Abstract
The serotonin subtype-4 (5-HT(4) ) 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-HT(4) receptor radioligands, namely [methoxy-(11) C](1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [(11) C]RX-1), and the [(18) F]3-fluoromethoxy analog ([(18) F]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-HT(4) receptor antagonist, on the same day for [(11) C]RX-1 and on different days for [(18) F]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-HT(4) receptor distribution with a trend for higher BP(ND) values from [(18) F]RX-2. One-tissue compartmental model provided good fits with well identified V(T) values for both radioligands. In the highest 5-HT(4) 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 [(11) C]RX-1 and [(18) F]RX-2 showed positive attributes for PET imaging of brain 5-HT(4) receptors, validating the radioligand design strategy. Synapse 68:613-623, 2014. © 2014 Wiley Periodicals, Inc.