Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO)

Samuel D Banister; Corinne Beinat; Shane M Wilkinson; Bin Shen; Cecilia Bartoli; Silvia Selleri; Eleonora Da Pozzo; Claudia Martini; Frederick T Chin; Michael Kassiou

doi:10.1016/j.ejmech.2015.02.004

Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO)

Eur J Med Chem. 2015 Mar 26:93:392-400. doi: 10.1016/j.ejmech.2015.02.004. Epub 2015 Feb 7.

Authors

Affiliations

¹ Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
² School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
³ Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Pharmaceutical Sciences, University of Florence, Via U. Schiff, 650019 Polo Scientifico Sesto Fiorentino, Italy.
⁵ Department of Pharmacy, University of Pisa, Via Bonanno 6, 56127 Pisa, Italy.
⁶ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 25725375
DOI: 10.1016/j.ejmech.2015.02.004

Abstract

Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay.

Keywords: DPA-714; Positron emission tomography; Pyrazolo[1,5-a]pyrimidine; Steroid; Translocator protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemistry
Acetamides / metabolism
Animals
Carrier Proteins / metabolism*
Cell Line, Tumor
Ethers / chemistry*
Protein Binding
Pyrazoles / chemistry*
Pyrazoles / metabolism*
Pyrimidines / chemistry*
Pyrimidines / metabolism*
Rats
Receptors, GABA-A / metabolism*

Substances

Acetamides
Carrier Proteins
Ethers
N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide
N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide
Pyrazoles
Pyrimidines
Receptors, GABA-A
Tspo protein, rat