A two‐step one‐pot radiosynthesis of the potent dopamine D2/D3 agonist PET radioligand [11C]MNPA

(R)‐(?)‐2‐[¹¹C]Methoxy‐N‐n‐propylnorapomorphine ([¹¹C]MNPA ([¹¹C]2)) is an agonist radioligand of interest for imaging D₂/D₃ receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)‐(?)‐2‐hydroxy‐10,11‐acetonide‐N‐n‐propylnoraporphine, 4) was prepared from (R)‐(?)‐2‐hydroxy‐N‐n‐propylnorapomorphine (1) in 30% yield. [¹¹C]2 was prepared from 4 via a two‐step one‐pot radiosynthesis. The first step, methylation of 4 with [¹¹C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [¹¹C]2 giving an overall incorporation yield from [¹¹C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [¹¹C]2, was produced from carbon‐11 generated from a 10‐min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [¹¹C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [¹¹C]2 was confirmed by comparing its LC‐MS/MS spectrum with those of reference 2 and (R)‐(?)‐10‐methoxy‐2,11‐dihydroxy‐N‐n‐propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.     

Development of a series of novel carbon‐11 labeled PDE10A inhibitors

Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon‐11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3‐(1H‐pyrazol‐5‐yl)pyridazin‐4(1H)‐one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)‐LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT‐1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon‐11 employing O‐methylation on the hydroxyl moiety using [¹¹C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [¹¹C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon‐11 labeled KIT‐5 and KIT‐6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [¹¹C]KIT‐6, named [¹¹C]T‐773, is a promising PET tool for further examination of PDE10A in human brain.     

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.     

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 11C‐labelled metomidate analogues as adrenocortical imaging agents

Clinical findings using [¹¹C]methyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate ([¹¹C]MTO, 1) show high uptake in lesions of adrenocortical origin, including adenomas, but low uptake in lesions of non‐adrenocortical origin. In this paper the synthesis and preclinical evaluation of two new ¹¹C‐labelled analogues of MTO, [¹¹C]methyl 1‐[(1R)‐1‐(4‐chlorophenyl)ethyl]‐1H‐imidazole‐5‐carboxylate ([¹¹C]CLM, 2) and [¹¹C]methyl 1‐[(1R)‐1‐(4‐bromophenyl)ethyl]‐1H‐imidazole‐5‐carboxylate ([¹¹C]BRM, 3), using frozen‐section autoradiography, organ distribution and a metabolic study are presented. Copyright © 2008 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.     

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‐(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 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.     

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 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.     

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 (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.     

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.     

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.     

(R)‐N‐Methyl‐3‐(3′‐[18F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (18F‐MFP3) as a potential PET imaging agent for norepinephrine transporter

A decline of norepinephrine transporter (NET) level is associated with several psychiatric and neurological disorders. Therefore positron emission tomography (PET) imaging agents are greatly desired to study the NET pathway. We have developed a C‐fluoropropyl analog of nisoxetine: (R)‐N‐methyl‐3‐(3′‐[¹⁸F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (¹⁸F‐MFP3) as a new potential PET radiotracer for NET with the advantage of the longer half‐life of fluorine‐18 (110 min compared with carbon‐11 (20 min). Synthesis of (R)‐N‐methyl‐3‐(3′‐fluoropropyl)phenoxy)‐3‐phenylpropanamine (MFP3) was achieved in five steps starting from (S)‐N‐methyl‐3‐ol‐3‐phenylpropanamine in approx. 3–5% overall yields. In vitro binding affinity of nisoxetine and MFP3 in rat brain homogenates labeled with ³H‐nisoxetine gave Ki values of 8.02 nM and 23 nM, respectively. For radiosynthesis of ¹⁸F‐MFP3, fluorine‐18 was incorporated into a tosylate precursor, followed by the deprotection of the N‐BOC‐protected amine group with a 15% decay corrected yield in 2.5 h. Reverse‐phase chromatographic purification provided ¹⁸F‐MFP3 in specific activities of >2000 Ci/mmol. Fluorine‐18 labeled ¹⁸F‐MFP3 has been produced in modest radiochemical yields and in high specific activities. Evaluation of ¹⁸F‐MFP3 in animal imaging studies is in progress in order to validate this new fluorine‐18 radiotracer for PET imaging of NET. Copyright © 2010 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 [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.     

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.     

First no‐carrier‐added radioselenation of an adenosine‐A1 receptor ligand

The precursor synthesis and the no‐carrier‐added (n.c.a.) radiosynthesis of the adenosine‐A₁ receptor ligand 5′‐(methyl[⁷⁵Se]seleno)‐N⁶‐cyclopentyladenosine ([⁷⁵Se] 1 ) are described in this report. A method was developed starting from elemental n.c.a. selenium‐75, followed by a three‐step polymer‐supported radioselenation and deprotection which gave the radioligand with a radiochemical yield of 30%, a radiochemical purity of > 99% and a specific radioactivity of > 300 GBq/mmol (8 Ci/mmol). Preparation time was 40 min. The nonradioactive compound 5′‐(methylseleno)‐N⁶‐cyclopentyladenosine ( 1 ) was pharmacologically evaluated in vitro and showed high affinity and selectivity for the adenosine‐A₁ receptor. These preliminary results suggest that this compound could be a useful radioligand for the noninvasive imaging of the brain adenosine‐A₁ receptors using positron emission tomography (PET) when labelled with the positron emitter selenium‐73 (half‐life: 7.1 h). Copyright © 2004 John Wiley & Sons, Ltd.