New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

Yongjun Gao; Andrew G. Horti; Hiroto Kuwabara; Hayden T. Ravert; Daniel P. Holt; Anil Kumar; Mohab Alexander; Dean F. Wong; Robert F. Dannals

doi:10.1016/j.bmcl.2008.10.012

New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

Yongjun Gao
, Andrew G. Horti
, Hiroto Kuwabara
, Hayden T. Ravert
, Daniel P. Holt
, Anil Kumar
, Mohab Alexander
, Dean F. Wong
, Robert F. Dannals

Precision Radiotheranostics Translation Center (PRTC)

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

8 Scopus citations

Abstract

A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, K_i = 2310, 1680 pM; (-)-NMI-EPB, K_i = 55, 68 pM). The enantiomers were stereoselectively radiolabeled with ¹¹C. In the distribution studies in the rodent brain [¹¹C](-)-NMI-EPB specifically labeled nAChR whereas [¹¹C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [¹¹C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

Original language	English
Pages (from-to)	6168-6170
Number of pages	3
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2008.10.012
State	Published - Dec 1 2008

Keywords

C-11
Enantiomers
Positron emission tomography (PET)
nAChR

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10.1016/j.bmcl.2008.10.012

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Gao, Y., Horti, A. G., Kuwabara, H., Ravert, H. T., Holt, D. P., Kumar, A., Alexander, M., Wong, D. F., & Dannals, R. F. (2008). New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors. Bioorganic and Medicinal Chemistry Letters, 18(23), 6168-6170. https://doi.org/10.1016/j.bmcl.2008.10.012

@article{7c33c0f252284eb4974a5081dab102dc,

title = "New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors",

abstract = "A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, Ki = 2310, 1680 pM; (-)-NMI-EPB, Ki = 55, 68 pM). The enantiomers were stereoselectively radiolabeled with 11C. In the distribution studies in the rodent brain [11C](-)-NMI-EPB specifically labeled nAChR whereas [11C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [11C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.",

keywords = "C-11, Enantiomers, Positron emission tomography (PET), nAChR",

author = "Yongjun Gao and Horti, \{Andrew G.\} and Hiroto Kuwabara and Ravert, \{Hayden T.\} and Holt, \{Daniel P.\} and Anil Kumar and Mohab Alexander and Wong, \{Dean F.\} and Dannals, \{Robert F.\}",

note = "Funding Information: The authors thank Dr. Ursula Scheffel and Paige Finley for their valuable help with the animal experiments, Robert C. Smoot for radiochemistry assistance. We thank Dr. Richard Wahl for fruitful discussions and support. This research was supported in part by the Division of Nuclear Medicine of Johns Hopkins University School of Medicine. ",

year = "2008",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2008.10.012",

language = "English",

volume = "18",

pages = "6168--6170",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Gao, Y, Horti, AG, Kuwabara, H, Ravert, HT, Holt, DP, Kumar, A, Alexander, M, Wong, DF & Dannals, RF 2008, 'New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 23, pp. 6168-6170. https://doi.org/10.1016/j.bmcl.2008.10.012

New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors. / Gao, Yongjun; Horti, Andrew G.; Kuwabara, Hiroto et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 23, 01.12.2008, p. 6168-6170.

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

TY - JOUR

T1 - New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

AU - Gao, Yongjun

AU - Horti, Andrew G.

AU - Kuwabara, Hiroto

AU - Ravert, Hayden T.

AU - Holt, Daniel P.

AU - Kumar, Anil

AU - Alexander, Mohab

AU - Wong, Dean F.

AU - Dannals, Robert F.

N1 - Funding Information: The authors thank Dr. Ursula Scheffel and Paige Finley for their valuable help with the animal experiments, Robert C. Smoot for radiochemistry assistance. We thank Dr. Richard Wahl for fruitful discussions and support. This research was supported in part by the Division of Nuclear Medicine of Johns Hopkins University School of Medicine.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, Ki = 2310, 1680 pM; (-)-NMI-EPB, Ki = 55, 68 pM). The enantiomers were stereoselectively radiolabeled with 11C. In the distribution studies in the rodent brain [11C](-)-NMI-EPB specifically labeled nAChR whereas [11C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [11C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

AB - A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, Ki = 2310, 1680 pM; (-)-NMI-EPB, Ki = 55, 68 pM). The enantiomers were stereoselectively radiolabeled with 11C. In the distribution studies in the rodent brain [11C](-)-NMI-EPB specifically labeled nAChR whereas [11C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [11C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

KW - C-11

KW - Enantiomers

KW - Positron emission tomography (PET)

KW - nAChR

UR - https://www.scopus.com/pages/publications/55549115005

U2 - 10.1016/j.bmcl.2008.10.012

DO - 10.1016/j.bmcl.2008.10.012

M3 - Article

C2 - 18930397

AN - SCOPUS:55549115005

SN - 0960-894X

VL - 18

SP - 6168

EP - 6170

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

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