Titel
On the Road towards Small-Molecule Programmed Cell Death 1 Ligand 1 Positron Emission Tomography Tracers: A Ligand-Based Drug Design Approach
Autor*in
Karsten Bamminger
CBmed GmbH—Center for Biomarker Research in Medicine
Chrysoula Vraka
Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna
... show all
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.
Stichwort
programmed cell death 1 ligand 1positron emission tomographycarbon-11radiotracer design
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:2037658
Erschienen in
Titel
Pharmaceuticals
Band
16
Ausgabe
7
ISSN
1424-8247
Erscheinungsdatum
2023
Publication
MDPI AG
Fördergeber
Erscheinungsdatum
2023
Zugänglichkeit
Rechte
Rechteangabe
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