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

Abstract Our previous studies indicated that 111 In-diethylenetriaminepentaacetic acid ( 111 In-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 111 In-DTPA- d -Phe 1 -octreotide. On the basis of the findings, we designed, synthesized and evaluated two Asp-modified 111 In-DTPA-conjugated octreotide derivatives, 111 In-DTPA-Asp 1 -octreotide and 111 In-DTPA-Asp 0 - d -Phe 1 -octreotide. While 111 In-DTPA-Asp 1 -octreotide showed negligible AR42J cell uptake, 111 In-DTPA-Asp 0 - d -Phe 1 -octreotide exhibited AR42J cell uptake similar to that of 111 In-DTPA- d -Phe 1 -octreotide. When administered to AR42J tumor-bearing mice, 111 In-DTPA-Asp 0 - d -Phe 1 -octreotide exhibited renal radioactivity levels significantly lower than did 111 In-DTPA- d -Phe 1 -octreotide at 1 and 3 h post-injection. No significant differences were observed in tumor accumulation between 111 In-DTPA-Asp 0 - d -Phe 1 -octreotide and 111 In-DTPA- d -Phe 1 -octreotide after 1 and 3 h injection. The findings in this study suggested that an interposition of an Asp at an appropriate position in 111 In-DTPA- d -Phe 1 -octreotide would constitute a useful strategy to develop 111 In-DTPA- d -Phe 1 -octreotide derivatives of low renal radioactivity levels while preserving tumor accumulation.