Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: Discovery of a novel TSPO PET ligand for cancer imaging

Dewei Tang; Eliot T. McKinley; Matthew R. Hight; Md Imam Uddin; Joel M. Harp; Allie Fu; Michael L. Nickels; Jason R. Buck; H. Charles Manning

doi:10.1021/jm4001874

Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: Discovery of a novel TSPO PET ligand for cancer imaging

Dewei Tang, Eliot T. McKinley, Matthew R. Hight, Md Imam Uddin, Joel M. Harp, Allie Fu, Michael L. Nickels, Jason R. Buck, H. Charles Manning

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

43 Scopus citations

Abstract

Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N, N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (¹⁸F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[¹⁸F]fluoroethoxy) phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (¹⁸F-6b) in high radiochemical yield and specific activity. In vivo studies of ¹⁸F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

Original language	English (US)
Pages (from-to)	3429-3433
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	8
DOIs	https://doi.org/10.1021/jm4001874
State	Published - Apr 25 2013
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: Discovery of a novel TSPO PET ligand for cancer imaging",

abstract = "Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N, N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (18F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy) phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18F-6b) in high radiochemical yield and specific activity. In vivo studies of 18F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.",

author = "Dewei Tang and McKinley, {Eliot T.} and Hight, {Matthew R.} and Uddin, {Md Imam} and Harp, {Joel M.} and Allie Fu and Nickels, {Michael L.} and Buck, {Jason R.} and Manning, {H. Charles}",

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T2 - Discovery of a novel TSPO PET ligand for cancer imaging

AU - Tang, Dewei

AU - McKinley, Eliot T.

AU - Hight, Matthew R.

AU - Uddin, Md Imam

AU - Harp, Joel M.

AU - Fu, Allie

AU - Nickels, Michael L.

AU - Buck, Jason R.

AU - Manning, H. Charles

PY - 2013/4/25

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N2 - Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N, N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (18F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy) phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18F-6b) in high radiochemical yield and specific activity. In vivo studies of 18F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

AB - Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N, N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (18F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy) phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18F-6b) in high radiochemical yield and specific activity. In vivo studies of 18F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

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Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: Discovery of a novel TSPO PET ligand for cancer imaging

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