A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies

Ding, Yu‐Shin; Kil, Kun-Eek; Lin, Kuo-Shyan; Ma, Wei; Yokota, Yasuno; Carroll, Ivy

doi:10.1016/j.bmcl.2005.10.075

Cited by 22 publications

(11 citation statements)

References 26 publications

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“…Unlike any other nAChR radioligands that we are aware of, including the nAChR radioligands developed by our group (about 70) and others, (−)-7-methyl-2- exo -[3′-(6-[ 18 F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ 18 F](−)- 6c , exhibits a unique combination of the optimally rapid brain kinetics, favorable metabolic profile, and high BPs. For comparison, all nAChR radioligands previously developed by us and others with similarly rapid kinetics exhibited low BP – ,,, and, vice versa, radioligands with similarly high BP values were very “slow” . In addition to these excellent imaging properties [ 18 F](−)- 6c , an antagonist of α4β2-nAChR (Figure ), displays even fewer side effects in mice than 1 and 2 .…”

Section: Discussionmentioning

confidence: 99%

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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

et al. 2008

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Several isomers of 7-methyl-2-exo-([(18)F]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 beta-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 D7.4= 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-[(18)F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D 7.4 = 0.99) exhibited optimal brain kinetics. [(18)F](-)-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 alpha4beta2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)- 6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

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Section: Discussionmentioning

confidence: 99%

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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

et al. 2008

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“…Very recently, a new potent and selective nicotinic antagonist 97 entered development as a radioligand for PET and SPECT studies. [271] Keywords: neurodegenerative disorders · nicotinic ligands · nicotinic receptors · pain…”

Section: Wwwchemmedchemorgmentioning

confidence: 99%

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

et al. 2007

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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“…29, 30 The synthesis of these two compounds is shown in Scheme 9 29 and Scheme 10, 30 respectively. Treatment of 29 with hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium (0) yielded the trimethyltin precursor 34 .…”

Section: Synthesis Of 3′-substituted Deschloroepibatidine Analogsmentioning

confidence: 99%

Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

Carroll¹

2009

HETEROCYCLES

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In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200–400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine’s unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.

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A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies

Cited by 22 publications

References 26 publications

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

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A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies

Cited by 22 publications

References 26 publications

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-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

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-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

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

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Product

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Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-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