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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

19F-COX2 probe IC50 value determination using a colorimetric assay against DuP697, a known COX2 inhibitor in a 96-well plate format. Data represent two independent experiments.
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Figure 2: 19F-COX2 probe IC50 value determination using a colorimetric assay against DuP697, a known COX2 inhibitor in a 96-well plate format. Data represent two independent experiments.

Mentions: In addition to being synthesized for use in facilitating the confirmation of the 18F-labeled product, the cold compound 11 was also used to assess the IC50 value. The assay was performed using 10 duplicate concentrations in a range comparable to DuP697, a known COX2 inhibitor. As shown in Figure 2, the Hill slopes of the curves that represent 19F-COX2 and DuP697 are -0.62 and -1.0, respectively; suggesting the specificity of the synthesized PET probe for COX2. After taking the background signal into account, the IC50 value of the 19F-COX2 compound was 661 nM.


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)

19F-COX2 probe IC50 value determination using a colorimetric assay against DuP697, a known COX2 inhibitor in a 96-well plate format. Data represent two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: 19F-COX2 probe IC50 value determination using a colorimetric assay against DuP697, a known COX2 inhibitor in a 96-well plate format. Data represent two independent experiments.
Mentions: In addition to being synthesized for use in facilitating the confirmation of the 18F-labeled product, the cold compound 11 was also used to assess the IC50 value. The assay was performed using 10 duplicate concentrations in a range comparable to DuP697, a known COX2 inhibitor. As shown in Figure 2, the Hill slopes of the curves that represent 19F-COX2 and DuP697 are -0.62 and -1.0, respectively; suggesting the specificity of the synthesized PET probe for COX2. After taking the background signal into account, the IC50 value of the 19F-COX2 compound was 661 nM.

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