Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2. 1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors

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

Research output: Contribution to journalArticle

Abstract

A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7- azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3′-(2-[ 18F]-fluoropyridin-5-yl))-5′-pyridinyl]-7-azabicyclo[2.2.1] heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.

Original languageEnglish (US)
Pages (from-to)3814-3824
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number16
DOIs
StatePublished - Aug 9 2007

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Heptanes
Positron emission tomography
Enantiomers
Nicotinic Receptors
Positron-Emission Tomography
Papio
Ligands
Derivatives
Imaging techniques
Enantioselectivity
Positrons
Isotopes
Rodentia
Brain
High Pressure Liquid Chromatography
Electrons
7-azabicyclo(2.2.1)heptane
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{5168063c639e4c3388a92dce5d9badef,
title = "Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2. 1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors",
abstract = "A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7- azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3′-(2-[ 18F]-fluoropyridin-5-yl))-5′-pyridinyl]-7-azabicyclo[2.2.1] heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.",
author = "Yongjun Gao and Andrew Horti and Hiroto Kuwabara and Ravert, {Hayden T.} and John Hilton and Daniel Holt and Anil Kumar and Mohab Alexander and Endres, {Christopher J.} and Wong, {Dean Foster} and Dannals, {Robert F}",
year = "2007",
month = "8",
day = "9",
doi = "10.1021/jm070224t",
language = "English (US)",
volume = "50",
pages = "3814--3824",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",

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TY - JOUR

T1 - Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2. 1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors

AU - Gao, Yongjun

AU - Horti, Andrew

AU - Kuwabara, Hiroto

AU - Ravert, Hayden T.

AU - Hilton, John

AU - Holt, Daniel

AU - Kumar, Anil

AU - Alexander, Mohab

AU - Endres, Christopher J.

AU - Wong, Dean Foster

AU - Dannals, Robert F

PY - 2007/8/9

Y1 - 2007/8/9

N2 - A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7- azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3′-(2-[ 18F]-fluoropyridin-5-yl))-5′-pyridinyl]-7-azabicyclo[2.2.1] heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.

AB - A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7- azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3′-(2-[ 18F]-fluoropyridin-5-yl))-5′-pyridinyl]-7-azabicyclo[2.2.1] heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.

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