title: Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor.
abstract: Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [(11)C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [(11)C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. , Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Oi
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Taro
authors.initials: T
authors.lastname: Terauchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D001345:Autoradiography; D008253:Macaca mulatta; D051379:Mice; D064446:Orexin Receptors; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000032:analysis*; D018013:Receptors, Neuropeptide / Q000032:analysis*
chemical_list: D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide