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.     

Synthesis of 3H‐ and 14C‐labeled AR‐A000002, a new and selective 5‐HT1B/1D ligand

AR‐A000002 is a novel and selective high‐affinity 5‐HT_1B/1D receptor antagonist. The compound has been shown to enhance 5‐HT turnover in the guinea pig brain in vivo and to increase the extracellular concentration of 5‐HT and the metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) in guinea pig frontal cortex. The observed effects suggest that the compound could be used for the treatment of affective disorders. The syntheses of labeled AR‐A000002 analogues as needed for the further pharmacological evaluation of this selective 5‐HT_1B/1D antagonist, are described. Copyright © 2004 John Wiley & Sons, Ltd.     

Receptor specificity of the 5HT2 receptor antagonist,LY53857

LY53857 is a potent antagonist at vascular 5HT₂ receptors that lacks prominent α₁ or dopamine antagonist activity. The present report investigates the interaction of LY53857 with other receptor mechanisms. LY53857 showed no agonist activity in the guinea pig trachea, guinea pig atria, guinea pig ileum, or rat vas deferens. Furthermore, LY53857 did not antagonize histamine (H₁) or β₂ receptors in the guinea pig trachea, β₁ in the guinea pig atria, muscarinic, or angiotensin I receptors in the guinea pig ileum. However, LY53857 did block α₂ receptors (?log K_B = 6.51) as determined by antagonism of the inhibitory effects of the selective β₂ agonist, UK-14,304, on the twitch response in the guinea pig ileum. LY53857 antagonized β₂ receptors at concentrations approximately 6000-fold higher than necessary to block 5HT₂ receptors (?log K_B = 10.3). Taken in concert, these data support the contention that LY53857 is a highly selective antagonist of 5HT₂ receptors, and that LY53857 is a useful tool with which to probe 5HT₂ receptors and serotonergic mechanisms.     

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.     

5‐HT modulates the rat mesenteric vasopressor outflow by 5‐HT1D sympatholytic receptors

5‐hydroxytryptamine (5‐HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5‐HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure (SBP), heart rate (HR) and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency‐dependent increases in MPP (9 ± 1.6, 25.7 ± 3.9 and 60.2 ± 5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5‐HT (1‐25 μg/kg), 5‐carboxamidotryptamine (5‐HT_1/7 agonist; 25 μg/kg) or L‐694,247 (5‐HT_1D agonist; 1‐25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8‐OH‐DPAT (5‐HT_1A), CGS‐12066B (5‐HT_1B), BRL 54443 (5‐HT_1e/1F), α‐methyl‐5‐HT (5‐HT₂), 1‐PBG (5‐HT₃), cisapride (5‐HT₄) or AS‐19 (5‐HT₇) (25 μg/kg each). Interestingly, i.a. L‐694,247 (25 μg/kg) also reduced the exogenous norepinephrine‐induced vasoconstrictions. Pretreatment with selective 5‐HT_1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L‐694,247‐ and 5‐HT‐induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5‐HT_1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms‐induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5‐HT_1D receptors.     

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.     

In vitro functional evaluation of isolaureline,dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors

Compounds with activity at serotonin (5‐hydroxytryptamine) 5‐HT₂ and α₁ adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5‐HT₂ and adrenergic α₁ receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5‐HT₂ and α₁ receptors with (R)‐isolaureline showing the greatest potency (pK_b = 8.14 at the 5‐HT_2C receptor). Both (R)‐ and (S)‐glaucine also antagonized α₁ receptors, but they behaved very differently to the other compounds at 5‐HT₂ receptors: (S)‐glaucine acted as a partial agonist at all three 5‐HT₂ receptor subtypes, whereas (R)‐glaucine appeared to act as a positive allosteric modulator at the 5‐HT_2A receptor.     

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.     

