Novel Mannich Bases, 5‐Arylimidazolidine‐2,4‐dione Derivatives with Dual 5‐HT1A Receptor and Serotonin Transporter Affinity

A computer aided ligand design study of imidazolidine‐2,4‐dione derivatives was conducted in order to obtain compounds with dual 5‐HT_1A receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5‐HT_1A, 5‐HT_2A, α₁ and SERT affinity. Two selected compounds ( 5 , 9 ) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy – 5‐HT_1A partial agonism and 5‐HT_2A antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α₁ receptors. The most promising compounds, 5‐arylimidazolidine‐2,4‐dione derivatives with 4‐(3‐chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5‐(2‐methoxyphenyl)‐3‐{1‐[4‐(3‐chlorophenyl)piperazin‐1‐yl]methyl}‐imidazolidine‐2,4‐dione), tested in the forced swim test in mice, exhibited a favorable antidepressant‐like profile without affecting spontaneous locomotor activity.     

Synthesis,docking studies,and pharmacological evaluation of 5HT2C ligands containing the N′‐cyanoisonicotinamidine or N′‐cyanopicolinamidine nucleus

N′‐Cyanoisonicotinamidine and N′‐cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5‐HT_1A, 5‐HT_2A, and 5‐HT_2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5‐HT_1A and 5‐HT_2C receptors and moderate or no affinity for other relevant receptors (D₁, D₂, α₁, and α₂). Compound 8e (K_i = 21.4 nM) was the most affine for the 5‐HT_2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c , instead, showed an interesting mixed 5‐HT_1A/5‐HT_2C activity with K_i values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5‐HT_2C ( 4a , 4c , 8b , and 8e ) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a , 8b , and 8e exerted antidepressant‐like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a , which displayed antipsychotic‐, antidepressant‐ and anxiolytic‐like properties. No side effects, like catalepsy, motor‐impairment or ethanol‐potentiating effects, were observed after the injection of the tested compounds.     

Synthesis,Hypoglycaemic, Hypolipidemic and PPARγ Agonist Activities of 5‐(2‐Alkyl/aryl‐6‐Arylimidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene‐1,3‐Thiazolidinediones

A novel series of 5‐(2‐alkyl/aryl‐6‐arylimidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene‐1,3‐thiazolidinediones were synthesized as possible PPARγ agonists. The structures of these target molecules were established by spectral and analytical data. All the newly synthesized compounds were screened for their in vivo hypoglycaemic and hypolipidemic activity in male Wistar rats. Further, compounds with good activity were screened for PPARγ agonist activity. Among the screened compounds, 5‐{[2‐Cyclohexyl‐6‐(4‐methoxyphenyl)imidazo[2,1‐b] [1,3,4]thiadiazol‐5‐yl]methylene}‐1,3‐thiazolidine‐2,4‐dione (3i) exhibits promising hypoglycaemic and hypolipidemic activity via potential PPARγ agonist activity.     

Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine‐2,6‐dione derivatives combining potent dopamine D₂, D₃ and serotonin 5‐HT_1A, 5‐HT_2A, 5‐HT_2C receptor properties. We describe the structure–activity relationships that led us to the promising derivative: 1‐(4‐(4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)piperidin‐1‐yl)butyl)‐4‐(4‐chlorophenyl)‐piperidine‐2,6‐dione 5 . The unique pharmacological features of compound 5 are a high affinity for dopamine D₂, D₃ and serotonin 5‐HT_1A, 5‐HT_2A, 5‐HT_2C receptors, together with a low affinity for the H₁ receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine‐induced climbing behavior and MK‐801‐induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.     

