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 ((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.
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Dewei
authors.initials: D
authors.lastname: Tang
authors.forename: Eliot T
authors.initials: ET
authors.lastname: McKinley
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hight
authors.forename: Md Imam
authors.initials: MI
authors.lastname: Uddin
authors.forename: Joel M
authors.initials: JM
authors.lastname: Harp
authors.forename: Allie
authors.initials: A
authors.lastname: Fu
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickels
authors.forename: Jason R
authors.initials: JR
authors.lastname: Buck
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods; D011720:Pyrazoles / Q000138:chemical synthesis*; D011743:Pyrimidines / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C581990:2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo(1,5-a)pyrimidin-3-yl)-N,N-diethylacetamide; D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human