111In-DTPA-D-Phe-1-Asp0-D-Phe1-octreotide exhibits higher tumor accumulation and lower renal radioactivity than 111In-DTPA-D-Phe1-octreotide

Introduction: In-111-DTPA-D-Phe(1)-octreotide scintigraphy is an important method of detecting neuroendocrine tumors. We previously reported that a new derivative of In-111-DTPA-D-Phe(1)-octreotide, In-111-DTPA-D-Phe(-1)-Asp(0)-D-Phe(1)-octreotide, accomplished the reduction of prolonged renal accumulation of radioactivity. The aim of this study was to evaluate the tumor accumulation of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide in vitro and in vivo by comparing it with In-111-DTPA-D-Phe(1)-octreotide. Methods: The tumor accumulation of this octreotide derivative was determined by measuring its uptake using cultured AR42J cells in vitro and biodistribution studies in vivo. The distribution of the radiotracer and the extent of somatostatin receptor-specific uptake in the tumor were estimated by a counting method using AR42J tumor-bearing mice. The radioactive metabolite species in the tumor and kidney were identified by HPLC analyses at 3 and 24 h post-injection of the In-111-DTPA-conjugated peptide. Results: In both cases, in vitro and in vivo, the tumor radioactivity levels of In-111-DTPA-D-Phe(-1)-Asp-D-Phe-loctreotide were approximately 2-4 times higher than those of In-111-DTPA-D-Phe(1)-octreotide. On in vitro cellular uptake inhibition and radioreceptor assay, In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide exhibited a binding affinity to somatostatin receptor highly similar to that of In-111-DTPA-D-Phe(1)-octreotide. As the additional cellular uptake of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide was significantly lower at low temperature than at 37 degrees C, it was considered that a cellular uptake pathway is involved in energy-dependent endocytotic processes. In the radiometabolite analysis of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide, In-111-DTPA-D-Phe-Asp-OH was a major metabolite in the tumor at 24 h post-injection. Conclusion: In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide exhibited higher tumor accumulation and persistence of tumor radioactivity than In-111-DTPA-D-Phe(1)-octreotide. We reasoned that this higher tumor accumulation would not be based on the receptor affinity but on a receptor-mediated endocytotic process involved in temperature-dependent cellular uptake. The present study demonstrated the great potential of the pharmaceutical development of a new radiolabeled peptide with high tumor accumulation and low renal radioactivity by the chemical modification of In-111-DTPA-D-Phe(1)-octreotide. (C) 2017 Elsevier Inc. All rights reserved.