title: Evaluation in monkey of two candidate PET radioligands, [11C]RX-1 and [18F]RX-2, for imaging brain 5-HT4receptors.
abstract: The serotonin subtype-4 (5-HT4) receptor, which is known to be involved physiologically in learning and memory, and pathologically in Alzheimer's disease, anxiety, and other neuropsychiatric disorders-has few radioligands readily available for imaging in vivo. We have previously reported two novel 5-HT4receptor radioligands, namely [methoxy-11C](1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [11C]RX-1), and the [18F]3-fluoromethoxy analog ([18F]RX-2), and in this study we evaluated them by PET in rhesus monkey. Brain scans were performed at baseline, receptor preblock or displacement conditions using SB 207710, a 5-HT4receptor antagonist, on the same day for [11C]RX-1 and on different days for [18F]RX-2. Specific-to-nondisplaceable ratio (BPND) was measured with the simplified reference tissue model from all baseline scans. To determine specific binding, total distribution volume (VT) was also measured in some monkeys by radiometabolite-corrected arterial input function after ex vivo inhibition of esterases from baseline and blocked scans. Both radioligands showed moderate to high peak brain uptake of radioactivity (2-6 SUV). Regional BPNDvalues were in the rank order of known 5-HT4receptor distribution with a trend for higher BPNDvalues from [18F]RX-2. One-tissue compartmental model provided good fits with well identified VTvalues for both radioligands. In the highest 5-HT4receptor density region, striatum, 50-60% of total binding was specific. The VTin receptor-poor cerebellum reached stable values by about 60 min for both radioligands indicating little influence of radiometabolites on brain signal. In conclusion, both [11C]RX-1 and [18F]RX-2 showed positive attributes for PET imaging of brain 5-HT4receptors, validating the radioligand design strategy. Synapse 68:613-623, 2014. © 2014 Wiley Periodicals, Inc.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Talakad G
authors.initials: TG
authors.lastname: Lohith
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsujikawa
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Morse
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Kacey B
authors.initials: KB
authors.lastname: Anderson
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
keywords: 5-HT4; PET; brain; carbon-11; fluorine-18; imaging; radioligand
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