Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography

Yongjun Gao; Hayden T. Ravert; Hiroto Kuwabara; Yingxian Xiao; Christopher J. Endres; John Hilton; Daniel P. Holt; Anil Kumar; Mohab Alexander; Dean F. Wong; Robert F. Dannals; Andrew G. Horti

doi:10.1016/j.bmc.2009.05.021

Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography

Yongjun Gao, Hayden T. Ravert, Hiroto Kuwabara, Yingxian Xiao, Christopher J. Endres, John Hilton, Daniel P. Holt, Anil Kumar, Mohab Alexander, Dean F. Wong, Robert F. Dannals, Andrew G. Horti

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of α4β2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for α4β2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope ¹¹C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics.

Original language	English (US)
Pages (from-to)	4367-4377
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	13
DOIs	https://doi.org/10.1016/j.bmc.2009.05.021
State	Published - Jul 1 2009

Keywords

Nicotinic acetylcholine receptor
PET
Radioligand
nAChR

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Gao, Y., Ravert, H. T., Kuwabara, H., Xiao, Y., Endres, C. J., Hilton, J., Holt, D. P., Kumar, A., Alexander, M., Wong, D. F., Dannals, R. F., & Horti, A. G. (2009). Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography. Bioorganic and Medicinal Chemistry, 17(13), 4367-4377. https://doi.org/10.1016/j.bmc.2009.05.021

Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography. / Gao, Yongjun; Ravert, Hayden T.; Kuwabara, Hiroto et al.
In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 13, 01.07.2009, p. 4367-4377.

Research output: Contribution to journal › Article › peer-review

Gao, Y, Ravert, HT, Kuwabara, H, Xiao, Y, Endres, CJ, Hilton, J, Holt, DP, Kumar, A, Alexander, M, Wong, DF, Dannals, RF & Horti, AG 2009, 'Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography', Bioorganic and Medicinal Chemistry, vol. 17, no. 13, pp. 4367-4377. https://doi.org/10.1016/j.bmc.2009.05.021

Gao Y, Ravert HT, Kuwabara H, Xiao Y, Endres CJ, Hilton J et al. Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography. Bioorganic and Medicinal Chemistry. 2009 Jul 1;17(13):4367-4377. doi: 10.1016/j.bmc.2009.05.021

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abstract = "The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of α4β2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for α4β2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope 11C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics.",

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author = "Yongjun Gao and Ravert, {Hayden T.} and Hiroto Kuwabara and Yingxian Xiao and Endres, {Christopher J.} and John Hilton and Holt, {Daniel P.} and Anil Kumar and Mohab Alexander and Wong, {Dean F.} and Dannals, {Robert F.} and Horti, {Andrew G.}",

note = "Funding Information: The authors thank Paige Finley for her help with the animal experiments, Robert C. Smoot for radiochemistry assistance, and James Fox, David J. Clough and Karen Edmonds for PET scanner operation. We are grateful to Judy W. Buchanan for editorial help. This research was supported by the Department of Radiology of Johns Hopkins University School of Medicine and U.S. Public Health Service grants from the National Institutes of Health (DA020777 and MH079017). The National Institute of Mental Health Psychoactive Drug Screening Program (Grant N01 MH32004) supported some of the in vitro studies.",

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Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in the brain with positron emission tomography

Abstract

Keywords

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