Modified PEG‐anilinoquinazoline derivatives as potential EGFR PET agents

Inhibition of epidermal growth factor receptor tyrosine kinase (EGFR‐TK) has emerged as a major approach for cancer‐targeted therapy. Consequently, there has been a great interest in the use of labeled EGFR‐TK inhibitors as positron emission tomography (PET) imaging agents. Currently, the developed agents did not yield adequate PET imaging of animal models probably due to poor solubility, rapid washout from blood, and low stability in vivo. In order to overcome these hurdles, new derivatives of previously reported inhibitors (ML04, 2) with decreased log P and increased solubility were designed and synthesized. These compounds (3–5) exhibited high autophosphorylation inhibitory potency with an IC₅₀ of 5–35 nM, decreased log P's (3.1, 3.34, and 3.45, respectively), and significantly increased solubility (630, 300, and 120 µg/mL, respectively) relative to the previously reported parent compound 2 (log P=3.7, solubility=3.5 µg/mL). The labeling of compound 5 with ¹⁸F] and compounds 3 and 4 with ¹¹C] and ¹²⁴I], respectively, involved a one‐step radiosynthesis. Compounds 3–5 were obtained with a total decay‐corrected radiochemical yields of 13, 31, and 5%, respectively, and were found to be stable in blood. The positive outcome achieved with compounds 3–5 merits further in vivo evaluation as PET bioprobes. Copyright © 2008 John Wiley & Sons, Ltd.