Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO).
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.
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Samuel D
SD
Banister
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Corinne
C
Beinat
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Shane M
SM
Wilkinson
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Bin
B
Shen
Department of Pharmaceutical Sciences, University of Florence, Via U. Schiff, 650019 Polo Scientifico Sesto Fiorentino, Italy.
Cecilia
C
Bartoli
Department of Pharmaceutical Sciences, University of Florence, Via U. Schiff, 650019 Polo Scientifico Sesto Fiorentino, Italy.
Silvia
S
Selleri
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56127 Pisa, Italy.
Eleonora
E
Da Pozzo
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56127 Pisa, Italy.
Claudia
C
Martini
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Frederick T
FT
Chin
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.
Michael
M
Kassiou
D000081:Acetamides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004987:Ethers / Q000737:chemistry*; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*
D000081:Acetamides; D002352:Carrier Proteins; D004987:Ethers; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; C507091:N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat
DPA-714; Positron emission tomography; Pyrazolo[1,5-a]pyrimidine; Steroid; Translocator protein