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Abstract: Direct fluorination at the 2′-arabino-position of a pyrimidine nucleoside has been a long-standing challenge, yet we recently reported such a stereospecific fluorination for the first time in the synthesis of [18F]FMAU, albeit in low yields. Herein we report the results of an investigation on stereospecific fluorination on a variety of precursors for synthesis of [18F]FMAU. Several precursors were synthesized in multiple steps and fluorination was performed at the 2′-arabino-position using K[18F]/kryptofix 2.2.2. All precursors produced [18F]FMAU in low yields. [Copyright &y& Elsevier]

Abstract: 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/μmol. 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. [Copyright &y& Elsevier]

Abstract: Cannabinoid receptor 2 (CB2) plays an important role in human physiology and the pathophysiology of different diseases, including neuroinflammation, neurodegeneration, and cancer. Several classes of CB2 receptor ligands, including 2-oxoquinoline derivatives, have been previously reported. We report the synthesis and results of in vitro receptor binding of a focused library of new fluorinated 2-oxoquinoline CB2 ligands. Twelve compounds, 13–16 18, 19, 21–24, 27, and 28 were synthesized in good yields in multiple steps. Human U87 glioma cells expressing either hCB1 (control) or hCB2 were generated via lentiviral transduction. In vitro competitive binding assay was performed using [3H]CP-55,940 in U87hCB1 and U87hCB2 cells. Inhibition constant (K i) values of compounds 13–16, 18, 19, 21–24, 27, and 28 for CB2 were >10,000, 2.8, 5.0, 2.4, 22, 0.8, 1.4, >10,000, 486, 58, 620, and 2400nM, respectively, and those for CB1 were >10,000nM. Preliminary in vitro results suggest that six of these compounds may be useful for therapy of neuropathic pain, neuroinflammatory diseases and immune disorders. In addition, compound 19, with its subnanomolar K i value, could be radiolabeled with 18F and explored for PET imaging of CB2 expression. [Copyright &y& Elsevier]

Herein, we describe the design, synthesis and deciphering of the key characteristics of the structure activity relationship (SAR) of trifluoromethyloxadiazole (TFMO) bearing class-IIa HDAC inhibitors. Our medicinal chemistry campaign of 23 compounds identified compound 1 as a highly potent inhibitor with sub nM affinity to class-IIa HDAC4 isoform. Therefore, We radiolabeled compound 1 (named thereafter as NT160) with [18F]fluoride thus producing the identical [ 18 F]-NT160 as a diagnostic tool for positron emission tomography (PET). [ 18 F]-NT160 was produced in high radiochemical purity (>95%), moderate radiochemical yield (2–5%) and moderate molar activity in the range of 0.30–0.85 GBq/umol (8.0–23.0 mCi/umol). We also established that [ 18 F]-NT160 can cross the blood brain barrier and bind to class-IIa HDACs in vivo. The combination of [ 18 F]-NT160 and 1 represent a novel theranostic pair using the same molecule to enable diagnostic PET imaging with [ 18 F]-NT160 followed by targeted therapy with NT160. [Display omitted] • Class-IIa HDAC dysregulation in the brain is relevant to cancer and the disorders of the central nervous system. • NT160 is a small molecule with sub-to-low nM affinity to all class-IIa HDAC isoforms. • NT160 inhibited the activity of class-IIa HDACs in human colon cancer cells HT-29 with low nM affinity. • PET imaging with [18F]-NT160 demonstrated brain entry and excellent pharmacokinetic profile for in vivo imaging. [ABSTRACT FROM AUTHOR]