Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET

[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.     

Selective in vivo labelling of brain 5-HT1A receptors by [3H]WAY 100635 in the mouse

The novel selective 5-HT1A receptor antagonist radioligand [3H]WAY 100635 ([O-methyl-3H]N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridyl)cyclohexane-carboxamide) was injected i.v. to mice in an attempt to label in vivo central 5-HT1A receptors. Although 5 min after the i.v. injection of [3H]WAY 100635 (4-7.6 muCi per mouse) the amount of tritium found in the whole brain only accounted for 1.5-1.8% of the injected radioactivity, regional differences in 3H accumulation already corresponded to those of 5-HT1A receptor density. Optimal data were obtained 1 h after [3H]WAY 100635 injection as the distribution of 3H in brain was exactly that of 5-HT1A receptor binding sites in mouse brain sections labelled in vitro with [3H]WAY 100635. In particular, high level of labelling was found in the lateral septum, gyrus dentatus and CA1 area of Ammon's horn in the hippocampus, dorsal raphe nucleus and entorhinal cortex. No labelling was found in he substantia nigra, and 3H accumulated in the cerebellum represented only 12-14% of that found in the hippocampus. Pretreatment with various drugs indicated that only 5-HT1A receptor ligands were able to decrease the accumulation of 3H in all the brain areas examined except in the cerebellum. Assuming that only non-specific binding took place in the latter structure, it was possible to calculate the ID50 values of 5-HT1A receptor agonists (8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl+ ++)piperazine) and S 20499 ((+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8- azaspiro-(4,5)-decane-7,9-dione)) and antagonists (spiperone, (-)-tertatolol, (+)-WAY 100135 (N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl- propanamide)) as inhibitors of 3H accumulation in the hippocampus of [3H]WAY 100635-injected mice. Comparison of these values with the in vitro affinity of the same ligands for hippocampal 5-HT1A receptors revealed marked variations in the capacity of 5-HT1A receptor agonists and antagonists to reach the brain when injected via the subcutaneous route in mice.     

The 5-HT1A and 5-HT2A/2C receptor antagonists WAY-100635 and ritanserin do not attenuate D-fenfluramine-induced fos expression in the brain

In a prospective randomised study we investigated end-tidal carbon dioxide levels during standard versus active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) assuming that the end-tital carbon dioxide reflects cardiac output during resuscitation. In each group 60 patients with out-of-hospital cardiac arrest were treated either with the standard or the ACD method. End-tidal CO2 (p(et)CO2, mmHg) was assessed with a side-stream capnometer following intubation and then every 2 min up to 10 min or restoration of spontaneous circulation (ROSC). There was no difference in p(et)CO2 between both patient groups. However, CO2 was significantly higher in patients who were admitted to hospital as compared to patients declared dead at the scene. All of the admitted patients had a p(et)CO2 of at least 15 mmHg no later than 2 min following intubation, none of the dead patients ever exceeded 15.5 mmHg. From these data we conclude that capnometry adds valuable information to the estimation of a patient's prognosis in the field (threshold, 15 mmHg), but we could not detect any difference in p(et)CO2 between ACD and standard CPR.     

Synthesis and in vitro evaluation of [carbonyl-11C]estramustine and [carbonyl-11C]estramustine phosphate

