Biomedical subjects

G Sedvall

Publications and source records attributed to G Sedvall.

At least 19 recordsLinked to original sources

PubMed2003

A systematic genomewide linkage study in 353 sib pairs with schizophrenia.

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

Genetic Linkage↗

PubMed2001

Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743.

The distribution of 5-HT(1B) and 5-HT(1D) receptors in the human post mortem brain was examined using whole hemisphere autoradiography and the radioligand [(3)H]GR 125743. [(3)H]GR 125743 binding was highest in the substantia nigra and the globus pallidus. Lower levels were detected in the striatum, with the highest densities in the ventromedial parts. In the amygdala, the hippocampus, the septal region and the hypothalamus, lower [(3)H]GR 125743 binding was observed, reflecting low densities of 5-HT(1B/1D) receptors. In the cerebral cortex, binding was similar in most regions, although restricted parts of the medial occipital cortex were markedly more densely labeled. Binding densities were very low in the cerebellar cortex and in the thalamus. Two methods were used to distinguish between the two receptor subtypes, the first using ketanserin to block 5-HT(1D) receptors and the second using SB 224289 to inhibit 5-HT(1B) receptor binding. The autoradiograms indicated that in the human brain, the 5-HT(1B) receptor is much more abundant than the 5-HT(1D) receptor, which seemed to occur only in low amounts mainly in the ventral pallidum. Although [(3)H]GR 125743 is a suitable radioligand to examine the distribution of 5-HT(1B) receptors in the human brain in vitro, the selectivities of ketanserin and SB 224289 are not sufficiently high to give definite evidence for the occurrence of the 5-HT(1D) receptor in the human brain.

Basal Ganglia↗

PubMed2001

Characterization of human cleaved N-CAM and association with schizophrenia.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule involved in cellular migration, synaptic plasticity, and CNS development. A 105- to 115-kDa isoform of N-CAM (cleaved N-CAM or cN-CAM) is increased in schizophrenia in hippocampus, prefrontal cortex, and CSF. We purified and partially characterized cN-CAM, a putative novel isoform, and confirmed that the first 9 amino acids were identical to exon 1 of N-CAM, without the signal sequence. Analysis of trypsin-digested cN-CAM fragments by matrix-assisted laser desorption ionization on a time-of-flight mass spectrometer (MALDI-TOF) yielded peptides that could be identified as being derived from the first 548 amino acid residues of the expected N-CAM amino acid sequence. Immunological identification with four specific N-CAM antisera directed toward cytoplasmic, secreted, variable alternative spliced exon, or GPI epitopes failed to indicate other known splice variants. Neuraminidase treatment of cN-CAM produced a minor alteration resulting in a faster migrating immunoreactive band, indicating partial glycosylation of cN-CAM. Membranous particles from cytosolic brain extract containing cN-CAM were obtained by ultracentrifugation; however, CSF contained few such particles. cN-CAM and synaptophysin were colocalized on these particles. Both cN-CAM and N-CAM 180 were present in synaptosomal preparations of human brain. Following incubation of synaptosomes or brain tissue without protease inhibitors, N-CAM 180 was degraded and cN-CAM was increased. A cN-CAM-like band was present in human fetal neuronal cultures, but not in fetal astrocyte cultures. Thus, cN-CAM represents a protease- and neuraminidase-susceptible fragment possibly derived by proteolytic cleavage of N-CAM 180. An enlargement in ventricular volume in a group of adult patients with schizophrenia over a 2-year interval was found to be correlated with CSF cN-CAM levels as measured at the time of the initial MRI scan (r = 0.53, P = 0.01). cN-CAM is associated with ventricular enlargement; thus, the release of N-CAM fragments may be part of the pathogenic mechanism of schizophrenia in vulnerable brain regions such as the hippocampus and prefrontal cortex. Alternatively, the increases in cN-CAM in schizophrenia may be a reflection of a more general abnormality in the regulation of proteolysis or of extracellular matrix stability.

Adult↗

PubMed2001

Reliability and reproducibility of brain tissue volumetry from segmented MR scans.

