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Synthesis and in vitro evaluation of N-substituted aza-trozamicol analogs as vesicular acetylcholine transporter ligands
Authors:Assaad Thaer  Mavel Sylvie  Parsons Stanley M  Kruse Shane  Galineau Laurent  Allouchi Hassan  Kassiou Michael  Chalon Sylvie  Guilloteau Denis  Emond Patrick
Affiliation:1. Université François-Rabelais de Tours, 37200 Tours, France;2. INSERM U619, 37044 Tours Cdx 09, CHRU, Hôpital Bretonneau, 37044 Tours, France;3. University of California, Department of Chemistry and Biochemistry, Santa Barbara, CA 93106, USA;4. Université François-Rabelais de Tours, Laboratoire de Chimie Physique, 31 av. Monge, 37200 Tours, France;5. Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Sydney 2050, Australia;6. Department of Pharmacology, University of Sydney, NSW 2006, Australia;1. Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL;2. Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL;1. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People’s Republic of China;2. Huaihe Hospital, Henan University, Kaifeng 475000, People’s Republic of China;3. Institute of Chemical Biology, Henan University, Kaifeng 475004, People’s Republic of China;1. Second Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, China;2. School of Chinese Pharmaceutical Science, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, China;1. College of Life Sciences, Henan Agricultural University, 95 Wenhua Road, Zhengzhou 450002, China;2. Key Laboratory of Enzyme Engineering of Agricultural Microbiology, Ministry of Agriculture, Henan Agriculture University, Henan 450002, China;3. College of Chemistry and Molecular Engineering, Tsinghua University, Beijing 100871, China
Abstract:As dysfunction of cerebral cholinergic neurotransmission is one of the main features in patients with Alzheimer's disease, in vivo imaging of the vesicular acetylcholine transporter (VAChT) can be of great value for the early diagnosis of this disease. Two series of positional isomers of m-iodobenzyltrozamicol (MIBT): 3-hydroxy-4-(N-phenylpiperazinyl)piperidine and 4-hydroxy-3-(N-phenylpiperazinyl)piperidine substituted by benzyl, aryl, alkyl or vinyl groups at the nitrogen have been synthesized. These compounds have been evaluated in vitro by competition studies and five compounds (N-benzyl derivatives) showed high affinity for the VAChT (11nM
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