Human and experimental diabetes mellitus extensively alters lipid metabolism. The eSS is a rat strain that develops a spontaneous diabetes of slow evolution, resembling the non-insulin-dependent diabetes mellitus of young people. We report here disturbances in lipid metabolism of 5-month old eSS rats compared to age-matched alpha-controls. Normal plasmatic glucose levels were found in the fasted state, whereas a diabetic curve was evident for eSS rats after glucose load. Triglyceride content was elevated in plasma and in liver microsomal preparations of eSS animals, when compared to the controls. The diabetic strain revealed a significant fall in the amount of linoleic acid in liver and kidney microsomes and in erythrocyte membranes. In liver, an increase in 22:6 (n-3) was also noted. A depression in the content of linoleic acid as well as an enhancement of docosahexaenoic acid were detected in phosphatidylcholine and phosphatidylethanolamine fractions from liver microsomes of eSS rats. The fatty acid pattern of eSS rat testis showed a raise in the relative percentage of arachidonic and a decrease in 22:5 (n-6), 22:5 (n-3) and 22:6 (n-3) acids compared to their controls. Diabetic rats exhibited a significant increase in microsomal cholesterol content and cholesterol/phospholipid ratio in liver and testis. In the latter tissue, higher values of fluorescence anisotropy were also observed. The current observations indicate that in early stages of the diabetes onset, when eSS rats are still normoglycemic, severe alterations of lipid metabolism may contribute to the establishment and progression of the diabetic syndrome.     

Atypical in vitro and in vivo binding of [3H]S-14506 to brain 5-HT1A receptors

The tritiated derivative of the potent 5-HT1A receptor agonist S-14506 ?1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pipera zine? was tested for its capacity to selectively label the serotonin 5-HT1A receptors both in vitro in the rat and the mouse brain, and in vivo in the mouse. In vitro studies showed that the pharmacological profile and the distribution of [3H]S-14506 specific binding sites (Kd = 0.15 nM) in different brain regions matched perfectly those of the prototypical 5-HT1A receptor ligand [3H]8-OH-DPAT. However, in the three regions examined (hippocampus, septum, cerebral cortex), the density of [3H]S-14506 specific binding sites was significantly higher (+66-90%) than that found with [3H]8-OH-DPAT. Whereas the specific binding of [3H]8-OH-DPAT was markedly reduced by GTP and Gpp(NH)p and increased by Mn2+, that of [3H]S-14506 was essentially unaffected by these compounds. In addition, the alkylating agent N-ethylmaleimide was much less potent to inhibit the specific binding of [3H]S-14506 than that of [3H]8-OH-DPAT. Measurement of in vivo accumulation of tritium one hour after i.v. injection of [3H]S-14506 to mice revealed marked regional differences, with about 2.5 times more radioactivity in the hippocampus than in the cerebellum. Pretreatment with 5-HT1A receptor ligands prevented tritium accumulation in the hippocampus but not in the cerebellum. Autoradiograms from brain sections of injected mice confirmed the specific in vivo labeling of 5-HT1A receptors by [3H]S-14506, therefore suggesting further developments with derivatives of this molecule for positron emission tomography in vivo in man.     

Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man

The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor subtype is of central interest in research on the pathophysiology and treatment of psychiatric disorders. Carbonyl-11 C-WAY-100635 is a new radioligand that, in PET experiments, provides high-contrast delineation of brain regions that are rich in 5-HT1A receptors. The aim of this PET study was to examine the prospects for quantitation of carbonyl-11C-WAY-100635 binding to 5-HT1A receptors in the human brain. METHODS: A PET examination was performed in each of six healthy male subjects after intravenous injection of carbonyl-11C-WAY-100635. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. The metabolite-corrected arterial input function was used in a kinetic three-compartment analysis, and the cerebellum was used as reference region in linear graphical and transient equilibrium analyses. RESULTS: The highest radioactivity concentration was observed in the neocortex and the raphe nuclei, whereas radioactivity was low in the cerebellum. The time-activity curves were well-described by a three-compartment model for all regions. Uptake in the cerebellum could not be described by a two-compartment model. The transient equilibrium and linear graphical analyses, which are both dependent on the cerebellum as the reference region, gave lower binding potential values than did the kinetic analysis. The metabolism was rapid, and the fraction of unchanged carbonyl-11C-WAY-100635 was <10% 10 min after injection in all human subjects. The major radioactive metabolites were unidentified polar components. One metabolite comigrated with reference cyclohexanecarboxylic acid, and another comigrated with reference desmethyl-WAY-100635. CONCLUSION: The suitability of carbonyl-11C-WAY-100635 for research on central 5-HT1A receptors in neuropsychiatric disorders was supported by the observation that the high signals in the neocortex and raphe nuclei can be described using a kinetic analysis with a metabolite-corrected arterial input function. It cannot be excluded that kinetically distinguishable nonspecific binding or the formation of a metabolite that passes the blood-brain barrier may represent measurable components of the low radioactivity in the cerebellum. Simplified quantitative methods, using the relatively low radioactivity in the cerebellum as reference, should accordingly be applied with some caution until the biochemical nature of the radioactivity is better understood and the reliability of these approaches has been confirmed in larger samples.     