Reliable measurement of different tissue volumes in the living brain is of great importance for human brain research. In this article, we report on the inter- and intraoperator reliability and scan-rescan reproducibility of segmented intracranial tissue volumes from MR images using the image analysis software suite BRAINS. The absolute data of tissue volume measurements are also presented. The reliability and consistency of the measurements of the segmented volumes were excellent. The segmentation is robust and rapid and the volume measurements are plausible and suitable for quantitative studies in clinical brain research.

Adolescent↗

PubMed2001

SPET imaging of central muscarinic acetylcholine receptors with iodine-123 labelled E-IQNP and Z-IQNP.

1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP) is a muscarinic acetylcholine receptor (mAChR) antagonist and the racemic ligand contains eight stereoisomers. In a single-photon emission tomography (SPET) study in monkeys we recently confirmed that [123I]E-(R,R)-IQNP ([123I]E-IQNP) is a radioligand with modest selectivity for the M1 and M4 subtypes, whereas [123I]Z-(R,R)-IQNP ([123I]Z-IQNP) is non-subtype selective. In the present SPET study, E- and Z-IQNP were examined in human subjects. SPET examination was performed on three male subjects after i.v. injection of [123I]E-IQNP and in another three after i.v. injection of [123I]Z-IQNP. The binding potential (BP) for [123I]E-IQNP was calculated using several quantitative approaches with the cerebellum as a reference region. High-performance liquid chromatography was used to measure radioligand metabolism in plasma. Following [123I]E-IQNP, the radioactivity was high in the neocortex and striatum, intermediate in the thalamus and low in the pons and cerebellum, which is consistent with the rank order for the regional density of M1 and M4 subtypes in vitro. For all regions, peak equilibrium was identified within the 48-h data acquisition. The simplified reference tissue approach using SPET data from 0 to 48 h was the most reliable in this limited series of subjects. Following injection of [123I]Z-IQNP, radioactivity was high in the neocortex and striatum, intermediate in the thalamus and pons and low in the cerebellum, which is in agreement with the density of M1, M2 and M4 subtypes as measured in vitro. Quantitative analyses provided indirect support for specific M2 binding of Z-IQNP in the cerebellum. The high selectivity of [123I]E-IQNP for M1 and M4 receptors allowed the use of cerebellum as a reference region devoid of specific binding, and may be advantageous for applied clinical studies of M1 and M4 receptors binding in man. [123I]Z-IQNP has potential for exploration of M2 receptor binding in the cerebellum.

Adult↗

PubMed2001

No association between serotonin 2A receptor gene variants and personality traits.

Among theories of biological underpinnings to personality traits, different mechanisms of the serotonergic system are perhaps the most common factors suggested to influence individual differences in personality traits. We have investigated two frequent variants in the serotonin 2A receptor gene (5-HT2A) and personality traits. Healthy Swedish subjects (n = 304) were assessed with the Karolinska Scales of Personality (KSP) inventory. After correction for multiple testing, no significant differences were found. We conclude that the investigated 5-HT2A gene variants do not significantly influence personality as assessed by the KSP in the present population.

Adult↗

PubMed2000

Autoradiographic localization of 5-HT(2A) receptors in the human brain using [(3)H]M100907 and [(11)C]M100907.

M100907 (MDL 100907, R-(+)-alpha-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol++ +) is a new selective antagonist of 5-HT(2A) receptors. The compound has been labeled with (11)C and proved useful for in vivo studies of 5-HT(2A) receptors using positron emission tomography (PET). In the present study the distribution of 5-HT(2A) receptors was examined in the postmortem human brain using whole hemisphere autoradiography and [(3)H]M100907 and [(11)C]M100907. The autoradiograms showed very dense binding to all neocortical regions, whereas the hippocampus was only weakly labeled with [(3)H]M100907. Other central brain regions, such as the basal ganglia and thalamus, showed low [(3)H]M100907 binding, reflecting low densities of 5-HT(2A) receptors. The cerebellum or structures of the brain stem were virtually devoid of 5-HT(2A) receptors. [(11)C]M100907 gave images qualitatively similar to those of [(3)H]M100907, although with lower spatial resolution. The labeling of human 5-HT(2A) receptors with [(3)H]M100907 was inhibited by the addition of the 5-HT(2A) receptor blockers ketanserin or SCH 23390 (10 microM), leaving a very low background of nonspecific binding. The 5-HT(1A) receptor antagonist WAY-100635 and the D(2)-dopamine receptor antagonist raclopride had no effect on the binding of [(3)H]M100907. The selective labeling of 5-HT(2A) receptors with [(3)H]M100907 clearly shows that this compound is suitable for further studies of the human 5-HT(2A) receptor subtype in vitro. The in vitro autoradiography of the distribution of 5-HT(2A) receptors obtained with radiolabeled M100907 provides detailed qualitative and quantitative information on the distribution of 5-HT(2A)-receptors in the human brain as well as reference information for the interpretation of previous initial results at much lower resolution in humans in vivo with PET and [(11)C]M100907.