Design,Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT₃ receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand‐based approach keeping in consideration the structural requirement of the pharmacophore of 5‐HT₃ receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5‐HT₃ receptor antagonism of all the compounds, which was denoted in the form of pA₂ value, was determined in longitudinal muscle myenteric plexus preparation from guinea‐pig ileum against 5‐HT₃ agonist, 2‐methyl‐5‐HT. Compound 8g (2‐methoxy‐1, 8‐naphthyridin‐3‐yl) (2‐methoxy phenyl piperazine‐1‐yl) methanone was identified as the most active compound, which expressed a pA₂ value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA₂ value exhibited promising antidepressant‐like activity, whereas compounds with lower pA₂ value did not show antidepressant‐like activity as compared to the control group.     

A novel method for the synthesis of carbon‐14‐labeled N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]propanamide and its use in quantitative whole‐body autoradiography studies

Sumitriptan ( 1 ), a non‐selective 5‐HT_1B/1D agonist is an effective therapeutic agent for the acute treatment of migraine, but it is contraindicated for use in patients with known heart disease. The first Selective Serotonin One F Receptor Agonist (SSOFRA), 5‐(4′‐fluorobenz‐amido)‐3‐(N‐methyl‐piperidin‐4‐yl)‐1H‐indole ( 2 ) was demonstrated to be clinically useful in the treatment of migraine. Although 2 exhibited high affinity for the 5‐HT_1F receptor as well as high selectivity for the 5‐HT_1F receptor relative to 5‐HT_1B and 5‐HT_1D receptors, it demonstrated appreciable affinity for the 5‐HT_1A receptor. Subsequently, a program was launched to discover SSOFRA's with improved selectivity over other 5‐HT₁ receptor subtypes. As a result of these efforts, N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]propanamide ( 3 ) was found to possess greater than 100‐fold selectivity over 5‐HT_1A, 5‐HT_1B and 5‐HT_1D receptors. Pursuant to a potential clinical investigation of 3 , its carbon‐14‐labeled isotopomer has been prepared by a circuitous route from unlabeled 3 and used in quantitative whole‐body autoradiography studies in rats. The results of these efforts are reported herein. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and evaluation of [O‐methyl‐11C]4‐[3‐[4‐(2‐methoxyphenyl)‐ piperazin‐1‐yl]propoxy]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione as a 5‐HT1A receptor agonist PET ligand

4‐[3‐[4‐(2‐Methoxyphenyl)piperazin‐1‐yl]propoxy]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione (4), a potent and selective 5‐HT_1A agonist, was labeled by ¹¹C‐methylation of the corresponding desmethyl analogue 3 with ¹¹C‐methyl triflate. The precursor molecule 3 was synthesized from commercially available endo‐N‐hydroxy‐5‐norbornene‐2,3‐dicarboximide in two steps with an overall yield of 40%. Radiosynthesis of ¹¹C‐4 was achieved in 35 min in 20±5% yield (n=6) at the end of synthesis with a specific activity of 2600±250 Ci/mmol. In vivo positron emission tomography (PET) studies in baboon revealed rapid uptake of the tracer into the brain. However, lack of specific binding indicates that ¹¹C‐4 is not useful as a 5‐HT_1A agonist PET ligand for clinical studies. Copyright © 2008 John Wiley & Sons, Ltd.     

The synthesis of carbon‐14 labeled (R)‐4‐(dipropylamino)‐1,3,4,5‐tetrahydrobenz[cd]indole‐6‐carboxamide hippurate. A partial ergoline with 5‐HT1A agonist activity and an 125I‐labeled analog

Partial ergoline agonists such as (R)‐4‐(dipropylamino)‐1,3,4,5‐tetrahydrobenz[cd]‐indole‐6‐carboxamide ( LY228729, 1a ) mimic a locked conformational analog of serotonin and in fact possess potent in vitro activity as agonists of the 5‐HT_1A receptor. In the course of pre‐clinical investigation of 1a for potential use as an anxiolytic agent, 1b was prepared in a five step synthesis from K¹⁴CN. In addition, an ¹²⁵I‐analog of 1a was prepared for aid in the development of a radioimmunoassay (RIA). Copyright © 2005 John Wiley & Sons, Ltd.     

