Synthesis and preliminary evaluation of [¹⁸F]-labeled 2-oxoquinoline derivatives for PET imaging of cannabinoid CB₂ receptor

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• 作者：Nashaat Turkman ; Aleksander Shavrin ; Vincenzo Paolillo ; Hsin Hsien Yeh ; Leo Flores ; Suren Soghomonian ; Brian Rabinovich ; Andrei Volgin ; Juri Gelovani ; Mian Alauddin ; ^{alauddin@mdanderson.org}
• 关键词：Cannabinoid receptor CB2 ; [18F]-2-oxoquinoline derivatives ; Positron emission tomography
• 刊名：Nuclear Medicine and Biology
• 出版年：2012
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：May, 2012
• 卷：39
• 期：4
• 页码：593-600
• 文件大小：556 K

摘要

Introduction

The cannabinoid receptor type 2 (CB₂) is an important target for development of drugs and imaging agents for diseases, such as neuroinflammation, neurodegeneration and cancer. Recently, we reported synthesis and results of in vitro receptor binding of a focused library of fluorinated 2-oxoquinoline derivatives as CB₂ receptor ligands. Some of the compounds demonstrated to be good CB₂-specific ligands with Ki values in the nanomolar to subnanomolar concentrations; therefore, we pursued the development of their ¹⁸F-labeled analogues that should be useful for positron emission tomography (PET) imaging of CB₂ receptor expression. Here, we report the radiosynthesis of two ¹⁸F-labeled 2-oxoquinoline derivatives and the preliminary in vitro and ex vivo evaluation of one compound as a CB₂-specific radioligand.

Methods

4-[¹⁸F]fluorobenzyl amine [¹⁸F]-3 was prepared by radiofluorination of 4-cyano-N,N,N-trimethylanilinium triflate salt followed by reduction with LiAlH₄ and then coupled with acid chlorides 11 and 12 to afford [¹⁸F]-13 and [¹⁸F]-14. In vitro CB₂ receptor binding assay was performed using U87 cells transduced with CB₂ and CB₁ receptor. Ex vivo autoradiography was performed with [¹⁸F]-14 on spleen and on CB₂- and CB₁-expressing and wild-type U87 subcutaneous tumors grown in mice.

Results

The radiochemical yields of [¹⁸F]-13 and [¹⁸F]-14 were 10%-15.0%with an average of 12%(n=10); radiochemical purity was >99%with specific activity 1200 mCi/渭mol. The dissociation constant Kd for [¹⁸F]-14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [¹⁸F]-14 in the CB₂-expressing tumor.

Conclusion

Two new [¹⁸F]-labeled CB₂ ligands have been synthesized. Compound [¹⁸F]-14 appears to be a potential PET imaging agent for the assessment of CB₂ receptor expression; however, poor solubility restrain its use in vivo.