Effect of molecular charges on renal uptake of ¹¹¹In-DTPA-conjugated peptides

The effect of molecular charges on renal accumulation of ¹¹¹In-DTPA-labeled low molecular weight (LMW) peptides was investigated using ¹¹¹In-DTPA-octreotide derivatives as models to design radiolabeled peptides that are taken up less by renal cells. The N-terminal D-phenylalanine (Phe) of ¹¹¹In-DTPA-D-Phe¹-octreotide was replaced with L-aspartic acid (Asp), L-lysine (Lys), L-methionine (Met) or L-Phe. Cellulose acetate electrophoresis indicated that both ¹¹¹In-DTPA-L-Phe¹-octreotide and ¹¹¹In-DTPA-L-Met¹-octreotide showed similar net charges, whereas ¹¹¹In-DTPA-L-^αLys¹-octreotide and ¹¹¹In-DTPA-L-Asp¹-octreotide had more positive and negative charges, respectively, at pH values similar to those in blood and glomerular filtrate. When injected into mice, significant differences were observed in the renal radioactivity levels. ¹¹¹In-DTPA-L-^αLys¹-octreotide showed the highest radioactivity levels from 10 min to 6 h postinjection, whereas the lowest radioactivity levels were observed with ¹¹¹In-DTPA-L-Asp¹-octreotide at all the postinjection intervals. These findings indicated that the replacement of only one amino acid in ¹¹¹In-DTPA-D-Phe¹-octreotide significantly altered net molecular charges of the resulting peptides and that the net charges of the ¹¹¹In-DTPA-octreotide derivatives significantly affected their renal uptake. Thus, an increase of negative charges in peptide molecules may constitute a strategy for designing ¹¹¹In-DTPA-conjugated LMW peptides with low renal radioactivity levels.