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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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Representative PET images in the brains of a rhesus monkey after intravenous administration of [76Br]SSR180711.Upper: Control monkey (saline pre-treated). Middle: Pretreatment with SSR180711 (5.0 mg/kg, 30 min before). Lower: Pretreatment with A85380 (1.0 mg/kg, 30 min before)
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pone-0003231-g002: Representative PET images in the brains of a rhesus monkey after intravenous administration of [76Br]SSR180711.Upper: Control monkey (saline pre-treated). Middle: Pretreatment with SSR180711 (5.0 mg/kg, 30 min before). Lower: Pretreatment with A85380 (1.0 mg/kg, 30 min before)

Mentions: Baseline PET scans showed rapid brain penetration and accumulation of [76Br]SSR180711 in the monkey brain (Figures 2–4). The peak time of radioactivity in the hippocampus was about 60 min after administration of the radioligand. Furthermore, the peak time of radioactivity in the other brain regions (occipital cortex, temporal cortex, frontal cortex, striatum, thalamus, and cerebellum) was about 30–40 min after administration of the radioligand. The distribution of radioactivity in the brain regions after administration of the radioligand was consistent with the distribution of α7 nAChRs in the monkey brain [25]–[27]. Uptake of radioactivity in the brain regions after intravenous administration of [76Br]SSR180711 was significantly decreased by pretreatment with the α7 nAChR agonist SSR180711 (5.0 mg/kg, i.v., 30 min)(Figures 2–4). Uptake of radioactivity (during 70–91 min) in the brain regions except the cerebellum (low receptor density) after intravenous administration of [76Br]SSR180711 was significantly decreased by pretreatment with the α7 nAChR agonist SSR180711 (5.0 mg/kg, i.v., 30 min)(Figures 4A). However, the distribution of radioactivity in the brain regions after intravenous administration of [76Br]SSR180711 was not altered by pretreatment with the selective α4β2 nAChR agonist A85380 (1.0 mg/kg, i.v., 30 min)[28], [29](Figures 2, 3 and 4B).


[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)

Representative PET images in the brains of a rhesus monkey after intravenous administration of [76Br]SSR180711.Upper: Control monkey (saline pre-treated). Middle: Pretreatment with SSR180711 (5.0 mg/kg, 30 min before). Lower: Pretreatment with A85380 (1.0 mg/kg, 30 min before)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2529405&req=5

pone-0003231-g002: Representative PET images in the brains of a rhesus monkey after intravenous administration of [76Br]SSR180711.Upper: Control monkey (saline pre-treated). Middle: Pretreatment with SSR180711 (5.0 mg/kg, 30 min before). Lower: Pretreatment with A85380 (1.0 mg/kg, 30 min before)
Mentions: Baseline PET scans showed rapid brain penetration and accumulation of [76Br]SSR180711 in the monkey brain (Figures 2–4). The peak time of radioactivity in the hippocampus was about 60 min after administration of the radioligand. Furthermore, the peak time of radioactivity in the other brain regions (occipital cortex, temporal cortex, frontal cortex, striatum, thalamus, and cerebellum) was about 30–40 min after administration of the radioligand. The distribution of radioactivity in the brain regions after administration of the radioligand was consistent with the distribution of α7 nAChRs in the monkey brain [25]–[27]. Uptake of radioactivity in the brain regions after intravenous administration of [76Br]SSR180711 was significantly decreased by pretreatment with the α7 nAChR agonist SSR180711 (5.0 mg/kg, i.v., 30 min)(Figures 2–4). Uptake of radioactivity (during 70–91 min) in the brain regions except the cerebellum (low receptor density) after intravenous administration of [76Br]SSR180711 was significantly decreased by pretreatment with the α7 nAChR agonist SSR180711 (5.0 mg/kg, i.v., 30 min)(Figures 4A). However, the distribution of radioactivity in the brain regions after intravenous administration of [76Br]SSR180711 was not altered by pretreatment with the selective α4β2 nAChR agonist A85380 (1.0 mg/kg, i.v., 30 min)[28], [29](Figures 2, 3 and 4B).

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