111 In-DTPA-d-Phe -1 -Asp 0 -d-Phe 1 -octreotide exhibits higher tumor accumulation and lower renal radioactivity than 111 In-DTPA-d-Phe 1 -octreotide.

INTRODUCTION: 111 In-DTPA-d-Phe1 -octreotide scintigraphy is an important method of detecting neuroendocrine tumors. We previously reported that a new derivative of 111 In-DTPA-d-Phe1 -octreotide, 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide, accomplished the reduction of prolonged renal accumulation of radioactivity. The aim of this study was to evaluate the tumor accumulation of 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide in vitro and in vivo by comparing it with 111 In-DTPA-d-Phe1 -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 24h post-injection of the 111 In-DTPA-conjugated peptide.

RESULTS: In both cases, in vitro and in vivo, the tumor radioactivity levels of 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide were approximately 2-4 times higher than those of 111 In-DTPA-d-Phe1 -octreotide. On in vitro cellular uptake inhibition and radioreceptor assay, 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide exhibited a binding affinity to somatostatin receptor highly similar to that of 111 In-DTPA-d-Phe1 -octreotide. As the additional cellular uptake of 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide was significantly lower at low temperature than at 37°C, it was considered that a cellular uptake pathway is involved in energy-dependent endocytotic processes. In the radiometabolite analysis of 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide, 111 In-DTPA-d-Phe-Asp-OH was a major metabolite in the tumor at 24h post-injection.

CONCLUSION: 111 In-DTPA-d-Phe-1 -Asp0 -d-Phe1 -octreotide exhibited higher tumor accumulation and persistence of tumor radioactivity than 111 In-DTPA-d-Phe1 -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 111 In-DTPA-d-Phe1 -octreotide.