PET-Based Biodistribution and Radiation Dosimetry of Epidermal Growth Factor Receptor–Selective Tracer <sup>11</sup>C-PD153035 in Humans

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...

Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 98%

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

Samén

Arnberg

et al. 2013

“…In the domain of reversible anilinoquinazoline chemical moieties, many drugs and their derivatives such as PD 153035, gefitinib, erlotinib, ZD 6474, and ML01 were labeled with diverse radionuclides such as 11 C, 123 I, 125 I, 18 F (17,18,20-22), and the radiometal 99m Tc using 2 different chelators (23). Among all these labeled reversible inhibitors, 11 C-PD153035 was the only one whose biodistribution and dosimetry were recently evaluated in healthy volunteers (22) and indicated a favorable radiation dose profile. These reversible compounds were labeled either at the functional group at the 6-or 7-position of the quinazoline ring or at the anilino moiety (Fig.…”

Section: Approaches For Imaging Egfr In Cancermentioning

confidence: 99%

Strategies for Molecular Imaging of Epidermal Growth Factor Receptor Tyrosine Kinase in Cancer

Mishani¹,

Hagooly²

2009

A wealth of research has focused on developing targeted cancer therapies by specifically inhibiting epidermal growth factor receptor tyrosine kinase (EGFR-TK). However, the outcome of most EGFR-TK-targeted drugs that were approved by the Food and Drug Administration or entered clinical trials has been only moderate. Enhancement of EGFR-targeted therapy hinges on a reliable in vivo quantitative molecular imaging method. Such a method would enable monitoring of receptor drug binding and receptor occupancy in vivo; determination of the duration of EGFR inhibition in vivo; and, potentially, identification of a primary or secondary mutation in EGFR leading to drug interaction or loss of EGFR recognition by the drug. This review analyzes the most recent strategies to visualize and quantify EGFR-TK in cancer by nuclear medicine imaging and describes future directions.

“…We previously demonstrated preclinically that 11 C-PD153035 tumor uptake correlates with EGFR expression (10) and characterized its biodistribution in healthy human volunteers as well as demonstrated tumor uptake in patients with NSCLC (11). Therefore, 11 C-PD153035 PET/CT has the potential to serve as an imaging biomarker for predicting which patients will benefit most from EGFR-TKI treatment.…”

mentioning

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

Self Cite

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.