Kinetic Modeling of 11 C-SB207145 Binding to 5-HT 4 Receptors in the Human Brain In Vivo

Theserotonin4receptor(5-HT4receptor)isknowntobeinvolved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT4 receptor radioligand, 11 C-SB207145, for in vivo brain imaging with PET in humans. Methods: For evaluation of reproducibility, 6 subjects were scanned twice with 11C-SB207145 on the same day. A further 2 subjects were scanned before and after blocking with the selective 5-HT4 receptor inverse agonist piboserod (SB207266). Arterial blood samples were drawn for the calculation of metabolite-corrected arterial input functions. Regions of interest were delineated automatically on the individual’s MR images coregistered to the PET images, and regional time‐activity curves were extracted. Quantitativetracerkineticmodelingwasinvestigatedwith1-and2-tissue-compartment models using plasma input functions and the simplified reference tissue model (SRTM). Results: 11 CSB207145 readily entered the brain and showed a distribution consistent with the known localization of the 5-HT4 receptor. Using plasma input models, the time‐activity data were well described by the 2-tissue-compartment model in all regions and allowed for the estimate of binding potentials relative to the reference region (BPND: striatum, 3.38 60.72; hippocampus, 0.82 6 0.19; parietal cortex, 0.30 6 0.08). Quantification with the 1-tissue-compartment model, 2-tissue-compartment model, and SRTM were associated with good test‐retest reproducibility andtime stability. However, theSRTM-generated BPNDvalues in the striatum were underestimated by 20%243% in comparison to the 2-tissue-compartment model. The blocking study with piboserod confirmed that the radioligand was selective for the 5-HT4 receptor, that the cerebellum was a suitable reference region devoid of specific binding, and that nonspecific binding was constant across brain regions. Conclusion: In vivo imaging of cerebral 5-HT4 receptors can be determined reliably using 11C