title: Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[(18)F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer.
abstract: A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure-activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 ((18)F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[(18)F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([(18)F]-14) in high radiochemical yield and specific activity. In vivo studies of [(18)F]-14 revealed this agent as a promising probe for molecular imaging of glioma.
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Yiu-Yin
authors.initials: YY
authors.lastname: Cheung
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), 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: Vanderbilt University Institute of Imaging Science (VUIIS), 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: Dewei
authors.initials: D
authors.lastname: Tang
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), 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: Jason R
authors.initials: JR
authors.lastname: Buck
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), 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 Neurosurgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D005910:Glioma / Q000175:diagnosis*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D057054:Molecular Imaging; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000032:analysis* / Q000096:biosynthesis
chemical_list: C000596633:7-chloro-N,N,5-trimethyl-4-oxo-3(6-((18)F)fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino(4,5-b)indole-1-acetamide; D000081:Acetamides; D007211:Indoles; D008024:Ligands; D018079:Receptors, GABA; C456740:SSR180575; C499229:TSPO protein, human
keywords: Fluorine-18; Glioma; PET; SSR180575; TSPO