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Enzymological characterization of ⁶⁴Cu-labeled neprilysin substrates and their application for modulating the renal clearance of targeted radiopharmaceuticals

Brandt, F.; Ullrich, M.; Wodtke, J.; Kopka, K.; Bachmann, M.; Löser, R.; Pietzsch, J.; Pietzsch, H.-J.; Wodtke, R.


The applicability of radioligands for targeted endoradionuclide therapy is limited due to radiation-induced deleterious effects to healthy tissues. This applies in particular to the kidneys as primary organs of elimination, which requires dosimetric estimates to justify internal radionuclide therapy. In this context, the targeting of enzymes of the renal brush border membrane by cleavable linkers between target molecule and radiolabel that permit the formation of fast eliminating radionuclide-carrying cleavage fragments gains increasing interest. Herein, we synthesized a small library of ⁶⁴Cu-labeled cleavable linkers and quantified their substrate potentials toward neprilysin (NEP), a highly abundant peptidase at the renal brush border membrane. This allowed for the derivation of structure-activity relationships and selected cleavable linkers were attached to the somatostatin receptor subtype 2 ligand [Tyr³]octreotate. Subsequent radiopharmacological characterization revealed that a substrate-based targeting of NEP in the kidneys with small molecules or peptides entails a certain degree of premature cleavage in the blood circulation by soluble and endothelium-derived NEP. However, for a tissue-specific targeting of NEP in the kidneys, the additional targeting of albumin in the blood by albumin-binding moieties is highlighted.

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  • ZRT

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