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      Drug Design, Development and Therapy (submit here)

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      Synthesis and evaluation of ortho-[ 18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging


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          An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development.


          The in vivo uptake of celecoxib was monitored with ortho-[ 18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[ 18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib.


          The IC 50 values were 0.039 μM and 0.024 μM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[ 18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[ 18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC 50 values of 0.5 μM and 46.5 μM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30–60 min after the administration of ortho-[ 18F]fluorocelecoxib through the tail vein. Study of ortho-[ 18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g).


          The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.

          Most cited references38

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          Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis.

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            Changing international trends in mortality rates for liver, biliary and pancreatic tumours.

            The age-standardized mortality rate for hepatocellular carcinoma is increasing in several countries. However, in England and Wales we previously reported an increase in mortality rates from intrahepatic cholangiocarcinoma. Trends in cholangiocarcinoma in most other industrialized countries are unknown. To further study trends in hepatobiliary and pancreatic tumours, we analysed mortality data from the United States, Japan, Australia and Europe. Age-standardized mortality rates for men and women for subcategories of liver tumours, tumours of the gall bladder and extrahepatic biliary tree and pancreas from 1979 to 1998 were obtained from the World Health Organization mortality database. We confirmed previously reported increases in hepatocellular carcinoma, but also found increases in other countries, particularly Australia (3-year average rise from 1.20 to 2.27, men). Mortality for intrahepatic cholangiocarcinoma increased in men in all countries studied, with the largest increases in Australia (from 0.10 to 0.70) and England and Wales (from 0.20 to 0.83). We present a hitherto unreported rise in age-standardized mortality rates from intrahepatic cholangiocarcinoma across four continents. The cause remains uncertain. An impact on the observed trends of improved diagnostic techniques and death certificate misclassification cannot be completely ruled out. Future research should include epidemiological studies to examine possible case-clustering and investigation of potential aetiological and host factors.
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              (18)F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography.

              Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β(+) decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for (18)F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to (18)F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing (18)F-incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for (18)F-fluorination. In this piece, we review all of the reactions known to date to install the (18)F substituent and other key (18)F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                24 May 2018
                : 12
                : 1467-1478
                [1 ]Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
                [2 ]Department of Surgery, Liver Research Center, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
                [3 ]Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
                [4 ]Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan
                [5 ]Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan
                [6 ]Department of Neurosurgery, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
                [7 ]Institute of Nuclear Engineering and Science, National Tsinghua University, Hsinchu, Taiwan
                Author notes
                Correspondence: Chung-Shan Yu, Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu 300, Taiwan, Email csyu@ 123456mx.nthu.edu.tw

                These authors contributed equally to this work

                © 2018 Chang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine
                celecoxib, fluorination, imaging, nsaids, blocking, pet


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