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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

Uptake (% injection dose/g tissue) of the 18F-COX2 probe 13 in non-fasted tumor-bearing mice (n = 3).
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Figure 5: Uptake (% injection dose/g tissue) of the 18F-COX2 probe 13 in non-fasted tumor-bearing mice (n = 3).

Mentions: To assess the specificity of the probes for the detection of COX2 expression, we performed in vivo PET imaging of non-fasted mice in which C57MG tumors had been implanted on the mammary fat pads. We monitored the distribution of the probe in breast cancer at several times after the intravenous bolus injection. The optimal emission data were collected during a static, whole-body scan 150 min after administration of the probe. PET and PET/CT images showed accumulation and retention of the 18F-COX2 probe 13 and that significant accumulation in the tumor resulted in high signal intensity compared to the background (p < 0.05; Figure 4). The PET data corroborates with Western blot and RT-PCR analysis. We also observed a predominant hepatic uptake of the probe. That outcome is reasonably understandable since lipophilic compounds tend to possess a strong affinity for the liver. In addition, the high liver-bowel activity observed in this study suggests the possibility of hepatobiliary excretion. The probe exhibited negligible signal in the bone, thus eliminating the notion of in vivo defluorination. Figure 5 shows the probe’s biodistribution in non-fasted tumor-bearing mice (n = 3) at 150 min post injection. The data shows that the probe accumulated in the tumor; however, the highest uptake was detected in the liver, followed by the intestine. It is very likely that the high activity observed in the intestine can be attributed partially to the stool residuals.


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)

Uptake (% injection dose/g tissue) of the 18F-COX2 probe 13 in non-fasted tumor-bearing mice (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Uptake (% injection dose/g tissue) of the 18F-COX2 probe 13 in non-fasted tumor-bearing mice (n = 3).
Mentions: To assess the specificity of the probes for the detection of COX2 expression, we performed in vivo PET imaging of non-fasted mice in which C57MG tumors had been implanted on the mammary fat pads. We monitored the distribution of the probe in breast cancer at several times after the intravenous bolus injection. The optimal emission data were collected during a static, whole-body scan 150 min after administration of the probe. PET and PET/CT images showed accumulation and retention of the 18F-COX2 probe 13 and that significant accumulation in the tumor resulted in high signal intensity compared to the background (p < 0.05; Figure 4). The PET data corroborates with Western blot and RT-PCR analysis. We also observed a predominant hepatic uptake of the probe. That outcome is reasonably understandable since lipophilic compounds tend to possess a strong affinity for the liver. In addition, the high liver-bowel activity observed in this study suggests the possibility of hepatobiliary excretion. The probe exhibited negligible signal in the bone, thus eliminating the notion of in vivo defluorination. Figure 5 shows the probe’s biodistribution in non-fasted tumor-bearing mice (n = 3) at 150 min post injection. The data shows that the probe accumulated in the tumor; however, the highest uptake was detected in the liver, followed by the intestine. It is very likely that the high activity observed in the intestine can be attributed partially to the stool residuals.

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