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 (68)Ga-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 (68)Ga and the radiolabeling was optimized with respect to the ligand amount, radiolabeling time, and temperature. Further, the (68)Ga 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 (68)Ga at room temperature while DOTA-Bn-E-[c(RGDfk)](2) and DTPA-Bn-E-[c(RGDfk)](2) were radiolabeled at high temperature. (68)Ga-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 (68)Ga-NOTA-Bn-E-[c(RGDfk)](2) was the best amongst the three radiotracers. (68)Ga-complexes of NOTA-Bn-E-[c(RGDfk)](2) and DOTA-Bn-E-[c(RGDfk)](2) showed excellent in vivo stability while (68)Ga-DTPA-Bn-E-[c(RGDfk)](2) showed significant metabolic degradation. CONCLUSION: These studies show that (68)Ga-NOTA-Bn-E-[c(RGDfk)](2) would be the most appropriate (68)Ga-labeled radiotracer and the most amenable for kit formulation.