Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

Yiu Yin Cheung; Michael L. Nickels; Dewei Tang; Jason R. Buck; H. Charles Manning

doi:10.1016/j.bmcl.2014.07.091

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

Yiu Yin Cheung, Michael L. Nickels, Dewei Tang, Jason R. Buck, H. Charles Manning

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

22 Scopus citations

Abstract

A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure-activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (¹⁸F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([¹⁸F]-14) in high radiochemical yield and specific activity. In vivo studies of [¹⁸F]-14 revealed this agent as a promising probe for molecular imaging of glioma.

Original language	English (US)
Pages (from-to)	4466-4471
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2014.07.091
State	Published - Sep 15 2014
Externally published	Yes

Keywords

Fluorine-18
Glioma
PET
SSR180575
TSPO

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Cheung, Y. Y., Nickels, M. L., Tang, D., Buck, J. R., & Manning, H. C. (2014). Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. Bioorganic and Medicinal Chemistry Letters, 24(18), 4466-4471. https://doi.org/10.1016/j.bmcl.2014.07.091

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. / Cheung, Yiu Yin; Nickels, Michael L.; Tang, Dewei et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 18, 15.09.2014, p. 4466-4471.

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

Cheung, YY, Nickels, ML, Tang, D, Buck, JR & Manning, HC 2014, 'Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 18, pp. 4466-4471. https://doi.org/10.1016/j.bmcl.2014.07.091

Cheung YY, Nickels ML, Tang D, Buck JR, Manning HC. Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. Bioorganic and Medicinal Chemistry Letters. 2014 Sep 15;24(18):4466-4471. doi: 10.1016/j.bmcl.2014.07.091

Cheung, Yiu Yin ; Nickels, Michael L. ; Tang, Dewei et al. / Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 18. pp. 4466-4471.

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title = "Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer",

abstract = "A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure-activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (18F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([18F]-14) in high radiochemical yield and specific activity. In vivo studies of [18F]-14 revealed this agent as a promising probe for molecular imaging of glioma.",

keywords = "Fluorine-18, Glioma, PET, SSR180575, TSPO",

author = "Cheung, {Yiu Yin} and Nickels, {Michael L.} and Dewei Tang and Buck, {Jason R.} and Manning, {H. Charles}",

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AU - Cheung, Yiu Yin

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AU - Buck, Jason R.

AU - Manning, H. Charles

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