In Vivo Quantification of Human Serotonin 1A Receptor Using 11C-CUMI-101, an Agonist PET Radiotracer

The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT1AR) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-C-11]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H, 4H)dione (C-11-CUMI-101), a novel 5-HT1A agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of C-11-CUMI-101 for human PET studies. Methods: PET scans were obtained for 7 adult human volunteers. C-11-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures. Results: When using binding potential (BPF = B-avail/K-D [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test-retest percentage difference was 9.90% +/- 5.60%. When using BPND (BPND = f(nd) x B-avail/K-D; BPND equals the product of BPF and f(nd) [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolite-corrected plasma input function (r(2) = 0.99; slope = 0.92). The time-stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest-based analysis, with higher spatial resolution. Conclusion: On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood-brain barrier permeability, and plasma and brain kinetics, C-11-CUMI-101 is suitable for the imaging of high-affinity 5-HT1A binding in humans.