Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]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 |
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| Institution: | 1. Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States;2. Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States;3. Program in Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, United States;4. Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, United States;5. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, United States;6. Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States;1. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6;2. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary;3. Egis Pharmaceuticals Plc., Chemical Research Division, PO Box 100, H-1475 Budapest, Hungary;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;3. Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt;1. Department of Chemistry, Faculty of Science University of Jiroft, Jiroft, 7867161167, Iran;2. Department of Chemistry, Shahid Bahonar University of Kerman, 76169, Kerman, Iran;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt;2. National Cancer Institute, Cairo University, Fom Elkhalig, Kasr Elaini St., Cairo 11796, Egypt;3. Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11787, Egypt;1. School of Chemical Engineering, Hanoi University of Science and Technology, 1 Dai Co Viet Road, Hanoi, Viet Nam;2. National Institute of Hygiene and Epidemiology, 1 Yersin Street, Hanoi, Viet Nam;3. Research Center for Environmental Technology and Sustainable Development, Hanoi University of Science, 334 Nguyen Trai Street, Hanoi, Viet Nam;4. Department of Industrial Engineering and BIOtech Research Centre, University of Trento, Via Mesiano, 77, I-38123 Trento, Italy |
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| Abstract: | A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino4,5-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-pyridazino4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (18F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino4,5-b]indole-1-acetamide (18F]-14) in high radiochemical yield and specific activity. In vivo studies of 18F]-14 revealed this agent as a promising probe for molecular imaging of glioma. |
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| Keywords: | TSPO Glioma PET Fluorine-18 SSR180575 |
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