Development of Radiogallium-Labeled Peptides for Platelet-Derived Growth Factor Receptor β (PDGFRβ) Imaging: Influence of Different Linkers

The purpose of this study is to develop peptide-based platelet-derived growth factor receptor β (PDGFRβ) imaging probes and examine the effects of several linkers, namely un-natural amino acids (D-alanine and β-alanine) and ethylene-glycol (EG), on the properties of Ga-DOTA-(linker)-IPLPPPRRPFFK peptides. Seven radiotracers, (67)Ga-DOTA-(linker)-IPLPPPRRPFFK peptides, were designed, synthesized, and evaluated. The stability and cell uptake in PDGFRβ positive peptide cells were evaluated in vitro. The biodistribution of [(67)Ga]Ga-DOTA-EG(2)-IPLPPPRRPFFK ([(67)Ga]27) and [(67)Ga]Ga-DOTA-EG(4)-IPLPPPRRPFFK ([(67)Ga]28), which were selected based on in vitro stability in murine plasma and cell uptake rates, were determined in BxPC3-luc-bearing nu/nu mice. Seven (67)Ga-labeled peptides were successfully synthesized with high radiochemical yields (>85%) and purities (>99%). All evaluated radiotracers were stable in PBS (pH 7.4) at 37 °C. However, only [(67)Ga]27 and [(67)Ga]28 remained more than 75% after incubation in murine plasma at 37 °C for 1 h. [(67)Ga]27 exhibited the highest BxPC3-luc cell uptake among the prepared radiolabeled peptides. As regards the results of the biodistribution experiments, the tumor-to-blood ratios of [(67)Ga]27 and [(67)Ga]28 at 1 h post-injection were 2.61 ± 0.75 and 2.05 ± 0.77, respectively. Co-injection of [(67)Ga]27 and an excess amount of IPLPPPRRPFFK peptide as a blocking agent can significantly decrease this ratio. However, tumor accumulation was not considered sufficient. Therefore, further probe modification is required to assess tumor accumulation for in vivo imaging.