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

Hall, Håkan; Lundkvist, Camilla; Halldin, Christer; Farde, Lars; Pike, Victor W.; McCarron, Julie A.; Fletcher, A; Cliffe, Ian A.; Barf, Tjeerd; Wikström, H.; Sedvall, Göran

doi:10.1016/s0006-8993(96)01131-6

Cited by 250 publications

(148 citation statements)

References 44 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Only k on , k off , and B max were considered for the optimization. The experimental designs were simulated using the COMKAT software (Muzic and Cornelius, 2001) based on previously measured arterial input functions (Wooten et al, 2011a) and a range of B max (40 to 100 pmol/mL), k off (0.01 to 0.1 per minute), and k on (0.004 to 0.04 per minute) values estimated from our previous studies and the literature values with comparable ligands (Gunn et al, 1998;Hall et al, 1997). As a validation of the selected experimental designs, simulated noise was added to each data point of the simulated regions of interest (ROIs) similar to a reported method (Logan et al, 2001) using the equation:…”

Section: Design Of the Multiple-injection Experimentsmentioning

confidence: 99%

“…In-vitro autoradiography measurements in the hippocampus of the cynomolgus monkey reveal a heterogeneous distribution of 5-HT 1A receptors across the hippocampal subfields, with highest binding in the area dentata, subiculum, and parasubiculum in the range of 50 to 100 fmol/mg of protein (Kö hler et al, 1986). In humans, post mortem in-vitro studies using [ 3 H]WAY-100635 have shown high levels of receptor density in the hippocampus areas ranging from 31 fmol/mg of wet tissue in the parahippocampus to 113 fmol/mg of wet tissue in the hippocampus CA1 pyramidal layer (Hall et al, 1997). A separate study also using [ 3 H]WAY-100635 found 5-HT 1A receptor densities of 200 to 300 fmol/mg of wet tissue in the CA1 of the hippocampus (Burnet et al, 1997).…”

Section: In-vivo Measurement Of 5-ht 1a B Maxmentioning

confidence: 99%

“…In-vitro measurements of B max have been reported with [ 11 C]WAY-100635 and validated by comparison with its tritiated form (Hall et al, 1997), finding high levels of 5-HT 1A receptor expression throughout the frontal, temporal, parietal, and cingulate cortices with the highest receptor density in the hippocampus (including regions CA1, subiculum, and uncus). In-vivo measurements of 5-HT 1A B max in humans have been measured using [ 18 F]MPPF, finding similar rank order in 5-HT 1A receptor expression across brain regions as in-vitro studies (Costes et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Hillmer

Moirano

Ahlers

et al. 2012

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

The goal of this work was to characterize the in-vivo behavior of [ 18 F]mefway as a suitable positron emission tomography (PET) radiotracer for the assay of 5-hydroxytryptamine 1A (5-HT 1A ) receptor density (B max ). Six rhesus monkeys were studied using a multiple-injection (M-I) protocol consisting of three sequential bolus injections of [ 18 F]mefway. Injection times and amounts of unlabeled mefway were optimized for the precise measurement of B max and specific binding parameters k off and k on for estimation of apparent K D . The PET time series were acquired for 180 minutes with arterial sampling performed throughout. Compartmental analysis using the arterial input function was performed to obtain estimates for K 1 , k 2 , k off , B max , and K Dapp in the cerebral cortex and raphe nuclei (RN) using a model that accounted for nontracer doses of mefway. Averaged over subjects, highest binding was seen in the mesial temporal and dorsal anterior cingulate cortices with B max values of 42 ± 8 and 36 ± 8 pmol/mL, respectively, and lower values in the superior temporal cortex, RN, and parietal cortex of 24 ± 4, 19 ± 4, and 13 ± 2 pmol/mL, respectively. The K Dapp of mefway for the 5-HT 1A receptor sites was 4.3 ± 1.3 nmol/L. In conclusion, these results show that M-I [ 18 F]mefway PET experiments can be used for the in-vivo measurement of 5-HT 1A receptor density.

show abstract

Section: Design Of the Multiple-injection Experimentsmentioning

confidence: 99%

Section: In-vivo Measurement Of 5-ht 1a B Maxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Hillmer

