Limits...
Convergent synthesis and evaluation of (18)F-labeled azulenic COX2 probes for cancer imaging.

Nolting DD, Nickels M, Tantawy MN, Yu JY, Xie J, Peterson TE, Crews BC, Marnett L, Gore JC, Pham W - Front Oncol (2013)

Bottom Line: After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis.This observation was supported after successfully using an (18)F labeling strategy that employed a much milder phosphate buffer.A biodistribution study and Western blot analysis corroborate with the imaging data.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Institute of Imaging Science, Vanderbilt University Nashville, TN, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

The design of a convergent synthesis approach to develop an azulene-based 18F-COX2 probe 13 and its related precursors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3539664&req=5

Figure 1: The design of a convergent synthesis approach to develop an azulene-based 18F-COX2 probe 13 and its related precursors.

Mentions: Herein, we describe a novel chemistry approach that uses a convergent synthesis methodology to develop azulene-based COX2 PET probes. Of note, we synthesized the main azulene ring using the procedure we reported previously (Pham et al., 2002; Nolting et al., 2009). The two other ring structures were assembled onto the azulene ring using commercially available analogs. To retain the biological activity as reported by Tomiyama et al. (1999), we designed the precursors specifically with 18F fluoride labeling in mind. Not only do we prefer this isotope due to its relatively long half-life, but also because replacing a hydrogen atom with a fluorine is likely to not affect biological activity since they are very similar sterically (Jalilian et al., 2000; Mueller et al., 2007). We also report herein, to our knowledge, the first time, a modified labeling condition that uses dipotassium phosphate (K2HPO4) for this family of compounds, which we found to be unstable using the conventional PET labeling process. Overall, the chemical yield of this 7-step synthesis of the nitro precursor 12 (Figure 1) is 25%. The biodistribution results and small animal PET imaging demonstrate the potential use of the 18F-COX2 probe in breast cancer imaging.


Convergent synthesis and evaluation of (18)F-labeled azulenic COX2 probes for cancer imaging.

Nolting DD, Nickels M, Tantawy MN, Yu JY, Xie J, Peterson TE, Crews BC, Marnett L, Gore JC, Pham W - Front Oncol (2013)

The design of a convergent synthesis approach to develop an azulene-based 18F-COX2 probe 13 and its related precursors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539664&req=5

Figure 1: The design of a convergent synthesis approach to develop an azulene-based 18F-COX2 probe 13 and its related precursors.
Mentions: Herein, we describe a novel chemistry approach that uses a convergent synthesis methodology to develop azulene-based COX2 PET probes. Of note, we synthesized the main azulene ring using the procedure we reported previously (Pham et al., 2002; Nolting et al., 2009). The two other ring structures were assembled onto the azulene ring using commercially available analogs. To retain the biological activity as reported by Tomiyama et al. (1999), we designed the precursors specifically with 18F fluoride labeling in mind. Not only do we prefer this isotope due to its relatively long half-life, but also because replacing a hydrogen atom with a fluorine is likely to not affect biological activity since they are very similar sterically (Jalilian et al., 2000; Mueller et al., 2007). We also report herein, to our knowledge, the first time, a modified labeling condition that uses dipotassium phosphate (K2HPO4) for this family of compounds, which we found to be unstable using the conventional PET labeling process. Overall, the chemical yield of this 7-step synthesis of the nitro precursor 12 (Figure 1) is 25%. The biodistribution results and small animal PET imaging demonstrate the potential use of the 18F-COX2 probe in breast cancer imaging.

Bottom Line: After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis.This observation was supported after successfully using an (18)F labeling strategy that employed a much milder phosphate buffer.A biodistribution study and Western blot analysis corroborate with the imaging data.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Institute of Imaging Science, Vanderbilt University Nashville, TN, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus