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

Introduction: The cannabinoid receptor type 2 (CB 2) 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 CB 2 receptor ligands. Some of the compounds demonstrated to be good CB 2-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 CB 2 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 CB 2-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 LiAlH 4 and then coupled with acid chlorides 11 and 12 to afford [ 18F]-13 and [ 18F]-14. In vitro CB 2 receptor binding assay was performed using U87 cells transduced with CB 2 and CB 1 receptor. Ex vivo autoradiography was performed with [ 18F]-14 on spleen and on CB 2- and CB 1-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/μmol. The dissociation constant Kd for [ 18F]-14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [ 18F]-14 in the CB 2-expressing tumor. Conclusion: Two new [ 18F]-labeled CB 2 ligands have been synthesized. Compound [ 18F]-14 appears to be a potential PET imaging agent for the assessment of CB 2 receptor expression; however, poor solubility restrain its use in vivo. © 2012 Elsevier Inc.