Potent 5-hydroxytryptamine3 receptor antagonist activity of RG 12915

RG 12915, N-(1-azabicyclo[2.2.2.]octan-3(S)-yl)-2-chloro-(5aS, 9aS)-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxamide, a potent antiemetic agent active in reducing emesis produced by antieoplastic agents, was examined in tests of 5-hydroxytryptamine₃ (5-HT₃) receptor blockade. RG 12915 was found to be a potent antagonist of 5-HT₃ receptor activation both in blocking 5-HT-induced contractions of guinea-pig ileum and in blocking the Bezold-Jarisch effect in the rat. Compared to several other 5-HT₃ antagonists, RG 12915 had a greater pA2 value (11.2) for blocking 5-HT-induced contractions of guinea pig ileum than zacopride (8.3); BRL 43694 (granisetron) (9.1); and GR 38032F (ondansetron) (7.4). Falls in heart rate due to 5-HT₃ receptor activation following intravenous (i.v.) administration of 5-HT (the Bezold-Jarisch effect) were also potently reduced by RG 12915. Minimum effective dose (MED) levels (in parentheses), defined as the lowest dose at which each compound produced a significant reduction in the Bezold-Jarisch effect, were determined for RG 12915 (1.0μg/kg, i.v.); zacopride (3.0); granisetron (9.0); and ondansetron (27.0). The order of potency in blocking 5-HT₃ receptor activation was generally the same as the order of potency in 5-HT₃ receptor binding. RG 12915 had a lower K_i value (0.17±0.02 nM, mean ± SEM) in binding studies using ³H-GR-65630 as the ligand in rat entorhinal cortex tissue than either zacopride (1.5±0.4); granisetron (1.7±0.3); or ondansetron (6.2±2.1). RG 12915 was also found active in blocking contractions of guinea pig ileum and the Bezold-Jarisch effect induced by the somewhat selective 5-HT₃ receptor agonist 2-methyl-secrotonin. The results support the idea that this orally active antiemetic agent is a potent antagonist of 5HT₃ receptor activation. © 1993 Wiley-Liss, Inc.     

Pharmacological evidence that 5‐HT1D activation induces renal vasodilation by NO pathway in rats

5‐HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5‐HT₂ activation). Nevertheless, 5‐HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5‐HT system may exert renal vasodilator actions, and, if so, characterize the 5‐HT receptors and possible indirect pathways. Renal perfusion pressure (PP), systemic blood pressure (SBP) and heart rate (HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5‐HT (0.00000125–0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine‐infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5‐HT₂ antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5‐HT_1/7 antagonist (methiothepin, 100 μg/kg i.v.) or 5‐HT_1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5‐CT or L‐694,247 (5‐HT_1D agonist) mimicked 5‐HT vasodilator effect, while other agonists (1‐PBG, α‐methyl‐5‐HT, AS‐19 (5‐HT₇), 8‐OH‐DPAT (5‐HT_1A) or CGS‐12066B (5‐HT_1B)) did not alter baseline haemodynamic variables. L‐694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5‐HT_1D, 1 mg/kg) or L‐NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP‐dependent K⁺ channel, 20 mg/kg). These outcomes suggest that 5‐HT_1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine‐infusion rats mediated by the NO pathway.     

Synthesis,radiofluorination, and preliminary evaluation of the potential 5‐HT2A receptor agonists [18F]Cimbi‐92 and [18F]Cimbi‐150

An agonist PET tracer is of key interest for the imaging of the 5‐HT_2A receptor, as exemplified by the previously reported success of [¹¹C]Cimbi‐36. Fluorine‐18 holds several advantages over carbon‐11, making it the radionuclide of choice for clinical purposes. In this respect, an ¹⁸F‐labelled agonist 5‐HT_2A receptor (5‐HT_2AR) tracer is highly sought after. Herein, we report a 2‐step, 1‐pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5‐HT_2AR. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5‐HT_2AR; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within‐scan displacement challenge with a 5‐HT_2AR antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5‐HT_2AR.     

