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5-hydroxy-L-[beta-C-11]tryptophan versus alpha-[C-11]methyl-L-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (PKPD)
Hospital Pharmacy, Uppsala University Hospital.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (PKPD)
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2007 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 27, no 4, 821-830 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n=4) on the same day. α-[11C]Methyl-L-tryptophan ([11C]AMT) and 5-Hydroxy-L-[β-11C]tryptophan ([11C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [11C]HTP into the brain (K1) was higher than that for [11C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k3) was also higher for [11C]HTP than for [11C]AMT in the striatum (0.046±0.024 versus 0.019±0.006 min-1) and thalamus (0.039±0.013 versus 0.016±0.007 min-1). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (Kacc) for [11C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [11C]AMT Kacc values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.

Place, publisher, year, edition, pages
2007. Vol. 27, no 4, 821-830 p.
Keyword [en]
α-Methyl-L-tryptophan, 5-Hydroxy-L-tryptophan, Biosynthesis, Positron emission tomography, Rhesus monkey, Serotonin
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94402DOI: 10.1038/sj.jcbfm.9600381ISI: 000245358800017PubMedID: 16896348OAI: oai:DiVA.org:uu-94402DiVA: diva2:168238
Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 34
Keyword
Pharmacokinetics/Pharmacotherapy, Brain serotonin, Neurotransmitter release, Neurotransmitter synthesis, Positron emission tomography, Tracer validation, Tracer modelling, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-6830 (URN)91-554-6549-8 (ISBN)
Public defence
2006-05-19, room B42, BMC, Uppsala, 09:15
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Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2011-02-08Bibliographically approved

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