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

The effect of molecular charges on renal accumulation of In-111-DTPA-labele d low molecular weight (LMW) peptides was investigated using In-111-DTPA-oc treotide derivatives as models to design radiolabeled peptides that are tak en up less by renal cells. The N-terminal D-phenylalanine (Phe) of In-111-D TPA-D-Phe(1)-octreotide was replaced with L-aspartic acid (Asp), L-lysine ( Lys), L-methionine (Met) or L-Phe. Cellulose acetate electrophoresis indica ted that both In-111-DTPA-L-Phe(1)-octreotide and In-111-DTPA-L-Met(1)-octr eotide showed similar net charges, whereas In-111-DTPA-L-(alpha)Lys(1)-octr eotide and In-111-DTPA-L-Asp(1)-octreotide had more positive and negative c harges, respectively, at pH values similar to those in blood and glomerular filtrate. When injected into mice, significant differences were observed i n the renal radioactivity levels. In-111-DTPA-L-(alpha)Lys(1)-octreotide sh owed the highest radioactivity levels from 10 min to 6 h postinjection, whe reas the lowest radioactivity levels were observed with In-111- DTPA-L-Asp( 1)-octreo tide at all the postinjection intervals. These findings indicated that the replacement of only one amino acid in In-111-DTPA-D-Phe(1)-octreo tide significantly altered net molecular charges of the resulting peptides and that the net charges of the In-111-DTPA-octreotide derivatives signific antly affected their renal uptake. Thus, an increase of negative charges in peptide molecules may constitute a strategy for designing In-111-DTPA-conj ugated LMW peptides with low renal radioactivity levels. (C) 2001 Elsevier Science Inc. All rights reserved.