New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT1A/5‐HT7 Receptor Ligands

A series of new long‐chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5‐HT_1A and 5‐HT₇ receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2H‐1,3‐benzoxazine‐2,4(3H)‐dione as imides, and 1‐(2‐methoxyphenyl)piperazine (o‐OMe‐PhP) and 1,2,3,4‐tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta‐ and hexamethylene chains as well as partly constrained m‐ and p‐xylyl moieties. In general, the new compounds were more active at the 5‐HT_1A than at the 5‐HT₇ receptor, and the o‐OMe‐PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o‐OMe‐PhP series, except for a small binding reduction for ligands containing the m‐xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure–activity relationship was visible only for the interaction of the compounds with the 5‐HT₇ receptor, which strongly favored flexible analogs.     

Solid‐Supported Synthesis and 5‐HT7/5‐HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

A series of arylpiperazinylbutyl derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6(1H)‐ones was designed and synthesized according to the new solid‐supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc‐protected glycine. The library representatives showed different levels of affinity for 5‐HT₇ and 5‐HT_1A receptors; compounds 13 , 14 and 18 – 20 were classified as dual 5‐HT₇/5‐HT_1A receptors ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.     

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

Since the year 1993, when 5‐HT₇ receptor (5‐HT₇R) was discovered, there is no selective 5‐HT₇R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5‐HT₇R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by “drug‐likeness” estimation of the first series of selective and potent 5‐HT₇R ligands among 5‐(4‐fluorophenyl)‐3‐(2‐hydroxy‐3‐(4‐aryl‐piperazin‐1‐yl)propyl)‐5‐methylimidazolidine‐2,4‐dione derivatives ( 11–16 ). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2 . The experiments showed promising drug‐like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13 . The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant‐like activity in the FST. Taking into account the beneficial properties of 13 , i.e., good drug‐like parameters, the significant antagonistic action, high selectivity to 5‐HT₇R, and its in vivo antidepressant‐like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5‐HT₇ receptor.     

The synthesis of (S)‐di‐n‐propyl‐(8‐isoxazol‐5‐yl‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)amine hydrochloride and its C‐14‐labeled isotopomer

The partial ergoline LY228729 (1) which was a potent 5HT_1A agonist has been studied clinically. Somewhat later, a related analog, (S)‐di‐n‐propyl‐(8‐isoxazol‐5‐yl‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)amine (2a) which in addition to potent 5HT_1A agonist activity was a muscarinic antagonist, was chosen for clinical development for use in the treatment of irritable bowel syndrome. In the course of pre‐clinical evaluation of 2a , radiolabeled material was required for ADME studies. In this paper, we have discussed the preparation of 2a and 2b (the C‐14‐labeled isotopomer of 2a ). Copyright © 2005 John Wiley & Sons, Ltd.     

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT_2A receptors (5‐HT_2AR) and muscarinic M₁ receptors (M₁R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M₁R (minimal displacement of [~K_d] [³H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K_i values at 5‐HT_2AR. In 5‐HT_2AR–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT_2AR functional activity of α‐PPP, and observed it competitively antagonized 5‐HT_2AR signaling stimulated by the 5‐HT₂R agonist (±)‐2,5‐dimethoxy‐4‐iodoamphetamine (DOI; K_b = 851 nM). To assess in vivo 5‐HT_2AR activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppression at 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT_2AR mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT_2AR K_is > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT_2AR in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT_2AR antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.     

Structure‐Based Identification of Aporphines with Selective 5‐HT2A Receptor‐Binding Activity

Selective blockade of the serotonin 5‐HT_2A receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5‐HT_2A receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand‐binding assays against rat serotonin (5‐HT_1A and 5‐HT_2A) and dopamine (D1 and D2) receptors. (R)‐Roemerine and (±)‐nuciferine were found to have high affinity for the 5‐HT_2A receptor (K_i = 62 and 139 nm , respectively), with (R)‐roemerine showing 20‐ to 400‐fold selectivity for the 5‐HT_2A receptor over the 5‐HT_1A, D1 and D2 receptors. Investigation into the ligand–receptor interactions suggested that the selectivity of (R)‐roemerine is due to it having stronger H‐bonding and dipole–dipole interactions with several of the key residues in the 5‐HT_2A receptor‐binding site.     