3H]MDL 100,907 labels 5-HT2A serotonin receptors selectively in primate brain

The selective antagonist for the 5-HT2A serotonin receptor MDL 100,907, recently characterized autoradiographically in rat brain, has been characterized as a radioligand for the visualization of this receptor in human and monkey brain. In both species [3H]MDL 100,907 binding to brain sections was saturable, had sub-nanomolar affinity (Kd = 0.14-0.19 nM in human brain; Kd= 0.16-0.19 nM in monkey brain) and presented a pharmacological profile consistent with its binding to 5-HT2A receptors (rank order of affinity for [3H]MDL 100,907-labeled receptors: MDL 100,907 > spiperone > ketanserin > mesulergine). The autoradiographical signal obtained with [3H]MDL 100,907 was compared to the signal obtained with [3H]ketanserin, [3H]RP62203 and [3H]mesulergine in both species, and to the distribution of 5-HT2A receptor mRNA as determined by in situ hybridization in monkey brain. At variance with the other radioligands, [3H]MDL 100,907 showed a single population of binding sites with extremely low levels of non-specific binding. As expected, mesulergine showed low affinity for [3H]MDL 100,907-labeled receptors and the autoradiographic pattern shown by [3H]mesulergine confirmed the lack of labeling of the 5-HT2A receptor by this radioligand in primate brain. The similarity of the distribution of [3H]MDL 100,907-labeled receptors and 5-HT2A mRNA in monkey brain, supports the selectivity of this radioligand for 5-HT2A receptors and suggests a somatodendritic localization of these receptors. The present results confirm [3H]MDL 100,907 as the radioligand of choice at present for the autoradiographic visualization of 5-HT2A receptors in mammalian brain including post-mortem human brain.     

Imaging 5-HT1A receptors with positron emission tomography: initial human studies with [11C]CPC-222

The novel radioligand [11C]CPC-222 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-2-bicyclo [2,2,2]octane carboxamide) was evaluated as an in vivo probe of the 5-HT1A receptors using positron emission tomography (PET). Three human volunteers were imaged with PET over a 90 min period following intravenous injection of the radioligand. There was a high accumulation of the radioligand in brain regions with a high density of 5-HT1A receptors. The peak cortical concentration was 1.0-2.5% of the injected dose per litre. The ratio of radioactivity in receptor-rich regions to that of the cerebellum reached a plateau of 2.5-4.0 by 45 min after injection. Analysis of the plasma revealed no detectable amount of the potential metabolite, radiolabelled WAY-100634. This new radioligand has suitable properties to study the 5-HT1A receptors in man with PET.     

Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord

We report on the autoradiographic distribution of 5-HT1B, 5-HT1D and 5-HT1F receptor subtypes in human brain, focusing on the brainstem and cervical spinal cord. We have used [3H]sumatriptan as a radioligand in the presence of suitable concentrations of 5-CT (5-carboxamidotryptamine) to define 5-HT1F receptors, and ketanserin, to discriminate between 5-HT1B and 5-HT1D receptors. In the brainstem the highest concentrations of [3H]sumatriptan binding sites were seen in substantia nigra. The spinal trigeminal nucleus, substantia gelatinosa of the spinal cord, nucleus of the tractus solitarius and periaqueductal grey, also showed significant levels of [3H]sumatriptan binding sites. In the brainstem and spinal cord the total population of 5-CT-insensitive receptors, corresponding to 5-HT1F receptors, ranged from 9.8% in the periaqueductal grey to 53.4% in the substantia gelatinosa. This population represented 67.0% of binding in layer V of the frontal cortex. The decrease in [3H]sumatriptan binding in the presence of 200 nM ketanserin, indicative of the presence of 5-HT1D receptors, was very limited throughout the human brain, only reaching 20% of total specific binding over the periaqueductal grey. The proportion of [3H]sumatriptan binding sites displaced by 5-CT and insensitive to ketanserin, corresponding to 5-HT1B receptors, was, in general, the most abundant, ranging from 43.8% in substantia gelatinosa to 69.9% in the periaqueductal grey. Significant levels of 5-HT1B and 5-HT1D receptors found in migraine control pain areas suggest their involvement in antinociceptive mechanisms.     

