[(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.

[ 11 C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT 2A ) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with INTRODUCTIONThe neurotransmitter serotonin (5-HT) is a modulator of a vast variety of normal physiologic effects and is also involved in the pathophysiology of central nervous system disorders such as depression and schizophrenia. The serotonin 2A (5-HT 2A ) receptor is the main excitatory 5-HT receptor in the human central nervous system, it is responsible for the hallucinogenic effects of recreational agonist drugs such as lysergic acid diethylamide and psilocybin, and 5-HT 2A receptor antagonism is a characteristic of atypical antipsychotics. 1 Furthermore, changes in 5-HT 2A receptor levels have been linked to the pathophysiology of human diseases such as depression. 2,3 Positron emission tomography (PET) has unsurpassed sensitivity and selectivity to detect and quantify specific proteins and processes in the human brain. Positron emission tomography imaging with radioligands is a widely used tool to quantify differences in receptor binding, for example, between patient and control groups, to quantify receptor occupancy of pharmacological interventions or to measure neurotransmitter release in vivo. 4,5 In clinical studies, 5-HT 2A receptor antagonists have for decades been in use as PET radioligands, most notably [ 18 F]altanserin and [ 11 C]MDL100907. 6 However, agonist PET radioligands may functionally possess several advantages over antagonists. Importantly, agonist radioligands in the dopamine system have an increased sensitivity to endogenously released neurotransmitter. Here, several studies using pharmacologically increased dopamine

The serotonin 4 receptor (5-HT 4 receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT 4 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 11 C-SB207145 on the same day. A further 2 subjects were scanned before and after blocking with the selective 5-HT 4 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: 11 C-SB207145 readily entered the brain and showed a distribution consistent with the known localization of the 5-HT 4 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 (BP ND : striatum, 3.38 6 0.72; 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 and time stability. However, the SRTM-generated BP ND 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-HT 4 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-HT 4 receptors can be determined reliably using 11 C-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.