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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Cheung, Yiu-Yin¹  Nickels, Michael L.^1,2  Tang, Dewei^1,2  Buck, Jason R.^1,2  Manning, H. Charles^1,2,3,4,5,6 

[1] Vanderbilt Univ, Med Ctr, Inst Imaging Sci VUIIS, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Program Chem & Phys Biol, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Dept Neurosurg, Nashville, TN 37232 USA

关键词: TSPO;    Glioma;    PET;    Fluorine-18;    SSR180575;   

DOI  :  10.1016/j.bmcl.2014.07.091

来源: Elsevier

【 摘 要 】

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 (F-18) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[F-18]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([F-18]-14) in high radiochemical yield and specific activity. In vivo studies of [F-18]-14 revealed this agent as a promising probe for molecular imaging of glioma. (C) 2014 Elsevier Ltd. All rights reserved.

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