A postmortem study to compare agonist and antagonist 5-HT1A receptor-binding sites in Alzheimer's disease.

Abstract

AIMS:

Positron emission tomography (PET) imaging using 5-HT1A receptor radioligands shows a decreased expression of this serotonin receptor in the hippocampus of patients with Alzheimer's disease (AD) at advanced stages. However, previous 5-HT1A receptor radioligands used in human imaging were antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the functional state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radioligand, which binds selectively to the functional state of the receptors, with the PET imaging obtained using an antagonist radioligand would therefore provide original information on 5-HT1A receptor impairment during AD.

METHODS:

Quantitative autoradiography using (18) F-F15599 and (18) F-MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of 18 patients with AD.

RESULTS:

Functional 5-HT1A receptors, labeled by (18) F-F15599, represented ~35% of total receptors, as estimated by (18) F-MPPF labeling. (18) F-F15599 binding decreased in dentate gyrus of patients with AD, as indicated by Braak's stages. In contrast, binding of (18) F-MPPF was statistically unchanged.

CONCLUSION:

These in vitro results support testing the concept of functional PET imaging using agonist radioligands in clinical studies.

• Authors: Guillaume Becker, Nathalie Streichenberger, Thierry Billard, Adrian Newman-Tancredi, Luc Zimmer
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 20 Issue 10 Pg. 930-4 (Oct 2014) ISSN: 1755-5949 [Electronic] England
• PMID: 25041947 (Publication Type: Journal Article)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• Piperazines
• Piperidines
• Pyrimidines
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT1 Receptor Antagonists
• Fluorodeoxyglucose F18
• Receptor, Serotonin, 5-HT1A

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnostic imaging, pathology)
• Autopsy
• Autoradiography
• Binding Sites (drug effects)
• Female
• Fluorodeoxyglucose F18 (pharmacokinetics)
• Hippocampus (diagnostic imaging, drug effects)
• Humans
• Male
• Middle Aged
• Piperazines (pharmacokinetics)
• Piperidines (pharmacokinetics)
• Positron-Emission Tomography
• Protein Binding (drug effects)
• Pyrimidines (pharmacokinetics)
• Receptor, Serotonin, 5-HT1A (metabolism)
• Serotonin 5-HT1 Receptor Agonists (pharmacokinetics)
• Serotonin 5-HT1 Receptor Antagonists (pharmacokinetics)