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.     

N‐Arylation of indoles with 4‐[18F]fluoroiodobenzene: synthesis of 18F‐labelled σ2 receptor ligands for positron emission tomography (PET)

The palladium‐mediated N‐arylation of indoles with 4‐[¹⁸F]fluoroiodobenzene as a novel radiolabelling method has been developed. Optimized reaction conditions were elaborated by variation of different catalyst systems (CuI/1,2‐diamines and Pd₂(dba)₃/phosphine ligands), bases and solvents in the reaction of indole with 4‐[¹⁸F]fluoroiodobenzene. Optimized reaction conditions (Pd₂(dba)₃/(2‐(dicyclohexyl‐phosphino)‐2′‐(N,N‐dimethylamino)‐biphenyl, NaOBu^t, toluene, 100°C for 20 min) were applied for the synthesis of ¹⁸F‐labelled σ₂ receptor ligands [¹⁸F]‐11 and [¹⁸F]‐13 which were obtained in 91 and 84% radiochemical yields, respectively. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of 3‐[(2S)‐azetidin‐2‐ylmethoxy]‐5‐[11C]‐methylpyridine,an analogue of A‐85380, via a Stille coupling

3‐[(2S)‐azetidin‐2‐ylmethoxy]‐5‐[¹¹C]‐methylpyridine (5d) , which might be a novel ligand for nicotinic receptors, was synthesized via coupling [¹¹C]iodomethane with tert‐butyl (2S)‐2‐({[5‐(trimethylstannyl)pyridin‐3‐yl]oxy}methyl) azetidine‐1‐carboxylate (4) at 80°C for 5 min with tri‐o‐tolylphosphine‐bound, unsaturated palladium(0), followed by deprotection using trifluoroacetic acid (TFA). The previous problem (solid‐phase extraction before injection on semi‐preparative LC) with automation of Stille coupling reactions has been overcome. In a typical experiment, 0.46 GBq of 5d was obtained from 5.2 GBq of [¹¹C]iodomethane. The decay‐corrected radiochemical yield was 39% (based on the quantity [¹¹C]iodomethane trapped). The synthesis time was 43 min from end of radionuclide production. During a production condition using 36 μAh of proton beam irradiation, a specific radioactivity of 50 GBq/μmol of the final product was obtained in biological buffer. Copyright © 2002 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‐(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 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.     

No‐carrier added synthesis of 18F‐labelled nucleosides using Stille cross‐coupling reactions with 4‐[18F]fluoroiodobenzene

The radiosyntheses of 5‐(4′‐[¹⁸F]fluorophenyl)‐uridine [¹⁸F]‐11 and 5‐(4′‐[¹⁸F]fluorophenyl)‐2′‐deoxy‐uridine [¹⁸F]‐12 are described. The 5‐(4′‐[¹⁸F]fluoro‐phenyl)‐substituted nucleosides were prepared via a Stille cross‐coupling reaction with 4‐[¹⁸F]fluoroiodobenzene followed by basic hydrolysis using 1 M potassium hy‐droxide. The Stille cross‐coupling reaction was optimized by screening various palladium complexes, additives and solvents. By using optimized labelling conditions (Pd₂(dba)₃/CuI/AsPh₃ in DMF/dioxane (1:1), 20 min at 65°C), 550 MBq of [4‐¹⁸F]fluoroiodobenzene could be converted into 120 MBq (33%, decay‐corrected) of 5‐(4′‐[¹⁸F]fluorophenyl)‐2′‐deoxy‐uridine [¹⁸F]‐12 within 40 min, including HPLC purification. Copyright © 2004 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.     

An improved synthesis of [11C]MENET via Suzuki coupling with [11C]methyl iodide

[¹¹C]MENET, a promising norepinephrine transporter imaging agent, was prepared by Suzuki cross coupling of 1 mg N‐t‐Boc pinacolborate precursor with [¹¹C]CH₃I in DMF using palladium complex generated in situ from Pd₂(dba)₃ and (o‐CH₃C₆H₄)₃P together with K₂CO₃ as the co‐catalyst, followed by deprotection with trifluoroacetic acid. This improved radiolabeling method provided [¹¹C]MENET in high radiochemical yield at end of synthesis (EOS, 51 ± 3%, decay‐corrected from end of ¹¹CH₃I synthesis, n = 6), moderate specific activity (1.5–1.9 Ci/µmol at EOS), and high radiochemical (>98%) and chemical purity (>98%) in a synthesis time of 60 ± 5 min from the end of bombardment. Copyright © 2013 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 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.     

Radiosynthesis of [11C]SL25.1188 via [11C]CO2 fixation for imaging monoamine oxidase B

Carbon‐11‐labelled (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐[¹¹C]‐one ([¹¹C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one‐pot procedure directly from [¹¹C]CO₂, thereby precluding the use of [¹¹C]COCl₂. Formulated [¹¹C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [¹¹C]CO₂, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n = 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [¹¹C]SL25.1188 at ambient temperature and is suitable for human imaging studies.     

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.     

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.     

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.     

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.     

