A Systematic Comparative Evaluation of 68Ga-Labeled RGD Peptides Conjugated with Different Chelators

Abstract

Purpose: The present paper reports a systematic study on the effect of bifunctional chelators (BFC) namely, NOTA, DOTA, and DTPA, on the radiochemical formulation, in vitro stability, and in vivo biological properties of 68Ga-labeled RGD peptide derivatives. Methods: The three RGD conjugates namely, NOTA-Bn-E-[c(RGDfk)]2, DOTA-Bn-E-[c(RGDfk)]2, and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled with 68Ga and the radiolabeling was optimized with respect to the ligand amount, radiolabeling time, and temperature. Further, the 68Ga complexes were assessed for their in vitro and in vivo stabilities. The biodistribution studies of the three radiolabeled conjugates were carried out in C57BL/6 mice bearing melanoma tumor at 30 min and 1 h post-adimistration. Results: NOTA-Bn-E-[c(RGDfk)]2 could be radiolabeled with 68Ga at room temperature while DOTA-Bn-E-[c(RGDfk)]2 and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled at high temperature. 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was found to be the most kinetically rigid in in vitro stability assay. The uptake of the three radiolabeled peptide conjugates in melanoma tumor was comparable at 1 h post-administration (NOTA; DOTA; DTPA (% I.D./g):: 2.78 ± 0.38; 3.08 ± 1.1; 3.36 ± 0.49). However, the tumor/background ratio of 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was the best amongst the three radiotracers. 68Ga-complexes of NOTA-Bn-E-[c(RGDfk)]2 and DOTA-Bn-E-[c(RGDfk)]2 showed excellent in vivo stability while 68Ga-DTPA-Bn-E-[c(RGDfk)]2 showed significant metabolic degradation. Conclusion: These studies show that 68Ga-NOTA-Bn-E-[c(RGDfk)]2 would be the most appropriate 68Ga-labeled radiotracer and the most amenable for kit formulation.