Moirano

Ahlers

et al. 2012

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

“…This large difference in K i is necessary because of low brain tissue 5-HT 7 receptor density (B max ) compared to 5-HT 1A receptor values in, e.g., hippocampus and cortical areas. 15,16 Therefore, the aim of this study was to synthesize, simplify, and fine-tune phenylpiperazinyl-butyloxindole derivatives in the search of radioligands for 5-HT 7 receptor PET imaging ( Figure 1). Thereby, we aimed to develop selective reference compounds suitable either for 11 C-or for 18 F-labeling.…”

mentioning

confidence: 99%

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Herth

Volk

Pallagi

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

ABSTRACT:The most recently discovered serotonin (5-HT) receptor subtype, 5-HT 7 , is considered to be associated with several CNS disorders. Noninvasive in vivo positron emission tomography (PET) studies of cerebral 5-HT 7 receptors could provide a significant advance in the understanding of the neurobiology and eventual dysfunctions of the 5-HT 7 receptor. To date, no appropriate 5-HT 7 receptor PET ligand has been developed. Here, we modified known 5-HT 7 selective phenylpiperazinyl-butyloxindole derivatives so that they may be labeled either with carbon-11 or fluorine-18. A set of potential 5-HT 7 ligands for PET molecular imaging was successfully synthesized. Two compounds (10 and 14) were tested against a range of targets. Both compounds display a promising in vitro profile with respect to PET imaging of the 5-HT 7 receptor in thalamic regions. KEYWORDS: Oxindole, 5-HT 7 receptor distribution, PET T he relatively recently discovered G-protein coupled 5-HT 7 receptor has been implicated in various central nervous system (CNS) disorders such as schizophrenia, depression, epilepsy, migraine, and in the control of circadian rhythm. 1 For example, the atypical antipsychotic drug amisulpride has antidepressant effects, 2,3 and a study in 5-HT 7 receptor knockout mice supports that the 5-HT 7 receptor antagonism of amisulpride alleviates depression symptoms. 4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology. Positron emission tomography (PET) is used to quantify neuroreceptor binding in vivo, and the availability of an appropriate PET radiotracer for the 5-HT 7 receptor would be of particular interest.Previous attempts of other groups to develop a 5-HT 7 receptor selective PET tracer have not been convincingly successful. 7,8 Most recently, 18 F-labeled SB-269970 derivatives were synthesized and evaluated in vivo in cats, 9,10 but in the absence of a validated reference region or an arterial input function it was not possible to fully evaluate the validity of those radiolabeled compounds. 11Several lead structures of 5-HT 7 receptor ligands have been identified within various structural classes. 12 Among these structures, phenylpiperazinyl-butyloxindoles display an interesting selectivity profile (Figure 1). 13,14 Some oxindoles showed inhibition constants (K i ) 2000-fold lower for the 5-HT 7 receptor than for the 5-HT 1A receptor. This large difference in K i is necessary because of low brain tissue 5-HT 7 receptor density (B max ) compared to 5-HT 1A receptor values in, e.g., hippocampus and cortical areas. 15,16 Received: July 31, 2012 Accepted: August 31, 2012 Published: August 31, 2012

show abstract

Regional Reductions in Serotonin 1A Receptor Binding in Juvenile Myoclonic Epilepsy

Meschaks¹,

Lindström²,

Halldin³

et al. 2005

Arch Neurol

View full text Add to dashboard Cite

Background: Juvenile myoclonic epilepsy (JME) is classified as primarily generalized epilepsy and as such is assumed to lack an anatomic substrate. Although neurochemical abnormalities are probable, few studies have investigated whether they exist in JME. Animal data and the high incidence of myoclonic seizures in serotoninintoxicated patients suggest that the serotonin system may be disturbed in JME.Objective: To test the hypothesis that JME is associated with a disturbed serotonin system and that this disturbance could be reflected in altered serotonin 1A receptor binding. Design:The serotonin 1A receptor binding potential (BP) was measured with positron emission tomography and serotonin 1A receptor antagonist carbonyl-carbon 11-WAY-100635. The BP was calculated using a reference tissue model in several limbic and neocortical regions and the raphe nuclei.

show abstract

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

Cited by 250 publications

References 44 publications

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Regional Reductions in Serotonin 1A Receptor Binding in Juvenile Myoclonic Epilepsy

Contact Info

Product

Resources

About

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

Cited by 250 publications

References 44 publications

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

Regional Reductions in Serotonin 1A Receptor Binding in Juvenile Myoclonic Epilepsy

Contact Info

Product

Resources

About

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET