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-Phe ¹ -octreotide scintigraphy is an important method of detecting neuroendocrine tumors. We previously reported that a new derivative of ¹¹¹ In-DTPA-d-Phe ¹ -octreotide, ¹¹¹ In-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 ¹¹¹ In-DTPA-d-Phe ^-1 -Asp ⁰ -d-Phe ¹ -octreotide in vitro and in vivo by comparing it with ¹¹¹ In-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 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 -Asp ⁰ -d-Phe ¹ -octreotide were approximately 2-4 times higher than those of ¹¹¹ In-DTPA-d-Phe ¹ -octreotide. On in vitro cellular uptake inhibition and radioreceptor assay, ¹¹¹ In-DTPA-d-Phe ^-1 -Asp ⁰ -d-Phe ¹ -octreotide exhibited a binding affinity to somatostatin receptor highly similar to that of ¹¹¹ In-DTPA-d-Phe ¹ -octreotide. As the additional cellular uptake of ¹¹¹ In-DTPA-d-Phe ^-1 -Asp ⁰ -d-Phe ¹ -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 -Asp ⁰ -d-Phe ¹ -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 -Asp ⁰ -d-Phe ¹ -octreotide exhibited higher tumor accumulation and persistence of tumor radioactivity than ¹¹¹ In-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 ¹¹¹ In-DTPA-d-Phe ¹ -octreotide.
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