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 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.     

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.     

Gas phase production of [11C]methyl iodide‐d3. Synthesis and biological evaluation of S‐[N‐methyl‐11C]citalopram and deuterated analogues

Three ¹¹C‐labelled tracers for the serotonin reuptake site, S‐[N‐methyl‐¹¹C]citalopram ( [¹¹C]‐4 ), S‐[N‐methyl‐d₃‐¹¹C]citalopram ( [¹¹C]‐12 ), and S‐[N‐methyl‐¹¹C]citalopram‐α,α‐d₂ ( [¹¹C]‐13 ) were synthesized and the distribution of radioactivity after injection of radioligand was examined ex vivo in rats. The deuterated analogue of (S)‐desmethylcitalopram, (S)‐1‐(4‐fluorophenyl)‐1‐(3‐methylamino‐[3‐d₂]‐propyl)‐1,3‐di‐hydro‐isobenzofuran‐5‐carbonitrile ( 11 ), was synthesized in a multi‐step synthesis from escitalopram ( 4 ) and used as precursor in the synthesis of [¹¹C]‐13 . In analogy with the reported gas phase synthesis of [ ¹¹ C]methyl iodide the first gas phase synthesis of [¹¹C]Methyl iodide‐d₃ is reported. The ¹H/²H kinetic isotope effect related to the synthesized compounds were investigated in ex vivo rat studies, where the brain regions of interest to cerebellum ratios of the tracers [¹¹C]‐4 , [¹¹C]‐12 and [¹¹C]‐13 were compared. The ex vivo data indicated no significant differences in binding in any of the investigated brain regions after injection of the three tracers. Copyright © 2004 John Wiley & Sons, Ltd.     

Development of a reliable remote‐controlled synthesis of β‐[11C]‐5‐hydroxy‐L‐tryptophan on a Zymark robotic system

Precise staging of neuroendocrine tumors (NET) using positron emission tomography (PET) tracers visualizing their specific metabolic activity is of interest. Besides [¹⁸F]FDOPA, staging NET with carbon‐11 labeled 5‐hydroxytryptophan (5‐HTP) is reported in recent literature. We implemented the multi‐enzymatic synthesis of enantiomerically pure [¹¹C]‐L‐5‐HTP on a Zymark robotic system to compare both tracers in patient studies. [¹¹C]‐5‐HTP can be synthesized in up to 24% radiochemical yields (EOB). Average specific activity is 44 000 GBq/mmol in ca. 50 min from [¹¹C]methyl iodide in radiochemical purities >99 %. The synthesis of 5‐HTP is difficult due to its multi‐enzymatic reaction steps but typical yields can be achieved of ca. 400 MBq. [¹¹C]‐5‐HTP is now reliably used in ongoing studies for staging NET. 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.     

Synthesis and 11C‐labelling of (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl) benzene for PET imaging of amyloid deposits†

Carboxylic acid derivatives of the amyloid‐binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid‐imaging agents. A neutral amyloid probe, (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl)benzene ( 3 ), devoid of any carboxylate groups has been designed and synthesized via a 12‐step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C‐11 via [¹¹C]methyl iodide ([¹¹C]CH₃I) methylation of a symmetric 4,4′‐dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post‐mortem AD brain, and exhibited good binding affinity (K_i=38±8 nM) for Aβ(1–40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [¹¹C] 3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [¹¹C] 3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR‐beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

5,11‐Dihydro‐11‐ethyl‐5‐methyl‐8‐{2‐{(1‐oxido‐4‐quinolinyl)oxy}ethyl}‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one, (1), labeled with carbon‐14 in the quinoline–benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63–1.75 GBq/mmol). In the first synthesis, 5,11‐dihydro‐11‐ethyl‐8‐(2‐hydroxyethyl)‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (2) was coupled to 4‐hydroxyquinoline, [benzene‐¹⁴C(U)]‐, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3‐chloroperoxybenzoic acid to give ([¹⁴C]‐(1a)) in 43% radiochemical yield. Second, 3‐amino‐2‐chloropyridine, [2,6‐¹⁴C]‐, was used to prepare 8‐bromo‐5,11‐dihydro‐11‐ethyl‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([¹⁴C]‐(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon‐14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([¹⁴C]‐(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio‐HPLC and radio‐TLC to be more than 98%. To prepare [¹³C₆]‐(1), [¹³C₆]‐4‐hydroxyquinoline was prepared from [¹³C₆]‐aniline and then coupled to (2) and oxidized as seen before. Copyright © 2008 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.     

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 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 (±) 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.     

