Synthesis and Evaluation of Three 18F-Labeled Aminophenylbenzothiazoles as Amyloid Imaging Agents

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• 作者：Kim Serdons ; Koen Van Laere ; Peter Janssen ; Hank F. Kung ; Guy Bormans ; Alfons Verbruggen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7090-7102
• 全文大小：1186K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

We have developed three fluorine-18 labeled 6-(methyl)amino-2-(4′-fluorophenyl)-1,3-benzothiazoles, which display high in vitro binding affinity for human amyloid β plaques (K_i ≤ 10 nM). The radiolabeled probes were synthesized by aromatic nucleophilic substitution of the corresponding nitro precursor with ¹⁸F-fluoride, followed by deprotection of the BOC group if required. Determination of the octanol/water partition coefficient, biodistribution studies in mice, and in vivo μPET studies in rats and a rhesus monkey showed that initial brain uptake was high and brain washout was fast in normal animals. Radiometabolites were quantified in plasma and brain of mice and in monkey plasma using HPLC. Of the tested compounds, [¹⁸F]2 (6-amino-2-(4′-[¹⁸F]fluorophenyl)-1,3-benzothiazole) shows the most favorable brain kinetics in mice, rats, and a monkey. Its polar plasma radiometabolites do not cross the blood−brain barrier. The preliminary results strongly suggest that this new fluorinated compound is a promising candidate as a PET brain amyloid imaging agent.