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 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.     

Adventitia removal does not modify the α1D‐adrenoceptors response in aorta during hypertension and ageing

1 The aim of the current study was to characterize the α₁‐adrenergic receptors (α₁‐ARs) present in the isolated tunica media of aorta, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during the course of ageing and hypertension (rats of 1, 3, 6 and 12 months of age). In all vessels, endothelium was removed. 2 In isolated aortic rings, phenylephrine increased contraction in a concentration‐ and age‐dependent manner and was impaired in old SHR compared with WKY rats. 3 The α₁‐AR selective antagonist prazosin showed high affinity (pA₂) in vessels from both rat strains. 4 The potency of the α_1A‐AR selective antagonists, RS 100329 (5‐methyl‐3‐[3‐[4‐[2‐(2,2,2,‐trifluoroethoxy) phenyl]‐1‐piperazinyl] propyl]‐2,4‐(1H)‐pyrimidinedione) and 5‐methylurapidil in antagonizing aortic phenylephrine‐responses was low. 5 The α_1D‐AR selective antagonist, BMY 7378 (8‐[2‐[4‐(2‐methoxyphenyl)‐1 piperazynil] ethyl]‐8‐azaspiro [4.5] decane‐7,9‐dione) potently blocked phenylephrine‐induced responses in aorta from both strains and at all ages. 6 Adventitia removal decreased E_max in older rats and modified the relative affinity (pD₂), but did not affect the affinity of the selective antagonists. 7 The results suggest that aorta tunica α_1D‐AR is the main subtype involved in phenylephrine‐induced contraction of rat aorta, while α_1A‐AR plays only a minor role. 8 Ageing and hypertension did not modify α₁‐ARs in the blood vessel and the tunica adventitia does not seem to participate in contraction, even though α₁‐ARs are expressed.     

Synthesis of potent lymphocyte function‐associated antigen‐1 inhibitors labeled with carbon‐14 and deuterium,part 1

The lymphocyte function‐associated antigen‐1 (LFA‐1) is an essential component in normal immune system function and is a target for drug discovery for its broad therapeutic potential in treating inflammatory diseases. Here, we report the synthesis of three potent antagonists of LFA‐1 labeled with carbon‐14 and deuterium to support drug metabolism and pharmacokinetics studies. Carbon‐14 labeled (R)‐1‐acetyl‐5‐(4‐bromobenzyl)‐3‐(3,5‐dichlorophenyl)‐5‐methyl‐imidazolidine‐2,4‐dione (1) was prepared in 27% radiochemical yield in two steps and with a specific activity of 2.1 GBq/mmol by using [¹⁴C]‐phosgene. Carbon‐14 labeled 5‐bromopyrimidine was used to prepare (R)‐5‐(1‐piperazinylsulfonyl)‐1‐(3,5‐dichlorophenyl)‐3‐[4‐(5‐pyrimidinyl)benzyl]‐3‐methyl‐1‐H‐imidazo[1,2a]imidazol‐2‐one (2) and (R)‐1‐[7‐(3,5‐dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐pyrimidin‐5‐yl‐benzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonyl]piperidin‐4‐carboxylic acid amide (3) via a Suzuki reaction with the corresponding boronic acid esters in 42% and 67% radiochemical yield and specific activities of 1.85 GBq/mmol and 1.95 GBq/mmol, respectively. Deuterium labeled piperazine was reacted with the sulfonyl chloride derivative (7), followed by a Suzuki coupling to the pyrimidine boronic ester to give deuterium labeled (2) in 47% yield. Deuterium labeled isonipecotamide was reacted in a similar way with the sulfonyl chloride derivative (14) to furnish deuterium labeled (3) in one step and in 94% yield. Copyright © 2011 John Wiley & Sons, Ltd.