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

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 (BP_ND) was measured with the simplified reference tissue model from all baseline scans. To determine specific binding, total distribution volume (V_T) 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 BP_ND values were in the rank order of known 5-HT₄ receptor distribution with a trend for higher BP_ND values from [¹⁸F]RX-2. One-tissue compartmental model provided good fits with well identified V_T values for both radioligands. In the highest 5-HT₄ receptor density region, striatum, 50-60% of total binding was specific. The V_T 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.