Synthesis and evaluation of novel F-18-labeled pyrimidine derivatives: potential FAK inhibitors and PET imaging agents for cancer detection

Abstract

Based on computer-assisted drug design, a series of novel pyrimidine derivatives was successfully synthesized and characterized by ¹H NMR, ¹³C HNMR, and MS spectra. All the new compounds were evaluated for their activity against focal adhesion kinase and showed low IC₅₀ values in comparison with control drugs. In particular, for compound 8i, its IC₅₀ value was 0.060 μM, suggesting its advantage as a focal adhesion kinase inhibitor. To evaluate the potentiality of these compounds as PET imaging agents in cancer detection, compounds 8a, 8c, 8h, and 8i were successively labeled with ¹⁸F. The four ¹⁸F-labeled pyrimidine derivatives showed appropriate log P values and high stability in physiological saline and mouse plasma. Noticeably, compound [¹⁸F]-8a with a 4-methoxyl group at the benzene ring exhibited good in vivo biodistribution data in mice bearing the S180 tumor, which promoted a further microPET imaging study of compound [¹⁸F]-8a. The microPET image of [¹⁸F-8a] administered into the S180 tumor-bearing mice acquired at 60 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggested that compound [¹⁸F]-8a might be a new probe for PET tumor imaging.