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

  • J Med Chem. 2024 Mar 5. doi: 10.1021/acs.jmedchem.3c02342.
Karsten Bamminger  1  2 ,  Verena Pichler  1  3 ,  Chrysoula Vraka  2 ,  Tanja Limberger  1  4 ,  Boryana Moneva  2 ,  Katharina Pallitsch  5 ,  Barbara Lieder  6  7 ,  Anna Sophia Zacher  2 ,  Stefanie Ponti  2 ,  Katarína Benčurová  2 ,  Jiaye Yang  4 ,  Sandra Högler  8 ,  Petra Kodajova  8 ,  Lukas Kenner  1  4  8 ,  Marcus Hacker  2 ,  Wolfgang Wadsak  1  2
Affiliations
  • 1. CBmed GmbH - Center for Biomarker Research in Medicine, 8010 Graz, Austria.
  • 2. Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • 3. Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
  • 4. Institute of Clinical Pathology, Medical University of Vienna, 1090 Vienna, Austria.
  • 5. Institute of Organic Chemistry, University of Vienna, 1090 Vienna, Austria.
  • 6. Institute of Physiological Chemistry, University of Vienna, 1090 Vienna, Austria.
  • 7. Institute of Clinical Nutrition, University of Hohenheim, 70599 Stuttgart, Germany.
  • 8. Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
PMID: 38442487 DOI: 10.1021/acs.jmedchem.3c02342
Abstract

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.

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