11C labelling of AG957—a potential tyrphostin radiotracer for PET

Carbon‐11 labelled 4‐(N‐2,5‐dihydroxybenzyl)amino methyl benzoate (AG957), a potential radiotracer for imaging bcr–abl receptors was synthesized. [¹¹C]AG957 was prepared by labelling 4‐aminobenzoic acid using [¹¹C]CH₃I, which affords the corresponding [¹¹C] methyl ester in excellent yields. Subsequent condensation of the amino group with 2,5‐dihydroxy‐benzaldehyde formed the respective Schiff base. Reduction of this compound with NaBH₃CN gave [¹¹C]AG957 in overall decay corrected radiochemical yield of 65–75% (based on ¹¹CH₃I) with an average specific radioactivity of 40 GBq/μmol (1.1 Ci/μmol). The total synthesis time from EOB including formulation was 45 min. At physiological pH, the compound was found to be sufficiently stable for in vitro and in vivo investigations. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 18F‐labelled biphenyls via SUZUKI cross‐coupling with 4‐[18F]fluoroiodobenzene

The SUZUKI reaction of organoboron compounds with 4‐[¹⁸F]fluoroiodobenzene has been developed as a novel radiolabelling technique in ¹⁸F chemistry. The cross‐coupling reaction of p‐tolylboronic acid with 4‐[¹⁸F]fluoroiodobenzene was used to screen different palladium complexes, bases and solvents. Optimized reaction conditions (Pd₂(dba)₃, Cs₂CO₃, acetonitrile, 60°C for 5 min) were further applied to the synthesis of various ¹⁸F‐labelled biphenyls bearing different functional groups. The reaction proceeded in excellent radiochemical yields of up to 94% within 5 min while showing good compatibility to many functional groups. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of [18F]ATPFU: a potential PET ligand for mTOR

Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR‐specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [¹⁸F]1‐(4‐(4‐(8‐oxa‐3‐azabicyclo[3.2.1]octan‐3‐yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6‐yl)phenyl)‐3‐(2‐fluoroethyl)urea [¹⁸F]ATPFU ([¹⁸F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4‐(4‐8‐oxa‐3‐azabicyclo[3.2.1]‐octan‐3yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6yl)aniline (10), were achieved from beta‐chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25–28%. [¹⁸F]Fluoroethylamine was prepared by heating N‐[2‐(toluene‐4‐sulfonyloxy)ethyl]phthalimide with [¹⁸F]fluoride ion in acetonitrile. [¹⁸F]1 was obtained by slow distillation under argon of [¹⁸F]FCH₂CH₂NH₂ into amine 10 that was pre‐treated with triphosgene at 0–5 °C. The total time required for the two‐step radiosynthesis including semi‐preparative HPLC purification was 90 min, and the overall radiochemical yield of [¹⁸F]1 for the process was 15 ± 5% based on [¹⁸F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37–74 GBq/µmol (N = 6).     

Synthesis and biological evaluation of S‐[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5‐HT1A receptors by positron emission tomography (PET)

The novel 2‐mercaptoimidazole derivatives, 1‐[4‐((2‐methoxyphenyl)‐1‐piperazinyl)butyl]‐2‐mercaptoimidazole ( 3 ) and methyl[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl] (2‐mercapto‐1‐methylimidazol‐5‐yl)methanamide ( 8 ), were efficiently labelled with ¹¹C through methylation of the thioketone function with [¹¹C]methyl iodide. The resulting radioligands 1‐[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl]‐2‐thio[¹¹C]methylimidazole ([¹¹C] 9 ) and methyl[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl] (2‐thio[¹¹C]methyl‐1‐methylimidazol‐5‐yl)‐methanamide ([¹¹C] 10 ) were synthesized in radiochemical yields of 20–30% (decay‐corrected, related to [¹¹C]CO₂) at a specific radioactivity of 0.2–0.4 Ci/µmol within 40–45 min including HPLC‐purification. The radiochemical purity exceeded 99%. The reference compounds 9 and 10 were tested in a competitive receptor binding assay to determine their affinity toward the 5‐HT_1A receptor. Both compounds exhibit excellent sub‐nanomolar affinities (IC₅₀=0.576±0.008 nM ( 9 ); IC₅₀=0.86±0.02 nM ( 10 )) for the 5‐HT_1A receptor while displaying a high selectivity towards the 5‐HT_2A subtype of receptors (IC₅₀>480 nM). By contrast, compound 9 also shows substantial binding for the alpha1‐adrenergic receptor (IC₅₀=3.00±0.02 nM) when compared with compound 10 (IC₅₀=54.5±0.6 nM). Preliminary biodistribution studies in rats showed an initial brain uptake of 1.14±0.11 and 0.37±0.04% ID/g after 5 min, which decreased to 0.18±0.04 and 0.16±0.01% ID/g after 60 min for compounds [¹¹C] 9 and [¹¹C] 10 , respectively. For both compounds, the cerebellum and rest of the brain uptake are very similar at the different time points. Unlike [¹¹C] 9 , the radioligand [¹¹C] 10 has significant uptake and retention in the adrenal glands. Due to their washout from the brain compounds [¹¹C] 9 and [¹¹C] 10 seem not to be good candidates as radioligands for imaging 5‐HT_1A receptors by PET. Copyright © 2005 John Wiley & Sons, Ltd.