Imaging pituitary vasopressin 1B receptor in humans with the novel PET radiotracer 11C-TASP699.

Arginine vasopressin (AVP) is a hormone that is mainly synthesized in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least three subtypes (V1A, V1B, V2). Among these subtypes, the V1B receptor (V1BR), highly expressed in the pituitary, is a primary regulator of the hypothalamic-pituitary-adrenal axis activity, and thus a potential target for the treatment of neuropsychiatric disorders, such as depression and anxiety. 11C-TASP699 is a novel PET radiotracer with high affinity and selectivity for the V1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11C-TASP699 in human 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 one- and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to calculate distribution volumes (V T). Relative test-retest variability (TRV) and absolute test-retest variability (aTRV) were calculated. Since no brain region could be used as a reference region, percent change in V T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentration of the drug. Results: 11C-TASP699 showed high uptake in the pituitary and no uptake in any brain regions. The 2TC model provided better fits than the 1TC model. The MA1 V T estimates were very similar to the 2TC V T estimates, so MA1 was the model of choice. TRV of V T was good (TRV: -2 ± 14%, aTRV: 11%). THY1773 reduced VT in a dose-dependent fashion, with IC50 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 human with substantial specific binding and good reproducibility of V T Therefore, this tracer is suitable for measurement of the V1BR in human pituitary and V1BR occupancy of TS-121, a novel V1BR antagonist.