title: In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems.
abstract: Neurotransmission mediated by substance P (SP) and NK(1) receptor has been implicated in the pathophysiology of analgesia, emesis and diverse neuropsychiatric conditions including depression and anxiety disorder. Several lines of clinical trials using NK(1) receptor antagonists have been conducted to date, and the efficiency of preclinical assessments for proof of concept and dose optimization could be greatly increased by configuring an in vivo analytical system that permits quantitative mapping of NK(1) receptors in the brains of small-size laboratory animals expressing "human-like" NK(1) receptors. Hence, we investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [(18)F]fluoroethyl-SPA-RQ, a modification of a recently established radioligand for NK(1) receptors. A pharmacokinetic assay could be performed for a rhesus monkey in an awake condition, which allows the circumvention of influences of anesthesia on SP neurotransmission. Coregistration of PET and magnetic resonance images acquired by small-animal-dedicated devices enabled detailed localization of NK(1) receptors in the gerbil and marmoset brains. The present study also revealed the potentials of SDZ NKT 343 as an antagonist for central NK(1) receptors. In conjunction with additional in vitro and ex vivo autoradiographic observations, our in vivo results have demonstrated a similarity in the binding pattern among the animals examined, justifying cross-species extrapolation of PET findings on the SP-NK(1) pathway.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Haneda
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Motoki
authors.initials: M
authors.lastname: Inaji
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Shigeru
authors.initials: S
authors.lastname: Obayashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.forename: Michiko
authors.initials: M
authors.lastname: Narazaki
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ikehira
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted / Q000379:methods; D066298:In Vitro Techniques; D010880:Piperidines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011323:Primates; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012377:Rodentia; D013373:Substance P / Q000378:metabolism; D013777:Tetrazoles / Q000493:pharmacokinetics
chemical_list: C517420:(2-fluoromethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)(2-phenylpiperidin-3-yl)amine; D005462:Fluorine Radioisotopes; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; D013373:Substance P