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

Abstract

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...

99mTc-HYNIC-MPG: A novel SPECT probe for targeting mutated EGFR

“…Previously, it was reported that PD153035 (N-(3-bromophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride) is a very good molecular TKI for lung cancers, but has potent toxicity and no effects on lung cancer patients with mutated EGFR. 12,14 Thus, it is important to design and synthesize novel types of small molecule TKIs with lower liver toxicity but specifically binding with mutated EGFR.…”

Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

“…[43][44][45][46] In this study, Log P values of excreted through the hepatobiliary pathway, which is often observed for small molecule radiotracers directed to the ATP-binding site of TKs. 20,23,47,48 This excretion route may be due to the moderately high lipophilicities of these radiotracers.…”

Selective intra-arterial administration of 18F-FDG to the rat brain — effects on hemispheric uptake

“…Interventional techniques may be a useful tool to overcome this problem by selective administration of targeted nanoparticles under MRI [20, 21]. For studies requiring radiotracers that undergo an important first passage metabolism in, for example, the liver, this principle could be of utmost importance, as we have recently demonstrated using these techniques [22]. …”