Iminodiacetic acid as bifunctional linker for dimerization of cyclic RGD peptides.

INTRODUCTION

In this study, I2P-RGD was used as the example to illustrate a novel approach for dimerization of cyclic RGD peptides. The main objective of this study was to explore the impact of bifunctional linkers (glutamic acid vs. iminodiacetic acid) on tumor-targeting capability and excretion kinetics of the Tc-labeled dimeric cyclic RGD peptides.

METHODS

HYNIC-I2P-RGD was prepared by reacting I2P-RGD with HYNIC-OSu in the presence of diisopropylethylamine, and was evaluated for its αβ binding affinity against I-echistatin bound to U87MG glioma cells. Tc-I2P-RGD was prepared with high specific activity (~185GBq/μmol). The athymic nude mice bearing U87MG glioma xenografts were used to evaluate its biodistribution properties and image quality in comparison with those of Tc-3P-RGD.

RESULTS

The IC value for HYNIC-I2P-RGD was determined to be 39±6nM, which was very close to that (IC=33±5nM) of HYNIC-3P-RGD. Replacing glutamic acid with iminodiacetic acid had little impact on αβ binding affinity of cyclic RGD peptides. Tc-I2P-RGD and Tc-3P-RGD shared similar tumor uptake values over the 2h period, and its αβ-specificity was demonstrated by a blocking experiment. The uptake of Tc-I2P-RGD was significantly lower than Tc-3P-RGD in the liver and kidneys. The U87MG glioma tumors were visualized by SPECT with excellent contrast using both Tc-I2P-RGD and Tc-3P-RGD.

CONCLUSION

Iminodiacetic acid is an excellent bifunctional linker for dimerization of cyclic RGD peptides. Bifunctional linkers have significant impact on the excretion kinetics of Tc radiotracers. Because of its lower liver uptake and better tumor/liver ratios, Tc-I2P-RGD may have advantages over Tc-3P-RGD for diagnosis of tumors in chest region.