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In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K - PLoS ONE (2010)

Bottom Line: However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain.On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

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. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers.

Methodology/principal findings: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.

Conclusions/significance: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

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Related in: MedlinePlus

Radiosynthesis of [11C]A-582941 and [11C]A-844606.
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pone-0008961-g001: Radiosynthesis of [11C]A-582941 and [11C]A-844606.

Mentions: Radiosynthesis of [11C]A-582941 and [11C]A-844606 by N-[11C]-methylation of the desmethyl precursor was carried out under various concentrations of NaOH as a base (Figure 1). The use of [11C]methyl triflate in acetone with two equimolar amounts of NaOH led to a sufficient radiochemical yield of each compound. The radiochemical yields using [11C]methyl triflate under these conditions for [11C]A-582941 and [11C]A-844606 were 16.8±11.98% (n = 8) and 40.0±16.8% (n = 7), respectively. Large excess or equimolar amounts of NaOH as a base led to a slight decrease of the radiochemical yields of [11C]A-582941 (10.3% for equimolar; 13.2% for 10 equimolar). The total preparation time for each tracer, including purification and formulation, was approximately 30 min from the end of irradiation. The radiochemical purities of each tracer were over 97%, and the specific activities at 30 min after the end of irradiation were in the range of 15–108 GBq/µmol for each radiotracer. The absence of any residual traces of the starting materials was verified by high performance liquid chromatography (HPLC) analysis.


In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K - PLoS ONE (2010)

Radiosynthesis of [11C]A-582941 and [11C]A-844606.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813863&req=5

pone-0008961-g001: Radiosynthesis of [11C]A-582941 and [11C]A-844606.
Mentions: Radiosynthesis of [11C]A-582941 and [11C]A-844606 by N-[11C]-methylation of the desmethyl precursor was carried out under various concentrations of NaOH as a base (Figure 1). The use of [11C]methyl triflate in acetone with two equimolar amounts of NaOH led to a sufficient radiochemical yield of each compound. The radiochemical yields using [11C]methyl triflate under these conditions for [11C]A-582941 and [11C]A-844606 were 16.8±11.98% (n = 8) and 40.0±16.8% (n = 7), respectively. Large excess or equimolar amounts of NaOH as a base led to a slight decrease of the radiochemical yields of [11C]A-582941 (10.3% for equimolar; 13.2% for 10 equimolar). The total preparation time for each tracer, including purification and formulation, was approximately 30 min from the end of irradiation. The radiochemical purities of each tracer were over 97%, and the specific activities at 30 min after the end of irradiation were in the range of 15–108 GBq/µmol for each radiotracer. The absence of any residual traces of the starting materials was verified by high performance liquid chromatography (HPLC) analysis.

Bottom Line: However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain.On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

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. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers.

Methodology/principal findings: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.

Conclusions/significance: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

Show MeSH
Related in: MedlinePlus