Design and Biological Evaluation of Small-Molecule PET-Tracers for Imaging of Programmed Death Ligand 1.
Fabian KrutzekCornelius K DonatMartin UllrichKristof ZarschlerMarie-Charlotte LudikAnja FeldmannLiliana R LoureiroKlaus KopkaSven StadlbauerPublished in: Cancers (2023)
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.
Keyphrases
- small molecule
- pet ct
- molecular docking
- high resolution
- dna binding
- binding protein
- positron emission tomography
- molecular dynamics simulations
- computed tomography
- protein protein
- high throughput
- skeletal muscle
- stem cells
- metabolic syndrome
- transcription factor
- cancer therapy
- single cell
- mesenchymal stem cells
- fluorescence imaging