11C]CHIBA-1001 as a Novel PET Ligand for α7 Nicotinic Receptors in the Brain: A PET Study in Conscious Monkeys

Kenji Hashimoto,Shingo Nishiyama,Hideo Tsukada,Masaomi Iyo,Takeru Kitashoji,Masaaki Matsuo,Hiroyuki Ohba,Tatsuhiko Kobashi,Makoto Takahagi,Henry Waldvogel

doi:10.1371/journal.pone.0003231

Abstract

BackgroundThe α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET) radioligands for imaging α7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of α7 nAChRs in the non-human primate brain.Methodology/Principal FindingsA receptor binding assay showed that CHIBA-1001 was a highly selective ligand at α7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [11C]CHIBA-1001 was consistent with the regional distribution of α7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective α7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective α4β2 nAChR agonist A85380 (1.0 mg/kg). Interestingly, the binding of [11C]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days); which is a non-human primate model of schizophrenia.Conclusions/SignificanceThe present findings suggest that [11C]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of α7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

Highlights

The most of neuronal nicotinic acetylcholine receptors are ligand-gated ion channels composed of a and b subunits that assemble to form pentamers with a variety of physiological and pharmacological properties
Conclusions/Significance: The present findings suggest that [11C]CHIBA-1001 could be a novel useful positron emission tomography (PET) ligand for in vivo study of the receptor occupancy and pathophysiology of a7 nicotinic acetylcholine receptors (nAChRs) in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease
Several lines of evidence suggest that a7 nAChRs play a role in the pathophysiology of neuropsychiatric diseases such as schizophrenia, Alzheimer’s disease, anxiety, depression, and drug addiction, and that a7 nAChRs are the most attractive therapeutic targets for these diseases [3,4,5,6,7,8,9,10,11]

Summary

Introduction

The most of neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels composed of a and b subunits that assemble to form pentamers with a variety of physiological and pharmacological properties. Studies using postmortem human brain samples have demonstrated alterations in the levels of a7 nAChRs in the brains of patients with schizophrenia [12,13] and Alzheimer’s disease [14,15,16]. It is of great interest to examine whether a7 nAChRs are altered in the living brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease. It is of interest to measure the receptor occupancy of potential therapeutic a7 nAChR drugs in the intact human brain. The a7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease. There are currently no suitable positron emission tomography (PET) radioligands for imaging a7 nAChRs in the intact human brain. We report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of a7 nAChRs in the non-human primate brain

Methods

Results

Conclusion