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

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...

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Published in:Journal of medicinal chemistry 2024-03, Vol.67 (5), p.4036-4062
Main Authors: Bamminger, Karsten, Pichler, Verena, Vraka, Chrysoula, Limberger, Tanja, Moneva, Boryana, Pallitsch, Katharina, Lieder, Barbara, Zacher, Anna Sophia, Ponti, Stefanie, Benčurová, Katarína, Yang, Jiaye, Högler, Sandra, Kodajova, Petra, Kenner, Lukas, Hacker, Marcus, Wadsak, Wolfgang
Format: Article
Language:English
Subjects:
B7-H1 Antigen - metabolism
Humans
Immunohistochemistry
Ligands
Positron-Emission Tomography - methods
Tissue Distribution
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c02342