Preparation of [11C]methyl nona‐fluorobutyl‐1‐sulfonate ([11C]MeONf) and its use in the synthesis of [11C]‐6‐OH‐BTA‐1

The rapid, simple and high‐yield synthesis of the extraordinarily reactive ¹¹C‐methylating agent, [¹¹C]methyl nona‐fluorobutyl‐1‐sulfonate ([¹¹C]MeONf), and its use in the synthesis of the promising β‐amyloid imaging agent, [¹¹C]‐6‐OH‐BTA‐1, is reported. In terms of radioactive methylation yields, [¹¹C]MeONf seems to surpass [¹¹C]methyl trifluoromethansulfonate ([¹¹C]MeOTf) as a methylating agent in this particular case giving the ¹¹C‐labelled compound in high‐preparative radiochemical yields between 27 and 29% EOS with a minimum formation of radioactive by‐products. Copyright © 2007 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.     

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.     

Synthesis of 1‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐ difluoro‐5‐(2‐halo‐1‐hydroxyethyl)benzenes and related derivatives: “thymine replacement” analogs of deoxythymidine for evaluation as antiviral and anticancer agents

A group of unnatural 1‐(2‐deoxy‐β‐D ‐ribofuranosyl)‐2,4‐difluorobenzenes having a variety of C‐5 substituents, designed as thymidine mimics, were synthesized for evaluation as antiviral and anticancer agents. The regiospecific addition of HOBr (generated from N‐bromosuccinimide in aqueous dioxane) across the 5‐vinyl substituent ( 4 ) afforded the corresponding 5‐[‐CH(OH)CH₂Br] product ( 5 ), whereas reaction of 4 with iodine in the presence of iodic acid (HOI) yielded the 5‐[CH(OH)CH₂I] product ( 6 ). The related 5‐[‐CH(OH)CHX₂ (X = Br, I)] analogs ( 11 , 12 ) were similarly prepared from the (E)‐5‐(2‐halovinyl) precursors ( 9 , 10 ). Treatment of the 5‐[‐CH(OH)CH₂X (X = Br, I)] compounds ( 5 , 6 ) with NaOH in aqueous dioxane afforded the 5‐oxiranyl product ( 8 ). The 5‐[‐CH(OMe)CH₂I] compound ( 7 ) was prepared by reaction of the 5‐vinyl compound (4) with ICl in MeOH (MeOI). This group of compounds ( 5 – 8 , 11 , 12 ) showed similar (marginal) activity against varicella‐zoster virus thymidine kinase positive (VZV/TK⁺) and thymidine kinase deficient (VZV/TK^–) infected cells. Thus, the viral TK enzyme did not provide a gene therapeutic effect. This group of compounds, which were evaluated using a wide variety of antiviral assay systems [(herpes simplex virus HSV‐1, HSV‐2), varicella‐zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency virus (HIV‐1, HIV‐2)], showed that these unnatural C‐aryl nucleoside mimics are inactive antiviral agents. Their failure to exhibit antiviral/anticancer activity could be due to the fact that they are not phosphorylated to the 5′‐monophosphate, or that incorporation of the active 5′‐triphosphate into DNA does not produce a cytotoxic effect, and/or that these C‐aryl nucleoside mimics do not act as inhibitors of thymidylate synthase, which may be required to produce a cytotoxic effect. Drug Dev. Res. 52:492–499, 2001. © 2001 Wiley‐Liss, Inc.     

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.     

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 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.     

Synthesis of the serotonin transporter ligand (±)‐10‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,10‐diazabicyclo‐[4.3.1]‐decane ([11C‐methyl]NS 2495) and first in vivo results

The serotonin transporter ligand (±)‐10‐[¹¹C]‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,10‐diazabicyclo‐[4.3.1]‐decane ([¹¹C‐methyl]NS 2495) was synthesized via a methylation reaction with [¹¹C]methyl iodide. The radiochemical purity exceeded 99% and the specific radioactivity was found to be 1.8 GBq/μmol at 40 min after the end of bombardment. The uptake of the tracer in the brain of a living pig was recorded by positron emission tomography (PET), first in a baseline condition, and again after treatment with citalopram (1 mg/kg, i.v.) to displace the specific binding. The distribution volume relative to the metabolism‐corrected arterial input was high in pig brain, ranging from 75–150 ml g^?1; treatment with citalopram uniformly reduced the distribution volume to 75 ml g^?1. Binding potential (pB) maps generated using the cerebellum as a reference tissue showed highest binding in the mesencephalon and cingulate cortex, where the magnitude of pB was close to 0.6. Thus, the pattern of binding in vivo agrees with the known pattern of serotonin innervations in pig brain. However, the specific binding was incompletely displaced by pre‐treatment with citalopram. Thus, [¹¹C‐methyl]NS 2495 can label serotonin transporters in a PET study of the brain of a living pig, but full displacement by cold citalopram was not obtained in vivo, possibly reflecting binding sites which are inaccessible to citalopram. Copyright © 2003 John Wiley & Sons, Ltd.