Assessment of <sup>11</sup>C‐labeled‐4‐<i>N</i>‐(3‐bromoanilino)‐6, 7‐dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression

Wang, Hui; J, Yu; Yang, Guoren; Song, Xianrang; Sun, Xuejun; Zhao, Shuqiang; Mu, Dianbin

doi:10.1111/j.1349-7006.2007.00562.x

Cited by 35 publications

(34 citation statements)

References 18 publications

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“…An unfortunate limitation of this study was the inability to obtain the tissue biomarkers for comparison to imaging. In a preclinical study, uptake of 11 C-PD153035 in different cell lines and their corresponding xenografts correlated strongly with the level of EGFR protein expression (10). A preclinical study of a related PET tracer, 11 C-erlotinib, found that, similarly, the uptake was highest in the cell line with the highest EGFR expression, but this was also the cell line that harbored an activating mutation in EGFR (15).…”

Section: Discussionmentioning

confidence: 97%

“…Automated synthesis and 11 C-radiolabeling of PD153035 from its precursor (ABX GmbH) were performed with a TRACERlab FX C system (GE Healthcare) and prepared for human use as described previously (10,11). Baseline 11 C-PD153035 PET/CT was performed within 1 wk before the initiation of treatment, and follow-up 11 C-PD153035 PET/CT was performed at 1-2 wk and 6 wk after the start of treatment.…”

Section: Pet/ctmentioning

confidence: 99%

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Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Meng¹,

Loo²,

Ma³

et al. 2011

J Nucl Med

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Outcomes are suboptimal when molecularly targeted therapies are used in patient populations unselected for the molecular target. This pilot study examines the correlation of PET using 11 C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline ( 11 C-PD153035), an imaging biomarker of epidermal growth factor receptor (EGFR), with outcomes in patients with nonsmall cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor erlotinib. Methods: Patients with advanced chemotherapy-refractory NSCLC were prospectively enrolled on a trial of erlotinib at a dose of 150 mg daily and imaged by 11 C-PD153035 PET/CT at baseline, after 1-2 wk, and after 6 wk from the start of treatment. Overall survival and progressionfree survival (OS and PFS, respectively) times were correlated with the 11 C-PD153035 standardized uptake value (SUV) at each of the imaging times. Results: Twenty-one patients were enrolled. Follow-up to progression was complete in all patients and to death in 18 of 21. By Cox regression analysis, baseline maximum SUV correlated strongly with OS and PFS (hazard ratio 5 0.40, P 5 0.002, and hazard ratio 5 0.044, P , 0.001, respectively) independent of histology. Patients with higher maximum SUV ($median) survived more than twice as long as patients with lower maximum SUV (median OS 5 11.4 vs. 4.6 mo, P 5 0.002; PFS 5 4.4 vs. 1.8 mo, P , 0.001). However, 11 C-PD153035 uptake on follow-up scans was less well correlated with survival. Conclusion: Our preliminary results suggest 11 C-PD153035 PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC of adenocarcinoma or squamous histology likely to respond to the EGFR tyrosine kinase inhibitor but not for monitoring treatment response.

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Section: Discussionmentioning

confidence: 97%

Section: Pet/ctmentioning

confidence: 99%

Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Meng¹,

Loo²,

Ma³

et al. 2011

J Nucl Med

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“…However, the uptake of radioactivity in tumors was changed little or not at all by the erlotinib treatment. If tissue uptake were primarily due to EGFR binding, then decreased uptake due to the blocking of binding sites would be expected (10,32). Tracer metabolism was not considered in those studies, and our results indicated that radiometabolites in tissue might make it difficult to detect blocking effects.…”

Section: Discussionmentioning

confidence: 78%

“…These characteristics make the molecule an attractive candidate as a PET tracer, and [ 11 C] PD153035 has been evaluated in several in vitro and in vivo studies. Promising in vivo results were observed in rodents (9)(10)(11). The tracer, labeled at position 6, was evaluated for radiation dosimetry (12) and for imaging of non-small cell lung cancer in humans; the uptake of radioactivity was positively correlated with an increased effectiveness of EGFR-directed therapy (13).…”