Characterization of desamino-5-[125I]iodo-3-methoxy-zacopride ([125I]MIZAC) binding to 5-HT3 receptors in the rat brain

1. Antagonists at 5-HT3 receptors have shown activity in animal models of mental illness, however, few radiolabeled 5-HT3 ligands are available for preclinical studies. MIZAC, an analogue of the selective 5-HT3 antagonist, zacopride, binds with high affinity (1.3-1.5 nM) to CNS 5-HT3 sites. The authors report here the selectivity of MIZAC for these sites in rat brain homogenates. 2. Ninety-seven percent of total specific binding of [125I]MIZAC (0.1 nM) of was displaced by bemesetron (3 microM), a selective 5-HT3 antagonist. Competition studies using ligands with known affinities for 5-HT3 sites give a high correlation with reported pKi values (r2 0.98). Bemesetron displaceable binding has a regional distribution consistent with that of the 5-HT3 receptor, i.e. highest in cortex and hippocampus, and lowest in striatum and cerebellum. 3. Potent antagonists present at concentrations sufficient to occupy 95% of other 5-HT receptor populations (1A, 1B, 1D, 2A, 2B, 2C, 5A, 5B, 6, and 7) showed minimal ability to displace [125I]MIZAC binding (3 nM). Specificity studies using radioligand binding assays selective for 5-HT4, 5-HT6, and 5-HT7 receptors, and for binding sites of other neurotransmitters indicate a high degree of selectivity of [125I]MIZAC for the 5-HT3 receptor. 4. [125I]MIZAC binds to an apparent low affinity (benzac) site having a unique pharmacology. Low affinity binding was displaceable by benztropine, but not by other muscarinic agents nor inhibitors of dopamine uptake. The regional distribution of the low affinity site differed markedly from that of the high affinity site. The apparent affinity of [125I]MIZAC for the benzac site is two orders of magnitude lower than for the 5-HT3 receptor. Given its high selectivity for 5-HT3 binding sites, [125I]MIZAC appears to be a promising ligand for labeling 5-HT3 receptors in vitro and in vivo.     

Autoradiographic mapping of 5-HT1B- and 5-HT1D receptors in human brain using [3H]alniditan, a new radioligand

[3H]alniditan, a new potent non-indole serotonin 5-HT1B/1D agonist, was used as a radioligand to characterize 5-HT1B and 5-HT1D receptor (previously termed 5-HT1D beta and 5-HT1D alpha) in various regions of the human brain. Quantitative receptor autoradiography was applied for high anatomical resolution and sensitivity. Highest densities of 5-HT1B/1D receptors were found in the substantia nigra and in the globus pallidus. High to moderate densities were measured in the caudate nucleus, putamen, nucleus accumbens, central gray and hippocampal formation. Very low densities were detected in various cortical regions. In the cerebellum no [3H]alniditan binding was detected. Selective 5-HT1B receptor labeling was achieved using [3H]alniditan in the presence of 300 nM of ketanserin (sufficient to block 5-HT1D receptor labeling). The identity of the 5-HT1B binding sites under these conditions was corroborated by the pIC50 of sumatriptan, which corresponded to its affinity for cloned human 5-HT1B receptors expressed in cells. Surprisingly, the distribution of selective 5-HT1B receptor labeling was completely identical to the distribution of labeling of 5-HT1B + 5-HT1D receptors. The present data indicate that [3H]alniditan is a suitable radioligand for measuring 5-HT1B/1D receptor in the human brain and that the 5-HT1B binding sites are predominant in the presently investigated regions of the human brain.     

