Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer 11 C-TASP699.

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 (V _1A , V _1B , and V ₂ ). Among these subtypes, the V _1B receptor (V _1B R), 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(4 H )-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V _1B R. The purpose of this study was to characterize the pharmacokinetic and binding profiles of ¹¹ C-TASP699 in humans and determine its utility in an occupancy study of a novel V _1B R antagonist, TS-121. Methods: Six healthy subjects were scanned twice with ¹¹ C-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 V _1B R 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: ¹¹ C-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: ¹¹ C-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 V _1B R in the human pituitary and the V _1B R occupancy of TS-121, a novel V _1B R antagonist.
(© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)