2 research outputs found
Enzymological Characterization of <sup>64</sup>Cu-Labeled Neprilysin Substrates and Their Application for Modulating the Renal Clearance of Targeted Radiopharmaceuticals
The applicability of radioligands for targeted endoradionuclide
therapy is limited due to radiation-induced toxicity to healthy tissues,
in particular to the kidneys as primary organs of elimination. The
targeting of enzymes of the renal brush border membrane by cleavable
linkers 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. Radiopharmacological characterization
revealed that a substrate-based targeting of NEP in the kidneys with
small peptides entails their premature cleavage in the blood circulation
by soluble and endothelium-derived NEP. However, for a kidney-specific
targeting of NEP, the additional targeting of albumin in the blood
is highlighted
Enzymological Characterization of <sup>64</sup>Cu-Labeled Neprilysin Substrates and Their Application for Modulating the Renal Clearance of Targeted Radiopharmaceuticals
The applicability of radioligands for targeted endoradionuclide
therapy is limited due to radiation-induced toxicity to healthy tissues,
in particular to the kidneys as primary organs of elimination. The
targeting of enzymes of the renal brush border membrane by cleavable
linkers 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. Radiopharmacological characterization
revealed that a substrate-based targeting of NEP in the kidneys with
small peptides entails their premature cleavage in the blood circulation
by soluble and endothelium-derived NEP. However, for a kidney-specific
targeting of NEP, the additional targeting of albumin in the blood
is highlighted