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Updated: Jul 1, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint
Karsten Bamminger1,2, Verena Pichler1,3, Chrysoula Vraka2
1CBmed GmbH - Center for Biomarker Research in Medicine, 8010 Graz, Austria.
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.
Insights
Developing novel positron emission tomography (PET) tracers for programmed cell death 1 ligand 1 (PD-1/PD-L1) shows promise for cancer therapy. However, challenges in in vivo uptake and biodistribution limit current small-molecule PET tracer development.
Area of Science:
- Radiochemistry
- Molecular Imaging
- Oncology
Background:
- Programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) checkpoint inhibitors are crucial cancer therapies, but patient response varies significantly.
- Predictive biomarkers are needed to identify patients who will benefit from PD-1/PD-L1 therapies.
- Current methods like immunohistochemistry (IHC) have limitations, including invasiveness and inability to capture expression heterogeneity.
Purpose of the Study:
- To synthesize and evaluate small-molecule positron emission tomography (PET) tracers for noninvasive imaging of PD-L1 expression.
- To address the limitations of IHC for PD-L1 assessment and improve patient stratification for immunotherapy.
Main Methods:
- Synthesis of a diverse library of small molecules targeting PD-L1, optimizing for high affinity.
- Radiolabeling of a lead compound (Compound 5c) with carbon-11.
- In vitro characterization including IC50 determination.
- In vivo biodistribution studies in xenograft models.
Main Results:
- Several small molecules demonstrated nanomolar affinities for PD-L1.
- Compound 5c showed high affinity (IC50 = 10.2 nM) and was successfully radiolabeled with carbon-11.
- In vivo studies revealed limited tracer uptake in xenografts and significant accumulation in excretory organs.
- Structure-activity relationships and biodistribution data were obtained.
Conclusions:
- Small-molecule PET tracers offer a potential noninvasive method for assessing PD-L1 expression.
- Significant challenges remain in achieving adequate in vivo tumor uptake and favorable biodistribution for PD-L1 PET tracers.
- Further optimization is required to develop effective small-molecule PD-L1 PET tracers for clinical application.
