5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography

Yi Zhang; Olga A. Pavlova; Svetlana I. Chefer; Andrew W. Hall; Varughese Kurian; La Verne L. Brown; Alane S. Kimes; Alexey G. Mukhin; Andrew G. Horti

doi:10.1021/jm030432v

5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography

Yi Zhang, Olga A. Pavlova, Svetlana I. Chefer, Andrew W. Hall, Varughese Kurian, La Verne L. Brown, Alane S. Kimes, Alexey G. Mukhin, Andrew G. Horti

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

55 Scopus citations

Abstract

Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from - 1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[¹⁸F]fluoro-5-(pyridin-3-yl)-A-85380 ([¹⁸F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[ ¹⁸F]fluoropyridin-5-yl)pyridine) ([¹⁸F]35), were radiolabeled with ¹⁸F. Comparison of PET data for [¹⁸F]31 and 2-[¹⁸F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [¹⁸F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[¹⁸F]FA. Therefore, [¹⁸F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

Original language	English (US)
Pages (from-to)	2453-2465
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	47
Issue number	10
DOIs	https://doi.org/10.1021/jm030432v
State	Published - May 6 2004
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Zhang, Y., Pavlova, O. A., Chefer, S. I., Hall, A. W., Kurian, V., Brown, L. V. L., Kimes, A. S., Mukhin, A. G., & Horti, A. G. (2004). 5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography. Journal of medicinal chemistry, 47(10), 2453-2465. https://doi.org/10.1021/jm030432v

5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity : Potential Probes for Imaging with Positron Emission Tomography. / Zhang, Yi; Pavlova, Olga A.; Chefer, Svetlana I. et al.

In: Journal of medicinal chemistry, Vol. 47, No. 10, 06.05.2004, p. 2453-2465.

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

Zhang, Y, Pavlova, OA, Chefer, SI, Hall, AW, Kurian, V, Brown, LVL, Kimes, AS, Mukhin, AG & Horti, AG 2004, '5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography', Journal of medicinal chemistry, vol. 47, no. 10, pp. 2453-2465. https://doi.org/10.1021/jm030432v

Zhang Y, Pavlova OA, Chefer SI, Hall AW, Kurian V, Brown LVL et al. 5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography. Journal of medicinal chemistry. 2004 May 6;47(10):2453-2465. doi: 10.1021/jm030432v

Zhang, Yi ; Pavlova, Olga A. ; Chefer, Svetlana I. et al. / 5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity : Potential Probes for Imaging with Positron Emission Tomography. In: Journal of medicinal chemistry. 2004 ; Vol. 47, No. 10. pp. 2453-2465.

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title = "5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography",

abstract = "Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from - 1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[18F]fluoro-5-(pyridin-3-yl)-A-85380 ([18F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[ 18F]fluoropyridin-5-yl)pyridine) ([18F]35), were radiolabeled with 18F. Comparison of PET data for [18F]31 and 2-[18F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [18F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[18F]FA. Therefore, [18F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.",

author = "Yi Zhang and Pavlova, {Olga A.} and Chefer, {Svetlana I.} and Hall, {Andrew W.} and Varughese Kurian and Brown, {La Verne L.} and Kimes, {Alane S.} and Mukhin, {Alexey G.} and Horti, {Andrew G.}",

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doi = "10.1021/jm030432v",

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T1 - 5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity

T2 - Potential Probes for Imaging with Positron Emission Tomography

AU - Zhang, Yi

AU - Pavlova, Olga A.

AU - Chefer, Svetlana I.

AU - Hall, Andrew W.

AU - Kurian, Varughese

AU - Brown, La Verne L.

AU - Kimes, Alane S.

AU - Mukhin, Alexey G.

AU - Horti, Andrew G.

PY - 2004/5/6

Y1 - 2004/5/6

N2 - Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from - 1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[18F]fluoro-5-(pyridin-3-yl)-A-85380 ([18F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[ 18F]fluoropyridin-5-yl)pyridine) ([18F]35), were radiolabeled with 18F. Comparison of PET data for [18F]31 and 2-[18F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [18F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[18F]FA. Therefore, [18F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

AB - Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from - 1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[18F]fluoro-5-(pyridin-3-yl)-A-85380 ([18F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[ 18F]fluoropyridin-5-yl)pyridine) ([18F]35), were radiolabeled with 18F. Comparison of PET data for [18F]31 and 2-[18F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [18F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[18F]FA. Therefore, [18F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

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