title: TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor.
abstract: 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. [(3)H]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 [(3)H]TASP0434299 to the membranes was dose-dependently displaced by several ligands for the V1B receptor. In addition, the intravenous administration of [(3)H]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 [(3)H]TASP0434299 can be used as an in vivo radiotracer to measure the occupancy of the V1B receptor. Finally, the intravenous administration of [(11)C]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.
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Kazumi
authors.initials: K
authors.lastname: Koga
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Mitsukane
authors.initials: M
authors.lastname: Yoshinaga
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyakoshi
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Takafumi
authors.initials: T
authors.lastname: Minamimoto
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.).
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: Pharmacology Laboratories (K.K., Y.U., S.C.) and Chemistry Laboratories (M.Y., N.M., N.O.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; and Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Y.N., Y.S., M.F., T.M., M.-R.Z., M.H., T.S.) s-chaki@so.taisho.co.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002250:Carbon Radioisotopes; D057809:HEK293 Cells; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D011744:Pyrimidinones / Q000378:metabolism*; D011849:Radioactive Tracers; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D011725:Pyridines; D011743:Pyrimidines; D011744:Pyrimidinones; D011849:Radioactive Tracers; D017483:Receptors, Vasopressin; C000619116:TASP0434299