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Updated: Jul 20, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
On the Road towards Small-Molecule Programmed Cell Death 1 Ligand 1 Positron Emission Tomography Tracers: A
Karsten Bamminger1,2, Verena Pichler1,3, Chrysoula Vraka2
1CBmed GmbH-Center for Biomarker Research in Medicine, 8010 Graz, Austria.
Abstract:
PD-1/PD-L1 immune checkpoint blockade for cancer therapy showed promising results in clinical studies. Further endeavors are required to enhance patient stratification, as, at present, only a small portion of patients with PD-L1-positive tumors (as determined by PD-L1 targeted immunohistochemistry; IHC) benefit from anti-PD-1/PD-L1 immunotherapy. This can be explained by the heterogeneity of tumor lesions and the intrinsic limitation of multiple biopsies. Consequently, non-invasive in vivo quantification of PD-L1 on tumors and metastases throughout the entire body using positron emission tomography (PET) imaging holds the potential to augment patient stratification. Within the scope of this work, six new small molecules were synthesized by following a ligand-based drug design approach supported by computational docking utilizing lead structures based on the (2-methyl-[1,1'-biphenyl]-3-yl)methanol scaffold and evaluated in vitro for potential future use as PD-L1 PET tracers. The results demonstrated binding affinities in the nanomolar to micromolar range for lead structures and newly prepared molecules, respectively. Carbon-11 labeling was successfully and selectively established and optimized with very good radiochemical conversions of up to 57%. The obtained insights into the significance of polar intermolecular interactions, along with the successful radiosyntheses, could contribute substantially to the future development of small-molecule PD-L1 PET tracers.
Insights
Researchers developed new small molecules for Positron Emission Tomography (PET) imaging to quantify Programmed Death-Ligand 1 (PD-L1) in tumors. This could improve patient selection for cancer immunotherapy by enabling non-invasive, whole-body PD-L1 assessment.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Immune checkpoint blockade targeting PD-1/PD-L1 shows promise in cancer therapy.
- Current patient stratification relies on PD-L1 immunohistochemistry (IHC), which has limitations due to tumor heterogeneity and biopsy constraints.
- Non-invasive in vivo quantification of PD-L1 using Positron Emission Tomography (PET) imaging could enhance patient stratification for immunotherapy.
Purpose of the Study:
- To synthesize and evaluate novel small molecules as potential PET tracers for quantifying PD-L1 expression in vivo.
- To explore ligand-based drug design and computational docking for developing PD-L1 PET imaging agents.
- To establish and optimize Carbon-11 labeling for the developed tracer candidates.
Main Methods:
- Ligand-based drug design and computational docking were employed to identify lead structures based on a (2-methyl-[1,1'-biphenyl]-3-yl)methanol scaffold.
- Six new small molecules were synthesized and evaluated in vitro for binding affinities.
- Carbon-11 (¹¹C) labeling was optimized for the most promising candidates, assessing radiochemical conversion and selectivity.
Main Results:
- The synthesized molecules and lead structures exhibited binding affinities in the nanomolar to micromolar range.
- Successful and selective Carbon-11 labeling was achieved, with radiochemical conversions reaching up to 57%.
- Insights into the role of polar intermolecular interactions in tracer binding were gained.
Conclusions:
- The developed small molecules show potential as PET tracers for non-invasive PD-L1 quantification.
- Successful radiosynthesis of ¹¹C-labeled tracers is feasible, supporting further development.
- These findings contribute to advancing the development of small-molecule PD-L1 PET tracers for improved cancer patient stratification.
