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

Introduction: The cannabinoid receptor type 2 (CB2) is an important target for development of drugs and imagine 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 F-18-labeled analogues that should be useful for positron emission tomography (PET) imagine of CB, receptor expression. Here, we report the radiosynthesis of two E-18-labeled 2-oxoquinoline derivatives and the preliminary in vitro and ex vivo evaluation of one compound as a CB2-specific radioligand. Methods: 4-[F-18]fluorobenzyl amine [F-18]-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 [F-18]-13 and [F-18]-14. In vitro CB2 receptor binding assay was performed using U87 cells transduced with CB2 and CB1 receptor. Ex vivo autoradiography was performed with [F-18]-14 on spleen and on CB2- and CB1-expressing and wild-type U87 subcutaneous tumors grown in mice. Results: The radiochemical yields of [E-18]-13 and [F-18]-14 were 10%-15.0% with an average of 12% (n=10); radiochemical purity was >99% with specific activity 1200 mCi/mu mol. The dissociation constant Kd for [F-18]-14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [F-18]-14 in the CB2-expressing tumor. Conclusion: Two new [F-18]-labeled CB2 ligands have been synthesized. Compound [E-18]-14 appears to be a potential PET imaging agent for the assessment of CB2 receptor expression; however, poor solubility restrain its use in vivo. (C) 2012 Elsevier Inc. All rights reserved.