Redesign of negatively charged In-DTPA-octreotide derivative to reduce renal radioactivity.

Introduction: Radiolabeled octreotide derivatives have been studied as diagnostic and therapeutic agents for somatostatin receptor-positive tumors. To prevent unnecessary radiation exposure during their clinical application, the present study aimed to develop radiolabeled peptides which could reduce radioactivity levels in the kidney at both early and late post-injection time points by introducing a negative charge with an acidic amino acid such as L-aspartic acid (Asp) at a suitable position in In-DTPA-conjugated octreotide derivatives.

Methods: Biodistribution of the radioactivity was evaluated in normal mice after administration of a novel radiolabeled peptide by a counting method. The radiolabeled species remaining in the kidney were identified by comparing their HPLC data with those obtained by alternative synthesis.

Results: The designed and synthesized radiolabeled peptide In-DTPA-d-Phe-Asp-d-Phe-octreotide exhibited significantly lower renal radioactivity levels than those of the known In-DTPA-d-Phe-octreotide at 3 and 24h post-injection. The radiolabeled species in the kidney at 24h after the injection of new octreotide derivative represented In-DTPA-d-Phe-OH and In-DTPA-d-Phe-Asp-OH as the metabolites. Their radiometabolites and intact In-DTPA-conjugated octreotide derivative were observed in urine within 24h post-injection.

Conclusion: The present study provided a new example of an In-DTPA-conjugated octreotide derivative having the characteristics of both reduced renal uptake and shortened residence time of radioactivity in the kidney. It is considered that this kinetic control was achieved by introducing a negative charge on the octreotide derivative thereby suppressing the reabsorption in the renal tubules and affording the radiometabolites with appropriate lipophilicity.