Adult↗

PubMed2000

Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease.

RATIONALE: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. OBJECTIVE: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. METHODS: Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. RESULTS: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. CONCLUSIONS: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.

Alzheimer Disease↗

PubMed2000

A 39-year followup of the Genain quadruplets.

The Genains, a unique group of monozygotic female quadruplets, all developed a schizophrenic disorder by age 24. They have been studied since the 1950s, because of the rarity of this occurrence (estimated to be one in 1.5 billion) and because their illnesses varied in severity. The identical inheritance would tend to rule out genetic differences as the cause of the neuropsychological differences; however, we cannot disentangle the effects of early brain injury and harsh punitive treatment as factors accounting for the differences in the severity of their disorders. We conducted neuropsychological examinations of the Genains at age 66, compared their test profiles, and contrasted certain test scores at 66 with those at ages 27 and 51. Test results indicate generally stable (or even improved) performance over time and support the notion that cognitive decline is not a degenerative process in schizophrenia. The Genains remind us of the exquisite interaction among variables that must be understood before additional, satisfactory progress can be made in preventing the development and predicting the course of schizophrenia.

Adult↗

PubMed1999

Preprotachykinin-A mRNA expression in the human and monkey brain: An in situ hybridization study.

The mRNA expression for preprotachykinin-A (PPT-A) was studied throughout the human and cynomolgus monkey brain to assess the neuroanatomical expression pattern of the PPT-A gene in primates. In situ hybridization showed that the PPT-A mRNA is expressed highly in specific regions of the postmortem human brain, including the striatum, islands of Calleja, hypothalamus (posterior, premammillary, medial mammillary, and ventromedial nuclei), superior and inferior colliculi, periaqueductal gray, and oculomotor nuclear complex. PPT-A mRNA-expressing neurons also were present in the paranigralis (ventral tegmental area) and were scattered in the bed nucleus stria terminalis throughout the sublenticular substantia innominata region, including the diagonal band of Broca and the nucleus basalis of Meynert. In the hippocampus, high PPT-A mRNA expression was localized predominantly to the polymorphic layer of the dentate gyrus; no labeled cells were present in the granular layer. Positively labeled cells also were found scattered in the CA regions as well as in the amygdaloid complex. Neocortical expression of PPT-A mRNA was localized mainly to the deep laminae (layers V/VI), except for the striate cortex (labeling was seen also in superficial layers). The subiculum, thalamus, globus pallidus, ventral pallidum, substantia nigra pars compacta, red nucleus, pontine nuclei, and cerebellum were characterized by very weak to undetectable expression of PPT-A mRNA. An expression pattern was evident in the monkey forebrain similar to that observed in the human, except for the absence of PPT mRNA-expressing cells in the medial mammillary nucleus despite intense expression in supramammillary, lateral mammillary, and premammillary nuclei. Overall, more similarities than differences are apparent between primate species in the expression pattern of the PPT-A gene. J. Comp. Neurol. 411;56-72, 1999.

Adult↗

PubMed1999

Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I.