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confidence: 99%

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

Samén

Arnberg

et al. 2013

J Nucl Med

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Several tracers have been evaluated as probes for noninvasive epidermal growth factor receptor (EGFR) quantification with PET. One of the most promising candidates is the 11 C-labeled analog of the EGFR tyrosine kinase inhibitor PD153035. However, previous in vitro studies indicated extensive metabolism of the tracer, which could be disadvantageous for the assessment of receptor density in vivo. The aim of this study was to investigate the in vivo metabolism of [ 11 C]PD153035 to determine whether alterations in metabolite formation are accompanied by changes in biodistribution and tumor uptake. Methods: EGFR-overexpressing human epidermoid carcinoma xenografts in rats were used in all examinations of tumor uptake. Cytochrome P450 enzymes of subfamilies CYP2D and CYP3A were inhibited before intravenous injection of [ 11 C] PD153035 into healthy and tumor-bearing male rats. Samples were taken from arterial blood and urine, and the occurrence of radioactive metabolites was assessed with radio-high-performance liquid chromatography. Dynamic PET examinations of healthy and tumorbearing animals were performed. In 1 rat, the effect of local intraarterial administration was examined. Results: [ 11 C]PD153035 labeled at position 6 was metabolized extensively in vivo in male rats, resulting in very low levels of the intact tracer in plasma only minutes after injection. The major identified radiolabeled metabolites found were the N-oxide and metabolites arising from O demethylation at position 7. They were reduced by inhibition of CYP2D and CYP3A enzymes. PET revealed enzyme activity-dependent changes in the radioactivity distribution in the liver and tumors. Local administration of [ 11 C]PD153035 greatly increased radioactivity levels in the adjacent tumor compared with levels typically found after intravenous administration. The highest tumor-to-muscle ratio at 60 min after intravenous injection was found in the untreated animals, whereas the overall highest ratio was found in the tumor near the intraarterial administration site. Conclusion: We suggest that the metabolism of [ 11 C]PD153035 should be taken into consideration when this tracer is used to quantify EGFR expression, as our results indicated that the distribution of radioactivity to EGFR-overexpressing tumors was affected by the rate of metabolism and the route of administration.Key Words: PET; epidermal growth factor receptor; metabolism; The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases. Overexpression of EGFR and its cognate ligands has been shown to contribute to increased proliferation and invasiveness of several tumor types (1). The intracellular portion of the EGFR consists of a tyrosine kinase domain that is activated by ligand binding and receptor dimerization and is a potential therapeutic target for the group of drugs known as tyrosine kinase inhibitors (TKIs). These drugs act by inhibiting the adenosine triphosphate-binding site of tyrosine kinase and thereby blocking subsequent diverse intracellu...

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“…11 C-radiolabeled PD153035 was verified as a powerful EGFRspecific imaging agent by many studies (2,3). The group of Shandong Tumor Hospital has a longstanding interest and expertise on the subject of EGFR molecular imaging with 11 C-PD153035.…”

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confidence: 99%

Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression

Liu¹,

J²,

Meng³

et al. 2009

J Nucl Med

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Assessment of ¹¹C‐labeled‐4‐N‐(3‐bromoanilino)‐6, 7‐dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression

Abstract: The aim of the present study was to investigate the biodistribution of

Cited by 35 publications

References 18 publications

Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression

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Assessment of 11C‐labeled‐4‐N‐(3‐bromoanilino)‐6, 7‐dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression

Abstract: The aim of the present study was to investigate the biodistribution of

Cited by 35 publications

References 18 publications

Molecular Imaging with 11C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Molecular Imaging with 11C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [11C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats

Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression

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Assessment of ¹¹C‐labeled‐4‐N‐(3‐bromoanilino)‐6, 7‐dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression

Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Molecular Imaging with ¹¹C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Metabolism of Epidermal Growth Factor Receptor Targeting Probe [¹¹C]PD153035: Impact on Biodistribution and Tumor Uptake in Rats