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-HT(1A)R) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-(11)C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione ((11)C-CUMI-101), a novel 5-HT(1A) agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of (11)C-CUMI-101 for human PET studies. PET scans were obtained for 7 adult human volunteers. (11)C-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. When using binding potential (BP(F) = 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 BP(ND) (BP(ND) = f(nd) × B(avail)/K(D); BP(ND) equals the product of BP(F) 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. On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood-brain barrier permeability, and plasma and brain kinetics, (11)C-CUMI-101 is suitable for the imaging of high-affinity 5-HT(1A) binding in humans.