We evaluated the following 111In-labeled somatostatin (SS) analogues (diethylenetriaminepentaacetic acid, DTPA; tetraazacyclododecanetetraacetic acid, DOTA): [DTPA0]octreotide, [DTPA0,Tyr3]octreotide, [DTPA0,d-Tyr1]octreotide, [DTPA0,Tyr3]octreotate [Thr(ol) in octreotide replaced with Thr], and [DOTA0,Tyr3]octreotide, in vitro and in vivo.

In vitro, all compounds showed high and specific binding to SS receptors in mouse pituitary AtT20 tumor cell membranes, and IC50s were in the nanomolar range. Furthermore, all compounds showed specific internalization in rat pancreatic tumor cells; uptake of [111In-DTPA0,Tyr3]octreotate was the highest of the compounds tested, and that of [111In-DTPA0,d-Tyr1]octreotide was the lowest. Biodistribution experiments in rats showed that, 4, 24, and 48 h after injection of [111In-DTPA0,Tyr3]octreotide, [111In-DTPA0,Tyr3]octreotate, and [111In-DOTA0,Tyr3]octreotide, radioactivity in the octreotide-binding, receptor-expressing tissues and tumor-to-blood ratios were significantly higher than those after injection of [111In-DTPA0]octreotide. Uptake of [111In-DTPA0,Tyr3]octreotate in the target organs was also, in vivo, the highest of the radiolabeled peptides tested, whereas that of [111In-DTPA0,d-Tyr1]octreotide was the lowest. Uptake of [111In-DTPA0,Tyr3]octreotide, [111In-DTPA0,Tyr3]octreotate, and [111In-DOTA0,Tyr3]octreotide in target tissues was blocked by >90% by 0.5 mg of unlabeled octreotide, indicating specific binding to the octreotide receptors. Blockade of [111In-DTPA0,d-Tyr1]octreotide was >70%. In conclusion, radiolabeled [DTPA0,Tyr3]octreotide and, especially, [DTPA0,Tyr3]octreotate and their DOTA-coupled counterparts are most promising for scintigraphy and radionuclide therapy of SS receptor-positive tumors in humans.

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This work was supported by Swiss National Science Foundation Grant 31-42516/94 and the “Regionale Krebsliga beider Basel” (both to H. R. M.).

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