Using a new, 125I-labeled, selective high affinity dopamine transporter ligand, N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methy lph enyl)nort ropane (PE2I), the distribution of the dopamine transporter was characterized in the normal postmortem human brain using whole hemisphere autoradiography. PE2I was radioiodinated to high specific radioactivity (2200 Ci/mmol, 81 GBq/micromol). PE2I binds to the dopamine transporter with high potency and, in contrast to beta-CIT, it has very low affinities for the serotonin and noradrenaline transporters. The autoradiograms showed very intense binding in basal ganglia (putamen, nucleus caudatus, nucleus accumbens) and lower binding in substantia nigra. Very low or no binding was found in other brain structures, including the neocortex or cerebellum. The labeling of human dopamine transporters with [125I]PE2I was inhibited by the dopamine transporter inhibitors GBR 12909 and beta-CIT, but not by citalopram (serotonin transporter inhibitor) or maprotiline (noradrenaline transporter inhibitor). Possibly due to the relatively high lipophilicity of the compound (theoretical log p = 4.68), it accumulated slightly in white matter. Thus, in vitro autoradiography using [125I]PE2I provided detailed qualitative and quantitative evidence that the dopamine transporter is almost exclusively localized in the basal ganglia of the human brain. Moreover, the autoradiograms indicate that [11C]PE2I and [123I]PE2I should be suitable for the in vivo visualization of the human dopamine transporter with PET or SPECT, respectively.

Adult↗

PubMed1999

Radiosynthesis and autoradiographic evaluation of [11C]NAD-299, a radioligand for visualization of the 5-HT1A receptor.

The selective 5-HT1A receptor antagonist NAD-299 ([R]-3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-1-benzopyran-5-carboxamide) was labeled with the positron-emitting radionuclide carbon-11. The radioligand was synthesized from NAD-195 ([R]-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethylsulfonyl oxy-3,4- dihydro-2H-1-benzopyran) in two radiochemical steps. A palladium-catalyzed reaction of NAD-195 and [11C]cyanide was followed by hydrolysis of the carbon-11-labeled nitrile intermediate with basic hydrogen peroxide. The total radiochemical yield, based on [11C]CO2 and corrected for decay, was 20-40%. The specific radioactivity was 24 GBq/mumol (900 Ci/mmol) at end of synthesis, with a radiochemical purity better than 99% and a total synthesis time of 40-45 min. Autoradiographic examination of [11C]NAD-299 binding in human brain postmortem demonstrated high binding in hippocampus, raphe nuclei, and neocortex. The binding in the hippocampus was higher than in the neocortex. Within the hippocampus, the densest binding was observed in the CA1 region. [11C]NAD-299 binding was inhibited by addition of the 5-HT1A receptor ligands WAY-100635, pindolol, (+/-)-8-OH-DPAT, 5-HT, and buspirone, leaving a low background of nonspecific binding. The results indicate that [11C]NAD-299 binds specifically to 5-HT1A receptors in the human brain in vitro and is a potential radioligand for positron emission tomography (PET) examination of 5-HT1A receptors in vivo.

Autoradiography↗

PubMed1998

D3 dopamine receptor mRNA is widely expressed in the human brain.

Considerable attention has been given to the association of the D3 dopamine receptor subtype and limbic function based on the abundant localization of D3 receptor sites and mRNA expression in the islands of Calleja and nucleus accumbens in experimental animals. Though most human anatomical studies have focused on the role of D3 receptors in limited brain structures, detailed information about the overall anatomical organization of the D3 receptor in the human brain is still, however, not available. In the current study, we examined the anatomical distribution of D3 receptor mRNA expression at different levels of the human brain in whole hemisphere horizontal cryosections using in situ hybridization. This approach made it possible to establish for the first time the wide and heterogenous expression of the D3 receptor gene throughout the human brain. As expected, the most abundant D3 mRNA expression levels were found in the islands of Calleja and discrete cell cluster populations within the ventral striatum/nucleus accumbens region. High levels were also evident within the dentate gyrus and striate cortex. Low to moderate D3 mRNA expression levels were apparent in most brain areas including all other cortical regions (highest in the anterior cingulate/subcallosal gyrus), caudate nucleus, putamen, anterior and medial thalamic nucleus, mammillary body, amygdala, hippocampal CA region, lateral geniculate body, substantia nigra pars compacta, locus coeruleus, and raphe nuclei. While the current anatomical map of D3 receptor mRNA expression in the human brain does confirm previous reports that D3 receptors may play important roles in limbic-related functions such as emotion and cognition, the findings also suggest other non-limbic functions for D3 mRNA-expressing cell populations such as processing of motor and sensory information.

