Gastrin-releasing-peptide (GRP)-receptors and αvβ3-integrins are widely discussed as potential target structures for oncological imaging with positron emission tomography (PET). Favored by the overexpression of receptors on the surface of
tumor cells good imaging characteristics can be achieved with highly specific radiolabeled receptor
ligands. PEGylated
bombesin (PESIN) derivatives as specific GRP receptor
ligands and RGD (one-letter codes for
arginine-glycine-aspartic acid)
peptides as specific αvβ3 binders were synthesized and tagged with a
silicon-
fluorine-acceptor (SiFA) moiety. The SiFA synthon allows for a fast and highly efficient isotopic exchange reaction at room temperature giving the [(18)F]
fluoride labeled
peptides in up to 62% radiochemical yields (d.c.) and ≥99% radiochemical purity in a total synthesis time of less than 20 min. Using nanomolar quantities of precursor high specific activities of up to 60 GBq μmol(-1) were obtained. To compensate the high lipophilicity of the SiFA moiety various hydrophilic structure modifications were introduced leading to significantly reduced logD values. Competitive displacement experiments with the PESIN derivatives showed a 32 to 6 nM affinity to the GRP receptor on PC3 cells, and with the RGD
peptides a 7 to 3 μM affinity to the αvβ3
integrins on U87MG cells. All derivatives proved to be stable in human plasma over at least 120 min. Small animal PET measurements and biodistribution studies revealed an enhanced and specific accumulation of the
RGD peptide (18)F-SiFA-LysMe3-γ-carboxy-d-Glu-RGD (17) in the
tumor tissue of U87MG
tumor-bearing mice of 5.3% ID/g whereas the PESIN derivatives showed a high liver uptake and only a low accumulation in the
tumor tissue of PC3 xenografts. Stability studies with
compound 17 provided further information on its metabolism in vivo. These results altogether demonstrate that the reduction of the overall lipophilicity of SiFA tagged RGD
peptides is a promising approach for the generation of novel potent (18)F-labeled imaging agents.