Potentiation of the time-dependent, antidepressant-induced changes in the agonistic behaviour of resident rats by the 5-HT1A receptor antagonist, WAY-100635

Acute and chronic antidepressant drug treatments respectively decrease and increase the aggressive behaviour of resident rats during encounters with unfamiliar conspecifics. We have now examined the effect of the 5-hydroxytryptamine1A receptor antagonist, WAY-100635, on fluoxetine-, paroxetine- or venlafaxine-induced changes in aggression. WAY-100635 (0.1 mg/kg), which did not modify behaviour when given alone, potentiated the venlafaxine (5.54 mg/kg)-induced reduction in aggression after acute treatment and, during chronic treatment, accelerated the fluoxetine (0.34 mg/kg/day)-induced increase in aggression, from day 5 to day 2. A similar change in time course was seen with paroxetine (0.33 mg/kg/day), although the increase in aggression was smaller. Venlafaxine (5.54 mg/kg/day, alone or co-administered with WAY-100635) increased aggression by day 2. During chronic treatment, therefore, venlafaxine, at the dose used, had a more rapid onset of action than either fluoxetine or paroxetine, whereas the fluoxetine- and paroxetine-, but not the venlafaxine-, induced increase in aggression was accelerated by WAY-100635. These studies further support the hypothesis that selective blockade of the 5-hydroxytryptamine1A receptor augments the effects of antidepressant drugs in an animal model predictive of antidepressant activity, presumably by concomitant blockade of the somatodendritic 5-hydroxytryptamine1A autoreceptor-mediated negative feedback system of serotonergic neurones.     

Characterization of 5-HT1A receptor-mediated [35S]GTPgammaS binding in rat hippocampal membranes

Stimulation of [35S]GTPgammaS binding by serotonin (5-hydroxytryptamine, 5-HT) receptor ligands was characterized in rat hippocampal membranes. The optimized assay contained 30-50 microg protein, 300 microM GDP and 0.1 nM [35S]GTPgammaS, incubated at 37 degrees C for 20 min. At 10 microM, the 5-HT1A receptor agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin [R(+)-8-OH-DPAT] stimulated GTPgammaS binding from 27.1 +/- 2.5 to 45.7 +/- 4.2 fmol/mg protein. Increasing the protein concentration did not affect the absolute difference between basal and maximal GTPgammaS binding nor the EC50, but decreased the percent stimulation. The non-selective agonists serotonin and 5-carboxamidotryptamine were 30-35% more efficacious, whereas the partial agonists buspirone and S(-)-8-hydroxy-2-(di-n-propylamino)tetralin stimulated GTPgammaS binding by 19 +/- 1 and 43 +/- 3%, respectively, compared to R(+)-8-OH-DPAT. Neither the 5-HT2 receptor agonist [(+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] (DOI) nor the 5-HT1A receptor antagonists WAY 100,635 (n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) and spiperone altered basal GTPgammaS binding. WAY 100,635 abolished the effect of R(+)-8-OH-DPAT, but only reduced the effect of serotonin by 88 +/- 3%. Finally, methiothepin antagonized R(+)-8-OH-DPAT-stimulated GTPgammaS binding and reduced basal GTPgammaS binding by itself. The reduction was not affected by WAY 100,635. We have characterized a method to assess functional activity at 5-HT1A receptors in rat hippocampal membranes by measuring agonist-induced [35S]GTPgammaS binding.     

