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Vasopressin 1B receptors (V 1B Rs) are abundantly expressed in the pituitary, and in vivo PET of V 1B Rs was recently enabled by our development of a specific radioligand, 11 C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, N - tert -butyl-2-[2-(6- 11 C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3- d ]pyrimidin-3(4 H )-yl]acetamide ( 11 C-TASP0410699, hereafter referred to as 11 C-TASP699), as a potent V 1B R radioligand producing a higher image contrast for the target than 11 C-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V 1B R and its selectivity for off-target molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of 11 C-TASP699. Serial doses of a selective V 1B R antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3- d ]pyrimidin-3(4 H )-yl]- N -isopropylacetamide hydrochloride (TASP0390325), were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with 11 C-TASP699 was conducted with or without nonradioactive V 1B R antagonists. Results: The half maximal inhibitory concentration (IC 50 ) of TASP699 for human V 1B Rs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC 50 values for off-target molecules exceeded 1 μM. PET imaging in monkeys demonstrated that the peak pituitary uptake of 11 C-TASP699 was almost equivalent to that of 11 C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of 11 C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for 11 C-TASP699 was approximately 2.5-fold greater than that of 11 C-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for V 1B Rs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with 11 C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion:  11 C-TASP699 yielded PET images of pituitary V 1B Rs with a higher contrast than 11 C-TASP0434299, supporting the applicability of 11 C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials.

High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699