5‐HT2C receptor antagonists: Potential in schizophrenia

The therapeutic success of clozapine and other so‐called atypical antipsychotics has focused attention on the serotonin (5‐hydroxytryptamine; 5‐HT) system and its interaction with the dopaminergic system as a treatment for psychotic illnesses. Clozapine has been shown to display high affinity for the 5‐HT₂ receptor family and it has been suggested that this, together with evidence that dopamine D₂ receptor blockade following clozapine treatment is lower than typical antipsychotics, contributes to the therapeutic profile of clozapine and, in particular, its efficacy in treating the negative symptoms of schizophrenia. Much attention has concentrated on the interaction of clozapine and atypical antipsychotics with the 5‐HT_2A receptor. In this review, we focus on the role of the 5‐HT_2C receptor in both the therapeutic profile of atypical antipsychotics and in the regulation of the dopaminergic system. We further suggest that 5‐HT_2C receptor antagonists may have therapeutic utility in the treatment of psychotic illnesses. Drug Dev. Res. 54:88–94, 2001. © 2001 Wiley‐Liss, Inc.     

Synthesis and preliminary PET study of the 5‐HT7 receptor antagonist [11C]DR4446

DR4446 (1‐methyl‐2a‐[4‐(4,5,6,7‐tetrahydrothieno[3,2‐c]pyridin‐5‐yl)butyl]‐2a,3,4,5‐tetrahydro‐1H‐benz[cd]indole‐2‐one) is a potent 5‐HT₇ receptor antagonist (K_i=9.7 nM) with a high selectivity over other 5‐HT family receptors (K_i for 5‐HT_1A: 770 nM; for other 5‐HT receptors: >1000 nM). As a positron emission tomography (PET) tracer for the 5‐HT₇ receptor, [¹¹C]DR4446 was synthesized at high radiochemical purity ( >98%) with specific activity of 73–120 GBq/μmol at the end of synthesis by the alkylation of the desmethyl precursor (1) with [¹¹C]CH₃I in the presence of NaH. A PET study in monkey demonstrated that [¹¹C]DR4446 had good permeability into the brain, and had a specific binding component in the brain regions including the thalamus, possibly an area in the 5‐HT₇ receptors. Metabolite analysis showed that [¹¹C]DR4446 was relatively stable and low percentages of two radio‐labeled metabolites were detected in the plasma of monkey using HPLC. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis,pharmacological evaluations,and molecular docking studies on a new 1,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine framework: Rigidification of D1 receptor selective 1‐phenylbenzazepines and discovery of a new 5‐HT6 receptor scaffold

The novel 1,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine framework, a structurally rigidified variant of the 1‐phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D₁ and other dopamine receptors and is selective for the 5‐HT₆ receptor. The affinity of these systems at the 5‐HT₆ receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D₁ receptor affinity of the rigidified compounds may be due in part to weaker H‐bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor–ligand H‐bonding interactions, salt bridges, and π–π interactions appear to be responsible for the 5‐HT₆ receptor affinity of the compounds. Compounds 10 (6,7‐dimethoxy‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) and 12 (6,7‐dimethoxy‐2‐methyl‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) have been identified as structurally novel, high affinity (K_i = 5 nM), selective 5‐HT₆ receptor ligands.     

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.     

Anti‐Alzheimer's multitarget‐directed ligands with serotonin 5‐HT6 antagonist,butyrylcholinesterase inhibitory,and antioxidant activity

Serotonin 5‐HT₆ receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5‐HT ₆ antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease‐modifying effect. Combining BuChE inhibition, 5‐HT ₆ antagonism, and antioxidant properties may result in multitarget‐directed ligands providing cognition‐enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5‐HT ₆ antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5‐HT ₆ receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K _i and K _b values against 5‐HT ₆ receptors of 41.8 and 74 nM, respectively, an IC ₅₀ value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti‐Alzheimer's agents.     

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.     

Selectivity of antagonists for the Cys‐loop native receptors for ACh, 5‐HT and GABA in guinea‐pig myenteric neurons

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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.