Evaluation in monkey of two candidate PET radioligands, [11C]RX-1 and [18F]RX-2, for imaging brain 5-HT4 receptors

Talakad G. Lohith, Rong Xu, Tetsuya Tsujikawa, Cheryl L. Morse, Kacey B. Anderson, Robert L. Gladding, Sami S. Zoghbi, Masahiro Fujita, Robert B. Innis, Victor W. Pike

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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-HT4 receptor 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-HT4 receptor 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 BPND values were in the rank order of known 5-HT4 receptor distribution with a trend for higher BPND values from [18F]RX-2. One-tissue compartmental model provided good fits with well identified VT values for both radioligands. In the highest 5-HT4 receptor density region, striatum, 50-60% of total binding was specific. The VT in 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-HT4 receptors, validating the radioligand design strategy. Synapse 68:613-623, 2014.

Original languageEnglish (US)
Pages (from-to)613-623
Number of pages11
Issue number12
StatePublished - Dec 1 2014


  • 5-HT
  • Brain
  • Carbon-11
  • Fluorine-18
  • Imaging
  • PET
  • Radioligand

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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