CONVERGENT SYNTHESIS AND EVALUATION OF 18F-LABELED AZULENIC COX2 PROBES FOR CANCER IMAGING
| Autor: | John C. Gore, Michael L. Nickels, Mohammed N. Tantawy, Lawrence J. Marnett, Todd E. Peterson, Brenda C. Crews, Jingping Xie, James Y. H. Yu, Wellington Pham, Donald D. Nolting |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Biodistribution Convergent synthesis lcsh:RC254-282 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine breast cancer In vivo medicine Original Research Article Azulene Thiazole 030304 developmental biology Cancer xenograft tumor 0303 health sciences medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tropolone Combinatorial chemistry 3. Good health Molecular Imaging PET chemistry Oncology 030220 oncology & carcinogenesis convergence synthesis Molecular imaging Preclinical imaging COX2 CT |
| Zdroj: | Frontiers in Oncology, Vol 2 (2013) Frontiers in Oncology |
| DOI: | 10.3389/fonc.2012.00207/full |
| Popis: | The overall objectives of this research are to (i) develop azulene-based positron emission tomography (PET) probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel (18)F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8 + 2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional (18)F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an (18)F labeling strategy that employed a much milder phosphate buffer. The (18)F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further investigation. |
| Databáze: | OpenAIRE |
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