Journal Article

Design and Biological Evaluation of Small-Molecule PET-Tracers for Imaging of Programmed Death Ligand 1

Loureiro, Liliana R., Zarschler, Kristof, Ludik, Marie-Charlotte, Feldmann, Anja, Donat, Cornelius K., Ullrich, Martin, Kopka, Klaus, Krutzek, Fabian, Stadlbauer, Sven

2023

Overview

Noninvasive molecular imaging of the PD-1/PD-L1 immune checkpoint is of high clinical relevance for patient stratification and therapy monitoring in cancer patients. Here we report nine small-molecule PD-L1 radiotracers with solubilizing sulfonic acids and a linker–chelator system, designed by molecular docking experiments and synthesized according to a new, convergent synthetic strategy. Binding affinities were determined both in cellular saturation and real-time binding assay (LigandTracer), revealing dissociation constants in the single digit nanomolar range. Incubation in human serum and liver microsomes proved in vitro stability of these compounds. Small animal PET/CT imaging, in mice bearing PD-L1 overexpressing and PD-L1 negative tumors, showed moderate to low uptake. All compounds were cleared primarily through the hepatobiliary excretion route and showed a long circulation time. The latter was attributed to strong blood albumin binding effects, discovered during our binding experiments. Taken together, these compounds are a promising starting point for further development of a new class of PD-L1 targeting radiotracers.

• Publisher: MDPI AG,MDPI
• Subject: Albumin / Animal experimentation / Apoptosis / Biodistribution / Biopsy / Cancer / Cancer therapies / Chlorine / Immune checkpoint inhibitors / Immune clearance / Immune response / Kidneys / Ligands / Liver / Microsomes / PD-1 protein / PD-L1 protein / Peptides / PET imaging / Positron emission tomography / Radioactive tracers / Radioisotopes / Tomography