Kinetic Modeling of 11C-SB207145 Binding to 5-HT4 Receptors in the Human Brain In Vivo

The serotonin 4 receptor (5-HT4 receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT4 receptor radioligand, C-11-SB207145, for in vivo brain imaging with PET in humans. Methods: For evaluation of reproducibility, 6 subjects were scanned twice with C-11-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. Quantitative tracer kinetic modeling was investigated with 1-and 2-tissue- compartment models using plasma input functions and the simplified reference tissue model (SRTM). Results: C-11-SB207145 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 +/- 0.72; hippocampus, 0.82 +/- 0.19; parietal cortex, 0.30 +/- 0.08). Quantification with the 1-tissue-compartment model, 2-tissue-compartment model, and SRTM were associated with good test-retest reproducibility and time stability. However, the SRTM-generated BPND values 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 C-11-207145 PET with arterial input in humans. SRTM showed high reproducibility and reliability but bias in the striatum, and therefore, the use of SRTM should be considered carefully for individual applications.