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

Tang D, McKinley ET, Hight MR, Uddin MI, Harp JM, Fu A, Nickels ML, Buck JR, Manning HC
J Med Chem. 2013 56 (8): 3429-33

PMID: 23521048 · PMCID: PMC3648642 · DOI:10.1021/jm4001874

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 ((18)F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ((18)F-6b) in high radiochemical yield and specific activity. In vivo studies of (18)F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

MeSH Terms (11)

Animals Biomarkers, Tumor Fluorine Radioisotopes Humans Positron-Emission Tomography Pyrazoles Pyrimidines Radiopharmaceuticals Rats Receptors, GABA Structure-Activity Relationship

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