Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity

Hong Fan; Evangelia Kotsikorou; Alexander F. Hoffman; Hayden T. Ravert; Daniel Holt; Dow P. Hurst; Carl R. Lupica; Patricia H. Reggio; Robert F. Dannals; Andrew G. Horti

doi:10.1016/j.ejmech.2008.03.040

Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity

Hong Fan, Evangelia Kotsikorou, Alexander F. Hoffman, Hayden T. Ravert, Daniel Holt, Dow P. Hurst, Carl R. Lupica, Patricia H. Reggio, Robert F. Dannals, Andrew G. Horti

School of Medicine

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

15 Scopus citations

Abstract

Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket.

Original language	English (US)
Pages (from-to)	593-608
Number of pages	16
Journal	European Journal of Medicinal Chemistry
Volume	44
Issue number	2
DOIs	https://doi.org/10.1016/j.ejmech.2008.03.040
State	Published - Feb 2009

Keywords

Cannabinoid receptor
Carbon-11
JHU75528
Molecular modeling
Positron emission tomography
Receptor docking
Rimonabant

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2008.03.040

Cite this

Fan, H., Kotsikorou, E., Hoffman, A. F., Ravert, H. T., Holt, D., Hurst, D. P., Lupica, C. R., Reggio, P. H., Dannals, R. F., & Horti, A. G. (2009). Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity. European Journal of Medicinal Chemistry, 44(2), 593-608. https://doi.org/10.1016/j.ejmech.2008.03.040

Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity. / Fan, Hong; Kotsikorou, Evangelia; Hoffman, Alexander F. et al.
In: European Journal of Medicinal Chemistry, Vol. 44, No. 2, 02.2009, p. 593-608.

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

Fan, H, Kotsikorou, E, Hoffman, AF, Ravert, HT, Holt, D, Hurst, DP, Lupica, CR, Reggio, PH, Dannals, RF & Horti, AG 2009, 'Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity', European Journal of Medicinal Chemistry, vol. 44, no. 2, pp. 593-608. https://doi.org/10.1016/j.ejmech.2008.03.040

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title = "Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity",

abstract = "Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket.",

keywords = "Cannabinoid receptor, Carbon-11, JHU75528, Molecular modeling, Positron emission tomography, Receptor docking, Rimonabant",

author = "Hong Fan and Evangelia Kotsikorou and Hoffman, {Alexander F.} and Ravert, {Hayden T.} and Daniel Holt and Hurst, {Dow P.} and Lupica, {Carl R.} and Reggio, {Patricia H.} and Dannals, {Robert F.} and Horti, {Andrew G.}",

note = "Funding Information: The authors are grateful to Ms. Paige Finley for the rodent experiments and Ms. Judy W. Buchanan for editorial work. This work was supported in part by NIH/NIMH grant MH-079017 (AGH) and NIH/NIDA Grants DA-03934 and DA-021358 (PHR).",

year = "2009",

month = feb,

doi = "10.1016/j.ejmech.2008.03.040",

language = "English (US)",

volume = "44",

pages = "593--608",

journal = "European Journal of Medicinal Chemistry",

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AU - Fan, Hong

AU - Kotsikorou, Evangelia

AU - Hoffman, Alexander F.

AU - Ravert, Hayden T.

AU - Holt, Daniel

AU - Hurst, Dow P.

AU - Lupica, Carl R.

AU - Reggio, Patricia H.

AU - Dannals, Robert F.

AU - Horti, Andrew G.

N1 - Funding Information: The authors are grateful to Ms. Paige Finley for the rodent experiments and Ms. Judy W. Buchanan for editorial work. This work was supported in part by NIH/NIMH grant MH-079017 (AGH) and NIH/NIDA Grants DA-03934 and DA-021358 (PHR).

PY - 2009/2

Y1 - 2009/2

N2 - Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket.

AB - Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket.

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KW - Carbon-11

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KW - Positron emission tomography

KW - Receptor docking

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Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): Development of ligands with optimized lipophilicity and binding affinity

Abstract

Keywords

ASJC Scopus subject areas

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