Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1

Karsten Bamminger; Verena Pichler; Chrysoula Vraka; Tanja Limberger; Boryana Moneva; Katharina Pallitsch; Barbara Lieder; Anna Sophia Zacher; Stefanie Ponti; Katarína Benčurová; Jiaye Yang; Sandra Högler; Petra Kodajova; Lukas Kenner; Marcus Hacker; Wolfgang Wadsak

doi:10.1021/acs.jmedchem.3c02342

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Title (eng)

Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1

Author

Karsten Bamminger

Verena Pichler

Chrysoula Vraka

Tanja Limberger

Boryana Moneva

Katharina Pallitsch

Barbara Lieder

Anna Sophia Zacher

Stefanie Ponti

Katarína Benčurová

Jiaye Yang

Sandra Högler

University of Veterinary Medicine Vienna

Petra Kodajova

University of Veterinary Medicine Vienna

Lukas Kenner

University of Veterinary Medicine Vienna

Marcus Hacker

Wolfgang Wadsak

Abstract (eng)

A substantial portion of patients do not benefit from programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) checkpoint inhibition therapies, necessitating a deeper understanding of predictive biomarkers. Immunohistochemistry (IHC) has played a pivotal role in assessing PD-L1 expression, but small-molecule positron emission tomography (PET) tracers could offer a promising avenue to address IHC-associated limitations, i.e., invasiveness and PD-L1 expression heterogeneity. PET tracers would allow for improved quantification of PD-L1 through noninvasive whole-body imaging, thereby enhancing patient stratification. Here, a large series of PD-L1 targeting small molecules were synthesized, leveraging advantageous substructures to achieve exceptionally low nanomolar affinities. Compound 5c emerged as a promising candidate (IC50 = 10.2 nM) and underwent successful carbon-11 radiolabeling. However, a lack of in vivo tracer uptake in xenografts and notable accumulation in excretory organs was observed, underscoring the challenges encountered in small-molecule PD-L1 PET tracer development. The findings, including structure-activity relationships and in vivo biodistribution data, stand to illuminate the path forward for refining small-molecule PD-L1 PET tracers.

Keywords (eng)

AssaysLigandsPositron Emission TomographyPrecursorsScreening assays

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4382

DOI

10.1021/acs.jmedchem.3c02342

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Title (eng)