]GMOM): a candidate PET tracer for imaging the PCP site of the NMDA ion channel

The N‐methyl‐D ‐aspartate (NMDA) ion channel plays an important role in a number of neurodegenerative disorders including stroke, Parkinson's disease, Huntington's Chorea, Alzheimer's disease, schizophrenia and epilepsy. To provide effective radioligands for imaging the PCP binding site of the NMDA ion channel, we synthesized and characterized in vitro the candidate PCP site ligand N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐methoxyphenyl)‐N′‐methylguanidine (GMOM: K_i = 5.2 ± 0.3 nM, log P = 2.34). The corresponding PET radiotracer [¹¹C]GMOM was synthesized with a radiochemical yield of 8.4 ± 3.2% EOS and with a specific activity of 1.23 ± 0.25 Ci/μmol EOS (n = 5). The average time required for synthesis, purification and formulation was 52 ± 5 min. The final product was prepared in a sterile saline solution suitable for in vivo use. Copyright © 2002 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.     

Synthesis of N‐(2,5‐dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)[carbonyl‐11C]acetamide ([carbonyl‐11C]DAA1106) and analogues using [11C]carbon monoxide and palladium(0) complex

N‐(2,5‐Dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)acetamide (DAA1106), a potent and selective ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with ¹¹C at the carbonyl position using a low concentration of [¹¹C]carbon monoxide and the micro‐autoclave technique. A combinatorial approach was applied to synthesize the analogues using similar reaction conditions. Palladium‐mediated carbonylation using tetrakis(triphenylphosphine)palladium, various amines and methyl iodide or iodobenzene was employed in the synthesis. The ¹¹C‐labelled products were obtained with 10–55% decay‐corrected radiochemical yields and the final product was more than 97% pure in all cases. Specific radioactivity was determined for the compound [carbonyl‐¹¹C]DAA1106 using a single experiment and a 10‐µA h bombardment. The specific radioactivity, measured 36 min after end of bombardment, was 455 GBq/µmol. Synthetic routes to the precursors and reference compounds were also developed. The presented approach is a novel method for the synthesis of [carbonyl‐¹¹C]DAA1106 and its analogues, and allows the formation of a library of ¹¹C‐labelled DAA1106 analogues which can be used to optimize the performance as a potential positron emission tomography tracer. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 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.     

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.     

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.     

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.     

Synthesis of N‐[1‐13C]caproyl‐N′‐phenylthiourea

An optimal synthesis of N‐[1‐¹³C]caproyl‐N′‐phenylthiourea with isotopic enrichment 82% is described, starting from barium [¹³C]carbonate, using five synthetic steps. Yields were 95% relative to caproyl chloride and 46% relative to barium carbonate. Oxidation of the title compound with manganese dioxide yields the corresponding ureide. Structural similarities with anticonvulsants such as phenacemide make N‐caproyl‐N′‐phenylthiourea an interesting model compound. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [N‐methyl‐11C]‐3‐[(6‐dimethylamino)pyridin‐3‐yl]‐2,5‐dimethyl‐N,N‐dipropylpyrazolo[1,5‐a]pyrimidine‐7‐amine: A potential PET ligand for in vivo imaging of CRF1 receptors

A convenient synthesis of [N‐methyl‐¹¹C]‐3‐[(6‐dimethylamino)pyridin‐3‐yl]‐2,5‐dimethyl‐N,N‐dipropylpyrazolo[1,5‐a]pyrimidine‐7‐amine (R121920), a highly selective CRF₁ antagonist has been developed as a potential PET ligand. 3 ‐ [(6 ‐ methylamino)pyridin ‐ 3 ‐ yl]‐2,5‐dimethyl‐N,N‐dipropylpyrazolo [1,5‐a]pyrimidine‐7‐amine ( 7 ), the precursor for radiolabelling was synthesized through a novel palladium catalyzed Suzuki coupling of aryl bromide 5 with heteroaryl boronate ester 4 . The requisite boronate ester 4 was synthesized in four steps from 2‐amino‐4‐bromopyridine in 50% overall yield. Although the synthesis of cold R121920 proceeded in 93% yield by sodium hexamethyl‐disilazide (NaHMDS) mediated N‐methylation of the desmethylamine 7 at ?78°C, the attempted radiosynthesis under various conditions using conventional bases were not successful. However, the radiolabeling of [¹¹C]R121920 was successfully carried out with [¹¹C]MeOTf in acetone at ?20°C in the absence of added basic reagents. The radiotracer was purified by RP‐HPLC followed by RP‐solid phase extraction. The yield of the reaction was 5% (at EOB) and the specific activity was >1000 Ci/mmol (at EOB) with a radiochemical purity >99%. Copyright © 2003 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 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.     

Fully automated synthesis and purification of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine

We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethylpiperazine (p‐[¹⁸F]MPPF). No‐carrier‐added [¹⁸F]F^? was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K₂CO₃ (0.7 mg). The nucleophilic [¹⁸F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH₄/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[¹⁸F]MPPF (retention time = 9.5 min). p‐[¹⁸F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 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 [1‐11C]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 [O‐methyl‐11C]‐4‐(1,3‐dimethoxy‐2‐propylamino)‐2,7‐dimethyl‐8‐(2,4‐dichlorophenyl)[1,5‐a]pyrazolo‐1,3,5‐triazine ([11C]DMP696): a potential PET ligand for CRF1 receptors

Synthesis of [O‐methyl‐¹¹C]‐4‐(1,3‐dimethoxy‐2‐propylamino)‐2,7‐dimethyl‐8‐(2,4‐dichlorophenyl)[1,5‐a]pyrazolo‐1,3,5‐triazine ([¹¹C]DMP696), a highly selective CRF₁ antagonist has been achieved. The total time required for the synthesis of [¹¹C]DMP696 is 30 min from EOB using [¹¹C]methyl triflate in THF, with a 16% yield (EOS) and >99% chemical and radiochemical purities along with a specific activity of >2000 Ci/mmol (EOS). Copyright © 2004 John Wiley & Sons, Ltd.