Design, synthesis and biological evaluation of negatively charged 111In-DTPA-octreotide derivatives

Our previous studies indicated that 111In-diethylenetriaminepentaacetic acid (111In-DTPA)-octreotide derivatives with an additional negative charge by replacing N-terminal d-phenylalanine (d-Phe) with an acidic amino acid such as l-aspartic acid (Asp) or its derivative exhibited low renal radioactivity levels when compared with 111In-DTPA-d-Phe1-octreotide. On the basis of the findings, we designed, synthesized and evaluated two Asp-modified 111In-DTPA-conjugated octreotide derivatives, 111In-DTPA-Asp1-octreotide and 111In-DTPA-Asp0-d-Phe1-octreotide. While 111In-DTPA-Asp1-octreotide showed negligible AR42J cell uptake, 111In-DTPA-Asp0-d-Phe1-octreotide exhibited AR42J cell uptake similar to that of 111In-DTPA-d-Phe1-octreotide. When administered to AR42J tumor-bearing mice, 111In-DTPA-Asp0-d-Phe1-octreotide exhibited renal radioactivity levels significantly lower than did 111In-DTPA-d-Phe1-octreotide at 1 and 3 h post-injection. No significant differences were observed in tumor accumulation between 111In-DTPA-Asp0-d-Phe1-octreotide and 111In-DTPA-d-Phe1-octreotide after 1 and 3 h injection. The findings in this study suggested that an interposition of an Asp at an appropriate position in 111In-DTPA-d-Phe1-octreotide would constitute a useful strategy to develop 111In-DTPA-d-Phe1-octreotide derivatives of low renal radioactivity levels while preserving tumor accumulation.

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