Development
and In Vivo Evaluation
of Small-Molecule Ligands for Positron Emission Tomography of Immune
Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1
posted on 2024-03-05, 23:04authored byKarsten Bamminger, Verena Pichler, Chrysoula Vraka, Tanja Limberger, Boryana Moneva, Katharina Pallitsch, Barbara Lieder, Anna Sophia Zacher, Stefanie Ponti, Katarína Benčurová, Jiaye Yang, Sandra Högler, Petra Kodajova, Lukas Kenner, Marcus Hacker, Wolfgang Wadsak
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.