title: New structure-activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO.
abstract: Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine.
authors.affiliation: Interdisciplinary Materials Science Program, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schulte
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickels
authors.affiliation: Interdisciplinary Materials Science Program, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Program in Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, United States; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: henry.c.manning@vanderbilt.edu.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D018079:Receptors, GABA; C499229:TSPO protein, human; C000606692:pyrazolylpyrimidine; C030686:acetamide
keywords: Cancer; Precision medicine; Pyrazolopyrimidine; SAR; TSPO