Brain Chemistry↗

PubMed1998

Regional distribution of neuropeptide Y Y2 receptor messenger RNA in the human post mortem brain.

The neuropeptide Y Y2 receptor is one of six receptor subtypes mediating the multiform physiological actions of neuropeptide Y. The Y2 receptor has been demonstrated to be the most predominant receptor subtype in the human brain and appears to be involved in many neuropeptide Y actions, such as the regulation of locomotor activity, cardiovascular functions, memory processing, circadian rhythms and release of other neurotransmitters. We have recently demonstrated the widespread and abundant distribution of neuropeptide Y Y1 receptor messenger RNA in the human cerebral cortex (different laminar patterns within distinct cortical regions), hippocampal dentate gyrus and striatum. To assess a possible differential distribution of Y1 and Y2 receptor messenger RNAs, the regional expression of neuropeptide Y Y2 messenger RNA-containing cells in the human brain was analysed, in particular within the cerebral cortex and striatum. In situ hybridization experiments revealed the localization of the Y2 messenger RNA signal throughout all cortical regions, with the highest intensity per cell apparent in lamina IV, with the exception of the striate cortex, which showed an intense labelling primarily in layer VI. The striatum expressed low to undetectable levels of the Y2 receptor messenger RNA. The dentate gyrus and the CA2 region presented the highest hybridization signals, while a very weak Y2 messenger RNA expression was found in the CA1 region and subiculum. Positive Y2 messenger RNA hybridization signals were also detected in the lateral geniculate nucleus, amygdala, substantia nigra, hypothalamus, cerebellum and choroid plexus. These results demonstrate the widespread distribution of neuropeptide Y Y2 receptor messenger RNA in the human brain, with a pattern of expression distinct from the Y1 subtype, suggesting that these two receptor subtypes may mediate different neuropeptide Y functions in the human brain, mainly through actions on different neuronal systems.

Adult↗

PubMed1998

Whole hemisphere autoradiography of the postmortem human brain.

Whole hemisphere autoradiography (WHA) with selective high-affinity radioligands is a new tool in studying the distribution of receptors and of other neuronal components postmortem in brains from controls vs. subjects with psychiatric and neurologic diseases. WHA can be performed with several different isotopes (e.g., 3H, 125I, and 11C), and is in addition to characterization studies also used as a tool in early radioligand development. Moreover, using this technique, high-resolution images are obtained that are complementary to those obtained in vivo with e.g., PET and SPECT. Results on dopamine and serotonin receptor subtypes as well as of their transporters show that WHA is a very suitable technique for the detailed characterization of the distribution in the whole human brain.

Animals↗

PubMed1998

Carbon-11-NNC 112: a radioligand for PET examination of striatal and neocortical D1-dopamine receptors.

UNLABELLED: The aim of this work was to explore the potential of a selective D1-dopamine receptor antagonist as a new radioligand for PET examination of striatal and neocortical D1-dopamine receptors. METHODS: The active (+)- and inactive (-)-enantiomers of [11C]NNC 112 were radiolabeled using the N-methylation approach and were examined by PET in cynomolgus monkeys and healthy men. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). RESULTS: N-methylation of the corresponding desmethyl precursors with [11C]methyl triflate gave high total radiochemical yield (50%-60%) and specific radioactivity (110 GBq/micromol). (+)-[11C]NNC 112 binding in cynomolgus monkeys was 5.77+/-0.31 and 2.36+/-0.14 times higher in the striatum and neocortex, respectively, than in the cerebellum at a transient equilibrium that appeared 40-50 min after injection. The binding of (+)-[11C]NNC 112 is stereoselective, because the brain distribution of the inactive (-)-enantiomer was on an equally low level for all brain regions. Displacement and pretreatment experiments using unlabeled SCH 23390 and ketanserin confirms that (+)-[11C]NNC 112 binds specifically and reversibly to D1-dopamine receptors. The radioactivity ratios of the striatum, frontal cortex and nucleus accumbens to the cerebellum were 3.8-4.0, 1.7-2.0 and 2.8-3.1, respectively, at a transient equilibrium that appeared 40-50 min after injection in four healthy human subjects. Linear graphical analysis gave distribution volume ratios of 3.9 and 1.5 in the putamen and frontal cortex, respectively. The fraction of the total radioactivity in human plasma representing unchanged (+)-[11C]NNC 112 was 85% at 5 min and 25% at 75 min after injection. CONCLUSION: (+)-[11C]NNC 112 should be a useful PET radioligand for quantitative examination of not only striatal but neocortical D1-dopamine receptors in man.

