RENAL METABOLISM OF IN-111-DTPA-D-PHE(1)-OCTREOTIDE IN-VIVO

The persistent localization of radioactivity in the kidney after admin istration of In-111-DTPA-D-Phe(1)-octreotide impairs the diagnostic ac curacy of this radiopharmaceutical. To better understand the mechanism s 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-Ph e(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 stab le after a 3 h incubation in murine serum at 37 degrees C. When inject ed into mice, the two In-111-DTPA-conjugated octreotide analogues show ed similar radioactivity elimination rates from the blood and accumula tion in the kidney with about 60% injected radioactivity being excrete d 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 obser ved in the radiolabeled species remaining in the kidney between the tw o; while In-111-DTPA-L-Phe(1)-octreotide was rapidly metabolized to th e final radiometabolite, In-111-DTPA-L-Phe, the metabolic rate of In-1 11-DTPA-D-Phe(1)-octreotide was so slow that various intermediate radi olabeled species were observed. However, both In-111-DTFA-D-Phe and In -111-DTPA-L-Phe remained in the lysosomal compartment of the renal cel ls as the final radiometabolites for long periods. These findings indi cated that although the metabolic stability of In-111-DTPA-D-Phe(1)-oc treotide in the renal cells may be partially involved, the slow elimin ation rate of the radiometabolite derived from In-111-DTPA-D-Phe(1)-oc treotide from the lysosomal compartment of renal cells would be predom inantly attributable to the persistent renal radioactivity levels of I n-111-DTPA-D-Phe(1)-octreotide.