Abstract 5585: Development and validation of the specificity of a novel azulene-based COX2 probe for cancer imaging.
Authors: Pham Wellington , Nolting Donald D. , Kumar Dileep J.S. , Mann John J. , Tantawy Mohammed N. , Peterson Todd E. , Marnett Larry , Gore John C. 
Published: August 2014

The overall objectives of this research are to (i) develop azulene-based 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 18F-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 18F 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 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer preclinical 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, using the PET probe and Western blot analysis corroborate with the imaging data. Taken together, these data demonstrate the potential for the use of this novel PET probe for imaging COX2 as a biomarker for the early detection and prediction of the progression of colorectal cancer. Currently, several probe optimization processes are presently being carried out in our laboratory, including the toxicity study and in vivo metabolite analysis. Detailed results of the biometric validation of the probe will be reported in a timely manner. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further investigation.

Citation Format: Wellington Pham, Donald D. Nolting, Dileep J.S. Kumar, John J. Mann, Mohammed N. Tantawy, Todd E. Peterson, Larry Marnett, John C. Gore. Development and validation of the specificity of a novel azulene-based COX2 probe for cancer imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5585. doi:10.1158/1538-7445.AM2013-5585