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

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.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…The regional distribution pattern of [ 11 C]CHIBA-1001 is consistent with what is expected in vitro (Falk et al, 2003;Court et al, 1999;2001;Marutle et al, 2001), but different from that of 42 nAChRs (Clementi, 2004). However, it is slightly different from the regional distribution in the monkey brain (Hashimoto et al, 2008). In the human brain, remarkable radioactivity accumulation was observed in the cerebellum.…”

“…[ 11 C]CHIBA-1001 distribution in the monkey brain measured by PET was consistent with the regional distribution of 7 nAChRs. Moreover, brain uptake of [ 11 C]CHIBA-1001 was dose-dependently blocked by pretreatment with the selective 7 nAChR agonist SSR180711, but was not altered by the selective 42 nAChR agonist A-85380 (Hashimoto et al, 2008). In the human brain, [ 11 C]CHIBA-1001 was found widely distributed in all brain regions.…”

Neuroimaging - Clinical Applications

“…As illustrated by the data in Tab. 2, the general suitability of these derivatives for imaging of α7 nAChR is supported by preclinical PET studies in pigs (Deuther-Conrad et al, 2011;Lehel et al, 2009) and nonhuman primates (Hashimoto et al, 2008) as well as a first clinical study (Toyohara et al, 2009). However, substantial enhancement in the affinity of the α7 nAChR PET ligands is required to improve image analysis, modelling, and eventually quantification of α7 nAChR in brain diseases.…”

“…However, substantial enhancement in the affinity of the α7 nAChR PET ligands is required to improve image analysis, modelling, and eventually quantification of α7 nAChR in brain diseases. Considering the low density of α7 nAChR in brain, the target affinity of the currently most promising tracers [ 11 C]CHIBA-1001 (K i ~ 35 nM; (Hashimoto et al, 2008;Toyohara et al, 2009) (Lehel et al, 2009) Papio anubis Dynamic PET scan Very high initial uptake followed by rapid clearance; Radiometa-bolites penetrate the BBB; High nonspecific binding consistent with the low affinity for α7 nAChR Selective uptake in the regions of the hippocampus, cortex and basal ganglia; gradual washouts; cerebellum with lowest binding (Toyohara et al, 2009) …”

Central in Vivo Nicotinic Acetylcholine Receptor Imaging Agents for Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT)

“…Only a few reports have been published for a7 subtype imaging agents for in vivo use. [16][17][18][19] We previously reported the small molecular weight radioiodinated compound, (R)-3Ј-(5-…”