Renal Metabolism of ¹¹¹In-DTPA-d-Phe¹-Octreotide in Vivo

Abstract

The persistent localization of radioactivity in the kidney after administration of 111In-DTPA-D-Phe1-octreotide impairs the diagnostic accuracy of this radiopharmaceutical. To better understand the mechanisms responsible for the renal radioactivity levels of 111In-DTPA-D-Phe1-octreotide, the renal metabolism of this compound was compared with 111In-DTPA-L-Phe1-octreotide, where the N-terminal D-phenylalanine was replaced with L-phenylalanine to facilitate metabolism. DTPA-D-Phe1-octreotide and DTPA-L-Phe1-octreotide were synthesized by solid-phase methods. Both 111In-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 degreesC. When injected into mice, the two 111In-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 111In-DTPA-L-Phe1-octreotide was rapidly metabolized to the final radiometabolite, 111In-DTPA-L-Phe, the metabolic rate of 111In-DTPA-D-Phe1-octreotide was so slow that various intermediate radiolabeled species were observed. However, both 111In-DTPA-D-Phe and 111In-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 111In-DTPA-D-Phe1-octreotide in the renal cells may be partially involved, the slow elimination rate of the radiometabolite derived from 111In-DTPA-D-Phe1-octreotide from the lysosomal compartment of renal cells would be predominantly attributable to the persistent renal radioactivity levels of 111In-DTPA-D-Phe1-octreotide.

First 18F-Labeled Tracer Suitable for Routine Clinical Imaging of sst Receptor-Expressing Tumors Using Positron Emission Tomography

“…The fact that for all of the fluorinated TOCA derivatives Ͼ96% of the initial cellular activity was externalized within 60 min under conditions inhibiting recycling (5 M TOC) indicates a negligible extent of intracellular ligand residualization. This represents one major disadvantage of radiohalogenated over radiometallated octreotide analogs, of which the charged radiometal-chelate-containing fragments remain trapped in the lysosomal compartments after degradation (7,47,48). The high extent of apparent intracellular retention of [ F-labeled TOCA derivatives in this study between 10 and 60 min p.i.…”

PET of CXCR4 Expression by a 68Ga-Labeled Highly Specific Targeted Contrast Agent

“…This is even more surprising, because comparable peptidic constructs with identical net charge such as the somatostatin analog 68 Ga-DOTATOC show renal activity levels of 8.2 %ID/g at 4 h after injection (37). The high degree of ligand retention has been explained by efficient reabsorption of the peptides at the renal brush border membrane and subsequent trapping of charged degradation products (38). One explanation for the very low kidney retention of 68 Ga-CPCR4-2 might be its high metabolic stability, leading to direct excretion in the urine.…”

Preparation and Biological Evaluation of Copper-64–Labeled Tyr3-Octreotate Using a Cross-Bridged Macrocyclic Chelator

“…Several studies have investigated the effect of charge on kidney uptake of both 64 Cu-and 111 In-labeled compounds (20,26,43). Indium-111-DTPA-conjugated peptides are retained in the kidney after reabsorption by renal tubular cells and lysosomal proteolysis (44,45). Renal retention of 111 In activity was greatest for positively charged peptide conjugates and lowest for negatively charged ones (43).…”