Adult↗

PubMed1997

Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635.

The distribution of 5-HT1A receptors was examined in the post-mortem human brain using whole hemisphere autoradiography and the selective 5-HT1A receptor antagonist [3H]WAY-100635 ([O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride). The autoradiograms showed very dense binding to hippocampus, raphe nuclei and neocortex. The labeling in neocortex was slightly lower than in the hippocampus and was mainly at superficial layers, although a faintly labeled band could be seen in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum, showed low densities caudatus and putamen, in cerebellum or in structures of the brain stem except in the raphe nuclei. The labeling of human 5-HT1A receptors with [3H]WAY-100635 was antagonised by the addition of 5-HT1A receptor ligands, 5-HT, buspirone, pindolol or 8-OH-DPAT (10 microM), leaving a very low background of non-specific binding. Saturation analysis of semiquantitative data from several human regions indicated that [3H]WAY-100635 has a Kd of approximately 2.5 nM. The selective labeling of 5-HT1A receptors with [3H]WAY-100635 clearly show that this compound is useful for further studies of the human 5-HT1a receptor subtype in vitro [11C]WAY-100635 is used for the characterization of 5-HT1A receptors with positron emission tomography (PET). WAY-100635 was also radiolabeled with the short-lived positron-emitting radionuclide carbon-11 (t1/2 = 20 min) and used for in vitro autoradiography on human whole hemisphere cryosections. [11C]WAY-100635 gave images qualitatively similar to those of [3H]WAY-100635, although with a lower resolution. Thus, the hippocampal formation was densely labeled, with lower density in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 microM), blocked all binding of [11C]WAY-100635. The in vitro autoradiography of the distribution of 5-HT1A receptors obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative information on the distribution of 5-HT1A-receptors in the human brain. Moreover, the studies give reference information for the interpretation of previous initial results at much lower resolution in humans with PET and [11C]Way-100635. These data provide a strong basis for expecting [11C]WAY-100635 to behave as a highly selective radioligand in vivo.

Autoradiography↗

PubMed1997

Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study.

Whole-hemisphere sections from six subjects were used in a quantitative autoradiographic study to characterize and to investigate the distribution of adenosine receptors, using [3H]DPCPX, [3H]CGS 21680, and [3H]SCH 58261 as radioligands. [3H]DPCPX-binding showed the pharmacology expected for adenosine A1 receptors and is therefore taken to mirror adenosine A1 receptors. Adenosine A1 receptors were widely distributed, with the highest densities in the stratum radiatum/pyramidale of the hippocampal region CA1. Adenosine A1 receptors were nonhomogeneously distributed in nucleus caudatus, globus pallidus, and cortical areas: In the cingulate and frontal cortex the deep layers showed the highest labeling, while in the occipital, parietal, temporal, and insular cortex it was highest in the superficial layers. In addition, we found very high levels of adenosine A1 receptors in structures known to be important for cholinergic transmission, especially the septal nuclei. The Bmax values and KD values for [3H]DPCPX-binding in stratum radiatum/pyramidale of CA1 and the superficial layer of insular cortex were 598 and 430 fmol/mg gray matter and 9.9 and 14.2 nM, respectively. [3H]CGS 21680-binding was multiphasic, but showed the pharmacology expected for adenosine A2A receptors and was taken to represent them. Adenosine A2A receptors were abundant in putamen, nucleus caudatus, nucleus accumbens, and globus pallidus pars lateralis. Specific [3H]CGS 21680-binding was also found in certain thalamic nuclei and throughout the cerebral cortex. The adenosine A2A receptor antagonist radioligand [3H]SCH 58261 was also found to label these extrastriatal structures. Thus, adenosine A2A receptors seem to be more widely distributed in the human brain than previously recognized.

Autoradiography↗