11C–C bond formation by palladium‐mediated cross‐coupling of alkenylzirconocenes with [11C]methyl iodide

A novel ¹¹C–C bond formation based on the palladium‐mediated cross‐coupling reaction of alkenylzirconocenes with [¹¹C]methyl iodide is described. The conversion of internal alkynes into the corresponding alkenylzirconocenes followed by transmetalation with Pd(PPh₃)₄ and subsequent cross‐coupling with [¹¹C]methyl iodide gave several ¹¹C‐labelled α,α′‐dimethyl‐substituted alkenes. The palladium complex Pd(PPh₃)₄ proved to be superior to Pt(PPh₃)₄ or Ni(PPh₃)₄ as transition metal complex. The scope and limitations of the novel palladium‐mediated cross‐coupling reaction of alkenylzirconocenes with [¹¹C]methyl iodide were tested with various internal alkynes. After heating at 60°C for 6 min radiochemical yields of up to 75% (based upon [¹¹C]methyl iodide) could be achieved. 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.     

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.     

Preparation of N′4‐[11C]methyl‐ciprofloxacin for positron emission tomography studies

The synthesis of N′₄‐[¹¹C]methyl‐ciprofloxacin for pharmacological studies using positron emission tomography is described. The starting material was treated with [¹¹C]methyl iodide at 120°C in DMF for 5 min. After HPLC separation on a C₁₈‐column with water/ethanol as mobile phase, the [¹¹C]methyl labelled compound was produced with a radiochemical yield of at least 25% (end of synthesis from [¹¹C]CO₂). Activities from 1.48 to 2.22 GBq (40 to 60 mCi) were obtained 1 h after the irradiation, ready for intravenous injection. The carrier ranged between 0.05 and 0.08 μmol (0.010–0.016 μmol/ml). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 2‐[11C]methoxy‐3,17β‐estradiol to measure the pharmacokinetics of an antitumor drug candidate, 2‐methoxy‐3,17β‐estradiol

2‐Methoxy‐3,17β‐estradiol, an endogenous estrogen metabolite, showed cytotoxicity in various cancer cell lines and also has antiangiogenic and proapoptotic activities. Clinical I and II trials of 2‐methoxy‐3,17β‐estradiol for multiple myeloma, advanced solid tumors, metastatic breast and prostate cancer are underway. We prepared 2‐[¹¹C]methoxy‐3,17β‐estradiol to measure the pharmacokinetics and organ distribution of 2‐methoxy‐3,17β‐estradiol in clinical trials. 2‐[¹¹C]Methoxy‐3,17β‐estradiol was synthesized from a precursor, 2‐hydroxy‐3,17β‐O‐bis(methoxymethyl)estradiol, in two steps with over 99% radiochemical purity. The overall reaction time was 45 min and the decay‐corrected radiochemical yield was 32.9%. The distribution coefficient (logP_7.4) of 2‐[¹¹C]methoxy‐3,17β‐estradiol at pH 7.4 was measured as 2.95. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and in vitro evaluation of 2‐[11C]methoxyestradiol‐3,17β‐O,O‐bissulfamate for in vivo studies of angiogenesis

In the present study, 2‐methoxyestradiol‐3,17β‐O,O‐bissulfamate (1), a known angiogenesis inhibitor, was prepared in a radiolabeled form by ¹¹C‐methylation of 2‐hydroxyestradiol‐3,17β‐O,O‐bis(N‐trityl)sulfamate (6) followed by detritylation. Synthesis of precursor 6 required a rather long step because of the presence of two sulfamoyl groups. The decay‐corrected radiochemical yield of [¹¹C]1 was 19 ± 2% based on [¹¹C]CH₃I, and the specific activity was 34–39 GBq/µmol. Although 1 is known to significantly inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs), its radiolabeled form, [¹¹C]1 was not avidly taken up by HUVECs, and the uptake increased slightly in a time‐dependent manner (156% at 60 min relative to a value of 100% at 5 min). These results suggest that further studies are warranted to determine the molecular target for [¹¹C]1. Copyright © 2011 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 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.     

A 11C‐Methyl stannane (5‐[11C]methyl‐1‐aza‐5‐stanna‐bicyclo[3.3.3]undecane) for use in palladium‐mediated [11C]C–C bond forming reactions with organohalides

The synthesis of a ¹¹C‐labelled methyl stannane, (5‐[¹¹C]methyl‐1‐aza‐5‐stanna‐bicyclo[3.3.3]undecane ( 2 )), and its use in palladium‐mediated Stille reactions to form [¹¹C]C–C bonds are described. Stannane 2 was synthesized from iodo[¹¹C]methane, 5‐chloro‐1‐aza‐5‐stanna‐bicyclo[3.3.3]undecane 1 and butyl lithium in 20–90% decay‐corrected radiochemical yield starting from iodo[¹¹C]methane. Subsequent reaction with a series of substituted aryl and vinyl halides produced the corresponding [¹¹C]methylated products 3–5 in up to 90% decay‐corrected radiochemical yield from the crude 2 . The total synthesis time, including purification, was 25–30 min from end of radionuclide production. 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 14C‐labelled myosmine, [2′‐14C] ‐3‐(1‐pyrrolin‐2‐yl)pyridine

¹⁴C‐Labelled myosmine ([2′‐¹⁴C]‐3‐(1‐pyrrolin‐2‐yl)pyridine) was synthesized for autoradiography studies starting from [carboxyl‐¹⁴C]‐nicotinic acid by initial esterification of the latter in the presence of 1,1,1‐triethoxyethane. Without any purification the ethyl nicotinate formed was directly reacted with N‐vinyl‐2‐pyrrolidinone in the presence of sodium hydride, yielding ¹⁴C‐labelled myosmine. The product was purified by silica gel column chromatography. The radiochemical yield was 15% and the specific activity 55.2 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

An asymmetric synthesis of l‐[3‐13C]alanine

l ‐[3‐¹³C]Alanine was synthesized from [¹³C]methyl iodide by using Dellaria's oxazinone, prepared from phenyl[2‐¹³C]bromoacetate and (S)‐2‐phenylglycinol, as a chiral glycine equivalent. Alkylation of the oxazinone with [¹³C]methyl iodide was achieved with high diastereoselectivity. Hydrolysis and removal of the chiral auxiliary of the alkylated oxazinone gave l ‐[3‐¹³C]alanine. Copyright © 2003 John Wiley & Sons, Ltd.     

Radiosynthesis of a 2‐substituted 4,5‐dihydro‐1H‐[2‐11C] imidazole: the I2 imidazoline receptor ligand [11C] benazoline

Benazoline (2‐naphthalen‐2‐yl‐4,5‐dihydro‐1H‐imidazole) is a selective high‐affinity ligand for the imidazoline I₂ receptor. This compound was labelled with carbon‐11 (T_1/2=20.4 min) at the number two carbon atom of its 2‐imidazoline ring. Cyclotron‐produced [¹¹C]carbon dioxide reacted with 2‐naphthylmagnesium bromide to give 2‐[carboxyl‐¹¹C]naphthoic acid in 60% radiochemical yield. The latter was heated with a mixture of ethylenediamine and its dihydrochloride at 300°C to give [¹¹C]benazoline in 16% overall yield, relative to [¹¹C]carbon dioxide and with a specific radioactivity of 54 GBq/μmol, decay corrected for end of irradiation. The procedure requires about 45 min from end of cyclotron irradiation. This method should be extendable to other imidazolines. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 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.     

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.     

[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 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 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.