Possible utility of peptide-transporter-targeting [19F]dipeptides for visualization of the biodistribution of cancers by nuclear magnetic resonance imaging

Stable-isotope-labeled probes suitable for magnetic resonance imaging (MRI) would have various potential medical applications, such as tumor imaging. Here, with the aim of developing MRI probes targeting peptide transporters, we synthesized a series of [F-19]dipeptides by introducing one or two fluorine atoms or a trifluoromethyl group into the benzene ring of L-phenylalanyl-psi[CS-N]-L-alanine (Phe-psi-Ala), which is resistant to cleavage by peptidases. The mono-and difluoro dipeptides were efficiently transported by PEPT1 and PEPT2. Moreover, (3,5)-difluoro Phe-psi-Ala was metabolically stable in human hepatocyte culture, and had a low distribution volume in mice. An acute toxicity study in mice revealed no apparent effect on body weight or behavior. The biodistribution and biodynamics of this compound could be clearly visualized by F-19-MRI in vivo, although specific signal enhancement was observed only in the bladder, but not in the tumor of tumor-xenografted mice. Although there was no specific signal enhancement of the tested compound at the tumor, the present study provides some challenging points regarding F-19-MRI probes for future investigation.