3H]Alnespirone: a novel specific radioligand of 5-HT1A receptors in the rat brain

Determination of the optimal assay conditions for the specific binding of a tritiated derivative of the novel potential anxiolytic drug alnespirone (S-20499, (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro-( 4,5)-decane-7,9-dione) allowed the demonstration that this radioligand bound with a high affinity (Kd = 0.36 nM) to a homogeneous class of sites in rat hippocampal membranes. The pharmacological properties of [3H]alnespirone specific binding sites matched exactly (r = 0.95) those of 5-HT1A receptors identified with [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as radioligand. Furthermore, membrane binding experiments and autoradiographic labeling of tissue sections showed that the regional distribution of [3H]alnespirone specific binding sites in the rat brain and spinal cord superimposed over that of 5-HT1A receptors specifically labeled by [3H]8-OH-DPAT. However, the differential sensitivity of [3H]alnespirone and [3H]8-OH-DPAT specific binding to various physicochemical effectors (temperature, pH, Mn2+, N-ethyl-maleimide) supports the idea that these two agonist radioligands did not recognize 5-HT1A receptors exactly in the same way. These differences probably account for the reported inability of alnespirone, in contrast to 8-OH-DPAT, to induce some 5-HT1A receptor-mediated behavioural effects in rats.     

Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907

The recently developed 5-HT2A receptor selective antagonist [3H]MDL100,907 ((+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]) has been characterized as a radioligand for the autoradiographic visualization of these receptors. [3H]MDL100,907 binding to rat brain tissue sections was saturable, had sub-nanomolar affinity (Kd = 0.2-0.3 nM), and presented a pharmacological profile consistent with its binding to 5-HT2A receptors (rank order of affinity for [3H]MDL100,907-labelled receptors: MDL100,907 > spiperone > ketanserin > mesulergine). The distribution of receptors labelled by [3H]MDL100,907 was compared to the autoradiographical patterns obtained with [3H]Ketanserin, [3H]Mesulergine, and [3H]RP62203 (N-[3-[4-(4-fluorophenyl)piperazin-1-y1]propyl]-1,8-naphtalenes ultam) and to the distribution of 5-HT2A receptor mRNA as determined by in situ hybridization. As opposed to the other radioligands, [3H]MDL100,907 labelled a single population of sites (5-HT2A receptors) and presented extremely low levels of non-specific binding. The close similarity of the distributions of [3H]MDL100,907-labelled receptors and 5-HT2A mRNA further supports the selectivity of this radioligand for 5-HT2A receptors and suggests a predominant somatodendritic localization of these receptors. The present results point to [3H]MDL100,907 as the ligand of choice for the autoradiographic visualization of 5-HT2A receptors.     

Repeated diazepam administration influences 5-HT1A receptor binding in the rat brain

Repeated administration of diazepam for 14 days (5 mg/kg daily) resulted in a significant increase of 5-HT1A receptor density in the midbrain of the rat. Bmax values were increased from 239.6 to 684.9 fmol/mg. The affinity constants (KD) were also increased, from 0.97 to 3.01 nM/l.     

18F]fluoroalkyl analogues of the potent 5-HT1A antagonist WAY 100635: radiosyntheses and in vivo evaluation

Two analogues of the potent 5-HT1A antagonist WAY 100635 have been synthesized and radiolabelled with 18F, namely N-[2-[4-(2-2'-[18F] fluoroethoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide ([18F]FEC) and N-[2-[4-(2-3'-[18F] fluoropropoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cycloh exa ne carboxamide ([18F]FPC). Biodistribution studies in rats showed selective uptake of both radiotracers in regions known to be rich in 5-HT1A receptors following i.v. injection. The ratio of radioactivity in hippocampus to that in the cerebellum was 5.5 (for [18F]FEC) and 7.5 (for [18F]FPC) at 60 min postinjection. Regional brain heterogeneity of radioactivity could be abolished by pretreatment with WAY 100635 and FPC but was unaffected by pretreatment with a variety of drugs including ketanserin, sulpiride, and SCH 23390. These results are compared vis-a-vis with those obtained using [11C]WAY 100635 to evaluate [18F]FEC and [18F]FPC as potential radiotracers for imaging 5-HT1A receptors by positron emission tomography.