In Vivo Evaluation of F-18-MNI698: An F-18-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

Adriana Alexandre S. Tavares*, Fabien Caille, Olivier Barret, Caroline Papin, Hsiaoju Lee, Thomas J. Morley, Krista Fowles, Daniel Holden, John P. Seibyl, David Alagille, Gilles D. Tamagnan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Serotonin 4 receptors (5-hydroxytryptamine receptor 4 [5HT4R]) hold promise as a novel therapeutic approach to multiple brain disorders, including Alzheimer and Huntington disease. In vivo imaging of these receptors with selective 5HT4R radiotracers and PET would be valuable to investigate alterations in 5HT4R in different brain disorders and to assist drug discovery. In this study, F-18-MNI698 was evaluated as a potential PET radiotracer for imaging of 5HT4R in the brain. Methods: Eighteen PET studies were performed in 3 adult rhesus monkeys. The radiotracer was administered as a bolus intravenous injection or bolus plus constant infusion (time that would be required to inject the bolus at the infusion rate=60 min), and arterial blood was collected for data quantification. Kinetic models were used to estimate distribution volumes and binding potentials, for which the cerebellum was used as a reference region. F-18-MNI698 test-retest variability and upper mass dose limits were determined. Preblocking studies using several doses of SB204070, a selective 5HT4R antagonist, were performed. Results: F-18-MNI698 avidly entered the monkey brain (peak percentage injected dose of similar to 6.6%), and its brain distribution was consistent with known 5HT4Rdensities. At 120 min after bolus injection and after the start of radiotracer infusion, only less than 5% and approximately 10% parent compound was present in blood, respectively. Measured binding potentials were under estimated by 22%-36% when noninvasive methods were used for data quantification in comparison with invasive methods. A good agreement was found between test-retest measurements. The radiotracer upper mass dose limit (

Original languageEnglish
Pages (from-to)858-864
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number5
DOIs
Publication statusPublished - May 2014

Keywords

  • 5HT4R
  • F-18-MNI698
  • test-retest
  • mass effect
  • SB204070
  • POSTMORTEM HUMAN BRAIN
  • 5-HT4 RECEPTORS
  • GRAPHICAL ANALYSIS
  • PET RECEPTOR
  • BINDING
  • PHARMACOLOGY
  • ANESTHESIA
  • AGONIST
  • TISSUE
  • RATS

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