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Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration: positron emission tomography studies in monkeys and rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala Imanet.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Hospital Pharmacy, University Hospital.
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2007 (English)In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 61, no 6, 440-449 p.Article in journal (Refereed) Published
Abstract [en]

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [11C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [11C]DASB. The binding of [11C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [11C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.

Place, publisher, year, edition, pages
2007. Vol. 61, no 6, 440-449 p.
Keyword [en]
Endogenous serotonin, positron emission tomography (PET), in vivo binding, [11C]DASB, brain
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-94401DOI: 10.1002/syn.20382ISI: 000245534800009PubMedID: 17372973OAI: oai:DiVA.org:uu-94401DiVA: diva2:168237
Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2012-12-04Bibliographically approved
In thesis
1. Imaging and Quantification of Brain Serotonergic Activity using PET
Open this publication in new window or tab >>Imaging and Quantification of Brain Serotonergic Activity using PET
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis investigates the potential of using positron emission tomography (PET) to study the biosynthesis and release of serotonin (5HT) at the brain serotonergic neuron. As PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes, emphasis was placed on the evaluation of these attributes.

The experiments established that the 5HT transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, [11C]DASB, is suitable for imaging and quantification of transporters in rats and rhesus monkeys. In addition, the binding of [11C]DASB in brain tissue is decreased when 5HT concentrations are increased by tranylcypromine administration. The sensitivity of [11C]DASB binding, under these experimental conditions, to increased endogenous 5HT concentrations demonstrates the potential of in vivo monitoring of 5HT release in rat and monkey models.

The irreversible binding of 5-hydroxy-L-[β-11C]tryptophan, [11C]HTP, in the monkey brain was lower in the presence of NSD1015, which was used to inhibit the decarboxylase step in 5HT synthesis. [11C]HTP seems thus to have potential for tracking changes in the activity of this biosynthesis enzyme. In contrast, the accumulation of [11C]HTP was unaffected by clorgyline, which was used to inhibit metabolism of the probe in the brain. This appears to indicate that elimination of the main metabolite from the brain could be negligible and thus will not alter [11C]HTP quantification. The extent and distribution of the irreversible binding of a substrate for the first enzyme in 5HT formation, α-[11C]methyl-L-tryptophan, [11C]AMT, was different from those for [11C]HTP. This suggests that the two studied probe compounds provide estimates related to the enzyme activity of different steps in the 5HT biosynthesis pathway.

A reference tissue version of the Patlak method for the analysis of data obtained by PET was also developed. This approach takes into account irreversible binding in the reference region and appears, therefore, to yield more reliable parameter estimates than the conventional reference Patlak analysis. The method is recommended for parameter estimation of [11C]HTP data when no metabolite-corrected plasma curve is available.

Knowledge of altered 5HT synthesis and release in disease states and the consequences for effective pharmacotherapy can improve our knowledge of the aetiology of certain psychiatric and neurological diseases and enhance our ability to design more effective drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 34
Pharmacokinetics/Pharmacotherapy, Brain serotonin, Neurotransmitter release, Neurotransmitter synthesis, Positron emission tomography, Tracer validation, Tracer modelling, Farmakokinetik/Farmakoterapi
urn:nbn:se:uu:diva-6830 (URN)91-554-6549-8 (ISBN)
Public defence
2006-05-19, room B42, BMC, Uppsala, 09:15
Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2011-02-08Bibliographically approved

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