Fig. 1
From: Reducing kidney uptake of radiolabelled exendin-4 using variants of the renally cleavable linker MVK
Left: (A) Radiolabelled peptides such as [111In]In-Ex4 are generally internalized at the kidney brush border membrane via endocytosis and consequently degraded in the lysosomes. The radioisotope together with the chelator persists in the lysosomes, resulting in high radioactivity levels in the kidney. (B) The cleavable linker MVK interspaced between the NOTA-chelator and the peptide is cleaved at the Met-Val bond by neprilysin at the apical brush border, generating the hydrophilic radiometal-chelator-Met metabolite, which is readily excreted through the urine. Using this approach, the radioisotope circumvents internalization and lysosomal degradation, alleviating radiation burden to the kidney. Right: Overview of the studied Ex4 derivatives. (C) Nle14,Lys40(NODAGA)-Ex4; the reference compound referred to as Ex4; (D) Nle14,Cys40(NOTA-Bn-MVK)-Ex4, referred to as MVK-Ex4 containing one cleavable linker sequence; (E) Nle14,Cys40(NOTA-Bn-MV-amBn-MVK)-Ex4, referred to as MV-MVK-Ex4 containing two cleavable linker sequences, of which one is comprised of the Lys; (F) Nle14,Cys40(NOTA-Bn-MVK(Me)2-amBn-MVK)-Ex4, referred to as MVK-MVK-Ex4 containing two full cleavable linker sequences