RT Journal Article SR Electronic T1 TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 495 OP 508 DO 10.1124/jpet.116.232942 VO 357 IS 3 A1 Kazumi Koga A1 Mitsukane Yoshinaga A1 Yoshikatsu Uematsu A1 Yuji Nagai A1 Naoki Miyakoshi A1 Yoko Shimoda A1 Masayuki Fujinaga A1 Takafumi Minamimoto A1 Ming-Rong Zhang A1 Makoto Higuchi A1 Norikazu Ohtake A1 Tetsuya Suhara A1 Shigeyuki Chaki YR 2016 UL http://jpet.aspetjournals.org/content/357/3/495.abstract AB A novel pyridopyrimidin-4-one derivative, N-tert-butyl-2-[2-(3-methoxyphenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP0434299), was characterized as a radioligand candidate for arginine vasopressin 1B (V1B) receptor. TASP0434299 exhibited high binding affinities for human and rat V1B receptors with IC50 values of 0.526 and 0.641 nM, respectively, and potent antagonistic activity at the human V1B receptor with an IC50 value of 0.639 nM without apparent binding affinities for other molecules at 1 μM. [3H]TASP0434299 bound to membranes expressing the human V1B receptor as well as those prepared from the rat anterior pituitary in a saturable manner. The binding of [3H]TASP0434299 to the membranes was dose-dependently displaced by several ligands for the V1B receptor. In addition, the intravenous administration of [3H]TASP0434299 to rats produced a saturable radioactive accumulation in the anterior pituitary where the V1B receptor is enriched, and it was dose-dependently blocked by the oral administration of 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]-N-isopropylacetamide hydrochloride, a V1B receptor antagonist, indicating that [3H]TASP0434299 can be used as an in vivo radiotracer to measure the occupancy of the V1B receptor. Finally, the intravenous administration of [11C]TASP0434299 provided positron emission tomographic images of the V1B receptor in the pituitary in an anesthetized monkey, and the signal was blocked by pretreatment with an excess of unlabeled TASP0434299. These results indicate that radiolabeled TASP0434299 is the first radioligand to be capable of quantifying the V1B receptor selectively in both in vitro and in vivo studies and will provide a clinical biomarker for determining the occupancy of the V1B receptor during drug development or for monitoring the levels of the V1B receptor in diseased conditions.