TY - JOUR
T1 - Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1
AU - Bamminger, Karsten
AU - Pichler, Verena
AU - Vraka, Chrysoula
AU - Limberger, Tanja
AU - Moneva, Boryana
AU - Pallitsch, Katharina
AU - Lieder, Barbara
AU - Zacher, Anna Sophia
AU - Ponti, Stefanie
AU - Benčurová, Katarína
AU - Yang, Jiaye
AU - Högler, Sandra
AU - Kodajova, Petra
AU - Kenner, Lukas
AU - Hacker, Marcus
AU - Wadsak, Wolfgang
N1 - Accession Number
WOS:001180645200001
PubMed ID
38442487
PY - 2024/3/14
Y1 - 2024/3/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85186973966&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c02342
DO - 10.1021/acs.jmedchem.3c02342
M3 - Article
C2 - 38442487
AN - SCOPUS:85186973966
SN - 0022-2623
VL - 67
SP - 4036
EP - 4062
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -