Discovery of (-)-7-methyl-2-exo-[3′-(6-[18F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties

Yongjun Gao; Hiroto Kuwabara; Charles E. Spivak; Yingxian Xiao; Kenneth Kellar; Hayden T. Ravert; Anil Kumar; Mohab Alexander; John Hilton; Dean F. Wong; Robert F. Dannals; Andrew G. Horti

doi:10.1021/jm800323d

Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties

Yongjun Gao, Hiroto Kuwabara, Charles E. Spivak, Yingxian Xiao, Kenneth Kellar, Hayden T. Ravert, Anil Kumar, Mohab Alexander, John Hilton, Dean F. Wong, Robert F. Dannals, Andrew G. Horti

School of Medicine

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

26 Scopus citations

Abstract

Several isomers of 7-methyl-2-exo-([¹⁸F]fluoropyridinyl- 5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with K_i = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D _7.4 = 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (K_i = 0.3 nM) ((-)-7-methyl-2-exo-[3′-(6-[¹⁸F] fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ ¹⁸F](-)-6c) and greatest lipophilicity (log D_7.4 = 0.99) exhibited optimal brain kinetics. [¹⁸F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [¹⁸F]-(-)-6c is a potentially superior replacement for 2-[¹⁸F]fluoro-A-85380 and 6-[ ¹⁸F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

Original language	English (US)
Pages (from-to)	4751-4764
Number of pages	14
Journal	Journal of medicinal chemistry
Volume	51
Issue number	15
DOIs	https://doi.org/10.1021/jm800323d
State	Published - Aug 14 2008

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Gao, Y., Kuwabara, H., Spivak, C. E., Xiao, Y., Kellar, K., Ravert, H. T., Kumar, A., Alexander, M., Hilton, J., Wong, D. F., Dannals, R. F., & Horti, A. G. (2008). Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties. Journal of medicinal chemistry, 51(15), 4751-4764. https://doi.org/10.1021/jm800323d

Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties. / Gao, Yongjun; Kuwabara, Hiroto; Spivak, Charles E. et al.
In: Journal of medicinal chemistry, Vol. 51, No. 15, 14.08.2008, p. 4751-4764.

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

Gao, Y, Kuwabara, H, Spivak, CE, Xiao, Y, Kellar, K, Ravert, HT, Kumar, A, Alexander, M, Hilton, J, Wong, DF, Dannals, RF & Horti, AG 2008, 'Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties', Journal of medicinal chemistry, vol. 51, no. 15, pp. 4751-4764. https://doi.org/10.1021/jm800323d

Gao Y, Kuwabara H, Spivak CE, Xiao Y, Kellar K, Ravert HT et al. Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties. Journal of medicinal chemistry. 2008 Aug 14;51(15):4751-4764. doi: 10.1021/jm800323d

Gao, Yongjun ; Kuwabara, Hiroto ; Spivak, Charles E. et al. / Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties. In: Journal of medicinal chemistry. 2008 ; Vol. 51, No. 15. pp. 4751-4764.

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title = "Discovery of (-)-7-methyl-2-exo-[3′-(6-[18F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties",

abstract = "Several isomers of 7-methyl-2-exo-([18F]fluoropyridinyl- 5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D 7.4 = 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2-exo-[3′-(6-[18F] fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ 18F](-)-6c) and greatest lipophilicity (log D7.4 = 0.99) exhibited optimal brain kinetics. [18F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [18F]-(-)-6c is a potentially superior replacement for 2-[18F]fluoro-A-85380 and 6-[ 18F]fluoro-A-85380, the only available nAChR PET radioligands for humans.",

author = "Yongjun Gao and Hiroto Kuwabara and Spivak, {Charles E.} and Yingxian Xiao and Kenneth Kellar and Ravert, {Hayden T.} and Anil Kumar and Mohab Alexander and John Hilton and Wong, {Dean F.} and Dannals, {Robert F.} and Horti, {Andrew G.}",

year = "2008",

month = aug,

day = "14",

doi = "10.1021/jm800323d",

language = "English (US)",

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pages = "4751--4764",

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T1 - Discovery of (-)-7-methyl-2-exo-[3′-(6-[18F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties

AU - Gao, Yongjun

AU - Kuwabara, Hiroto

AU - Spivak, Charles E.

AU - Xiao, Yingxian

AU - Kellar, Kenneth

AU - Ravert, Hayden T.

AU - Kumar, Anil

AU - Alexander, Mohab

AU - Hilton, John

AU - Wong, Dean F.

AU - Dannals, Robert F.

AU - Horti, Andrew G.

PY - 2008/8/14

Y1 - 2008/8/14

N2 - Several isomers of 7-methyl-2-exo-([18F]fluoropyridinyl- 5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D 7.4 = 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2-exo-[3′-(6-[18F] fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ 18F](-)-6c) and greatest lipophilicity (log D7.4 = 0.99) exhibited optimal brain kinetics. [18F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [18F]-(-)-6c is a potentially superior replacement for 2-[18F]fluoro-A-85380 and 6-[ 18F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

AB - Several isomers of 7-methyl-2-exo-([18F]fluoropyridinyl- 5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D 7.4 = 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2-exo-[3′-(6-[18F] fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ 18F](-)-6c) and greatest lipophilicity (log D7.4 = 0.99) exhibited optimal brain kinetics. [18F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [18F]-(-)-6c is a potentially superior replacement for 2-[18F]fluoro-A-85380 and 6-[ 18F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

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