化学
脑啡肽酶
肾
画笔边框
白蛋白
劈理(地质)
配体(生物化学)
肽
酶
膜
生物化学
受体
生物物理学
小泡
内科学
工程类
岩土工程
生物
医学
断裂(地质)
作者
Florian Brandt,Martin Ullrich,Johanna Wodtke,Klaus Kopka,Michael Bachmann,Reik Löser,Jens Pietzsch,Hans‐Jürgen Pietzsch,Robert Wodtke
标识
DOI:10.1021/acs.jmedchem.2c01472
摘要
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.
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