Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V1A, V1B, and V2). Among these subtypes, the V1B receptor (V1BR), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N-tert-butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11C-TASP699 in humans and determine its utility in an occupancy study of a novel V1BR antagonist, TS-121. Methods: Six healthy subjects were scanned twice with 11C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V1BR occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume (V T). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in V T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results: 11C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 V T estimates were similar to the 2TC V T estimates, MA1 was the model of choice. The TRV of V T was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced V T in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: 11C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of V T Therefore, this tracer is suitable for measurement of V1BR in the human pituitary and the V1BR occupancy of TS-121, a novel V1BR antagonist.
