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[11C]CHIBA-1001 as a novel PET ligand for alpha7 nicotinic receptors in the brain: a PET study in conscious monkeys.

Hashimoto K, Nishiyama S, Ohba H, Matsuo M, Kobashi T, Takahagi M, Iyo M, Kitashoji T, Tsukada H - PLoS ONE (2008)

Bottom Line: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 nAChRs.The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective alpha7 nAChR agonist SSR180711 (5.0 mg/kg).However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 nAChR agonist A85380 (1.0 mg/kg).

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp

ABSTRACT

Background: The alpha7 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 alpha7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of alpha7 nAChRs in the non-human primate brain.

Methodology/principal findings: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 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 alpha7 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 alpha7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 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/significance: The 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 alpha7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

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Synthesis of [76Br[SSR180711 and [11C]CHIBA-1001.
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pone-0003231-g001: Synthesis of [76Br[SSR180711 and [11C]CHIBA-1001.

Mentions: The distribution, density, and activity of receptors in the living brain can be visualized noninvasively by radioligands labeled for positron emission tomography (PET), and the receptor binding can be quantified by appropriate tracer kinetic models, which can be modified and simplified for particular applications [17]–[19]. The PET ligands ([11C]nicotine and 2-[18F]fluoro-A85380) for α4β2 nAChRs have been used in clinical studies [20]–[22]. However, there have been no clinical studies using PET ligands for α7 nAChRs in the human brain. Therefore, it is very important to develop a safe PET ligand for quantification of α7 nAChRs in the human brain. Very recently, researchers at Sanofi-Aventis developed the novel selective α7 nAChR agonist SSR180711 (4-bromophenyl 1,4-diazabicyclo(3.2.2) nonane-4-carboxylate)(Figure 1) [23], [24], which is under clinical study.


[11C]CHIBA-1001 as a novel PET ligand for alpha7 nicotinic receptors in the brain: a PET study in conscious monkeys.

Hashimoto K, Nishiyama S, Ohba H, Matsuo M, Kobashi T, Takahagi M, Iyo M, Kitashoji T, Tsukada H - PLoS ONE (2008)

Synthesis of [76Br[SSR180711 and [11C]CHIBA-1001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2529405&req=5

pone-0003231-g001: Synthesis of [76Br[SSR180711 and [11C]CHIBA-1001.
Mentions: The distribution, density, and activity of receptors in the living brain can be visualized noninvasively by radioligands labeled for positron emission tomography (PET), and the receptor binding can be quantified by appropriate tracer kinetic models, which can be modified and simplified for particular applications [17]–[19]. The PET ligands ([11C]nicotine and 2-[18F]fluoro-A85380) for α4β2 nAChRs have been used in clinical studies [20]–[22]. However, there have been no clinical studies using PET ligands for α7 nAChRs in the human brain. Therefore, it is very important to develop a safe PET ligand for quantification of α7 nAChRs in the human brain. Very recently, researchers at Sanofi-Aventis developed the novel selective α7 nAChR agonist SSR180711 (4-bromophenyl 1,4-diazabicyclo(3.2.2) nonane-4-carboxylate)(Figure 1) [23], [24], which is under clinical study.

Bottom Line: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 nAChRs.The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective alpha7 nAChR agonist SSR180711 (5.0 mg/kg).However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 nAChR agonist A85380 (1.0 mg/kg).

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp

ABSTRACT

Background: The alpha7 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 alpha7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of alpha7 nAChRs in the non-human primate brain.

Methodology/principal findings: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 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 alpha7 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 alpha7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 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/significance: The 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 alpha7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

Show MeSH
Related in: MedlinePlus