Renal metabolism of 111In-DTPA-D-Phe1-octreotide in vivo

The persistent localization of radioactivity in the kidney after administration of In-111-DTPA-D-Phe(1)-octreotide impairs the diagnostic accuracy of this radiopharmaceutical. To better understand the mechanisms responsible for the renal radioactivity levels of In-111-DTPA-D-Phe(1)-octreotide, the renal metabolism of this compound was compared with In-111-DTPA-L-Phe(1)-octreotide, where the N-terminal D-phenylalanine was replaced with L-phenylalanine to facilitate metabolism. DTPA-D-Phe(1)-octreotide and DTPA-L-Phe(1)-octreotide were synthesized by solid-phase methods. Both In-111-DTPA-conjugated octreotide analogues were prepared with radiochemical yields of over 96%, and both remained stable after a 3 h incubation in murine serum at 37 degrees C. When injected into mice, the two In-111-DTPA-conjugated octreotide analogues showed similar radioactivity elimination rates from the blood and accumulation in the kidney with about 60% injected radioactivity being excreted in the urine by 24 h postinjection. Over 85% of the radioactivity in the urine existed as intact peptides for both analogues. Despite the similar renal radioactivity levels, significant differences were observed in the radiolabeled species remaining in the kidney between the two; while In-111-DTPA-L-Phe(1)-octreotide was rapidly metabolized to the final radiometabolite, In-111-DTPA-L-Phe, the metabolic rate of In-111-DTPA-D-Phe(1)-octreotide was so slow that various intermediate radiolabeled species were observed. However, both In-111-DTFA-D-Phe and In-111-DTPA-L-Phe remained in the lysosomal compartment of the renal cells as the final radiometabolites for long periods. These findings indicated that although the metabolic stability of In-111-DTPA-D-Phe(1)-octreotide in the renal cells may be partially involved, the slow elimination rate of the radiometabolite derived from In-111-DTPA-D-Phe(1)-octreotide from the lysosomal compartment of renal cells would be predominantly attributable to the persistent renal radioactivity levels of In-111-DTPA-D-Phe(1)-octreotide.