Synthesis and Preclinical Evaluation of ⁶⁸Ga-Labeled Radiotracers for Monitoring PD-L1 Expression in Tumors

Programmed
death-ligand 1 (PD-L1) plays a crucial role in tumor
immune evasion, making it an important biomarker and a validated target
for cancer immunotherapy. In this study, we designed, synthesized,
and preclinically evaluated a series of novel PD-L1-targeted radiotracers
based on a phenoxymethyl-biphenyl scaffold. Our design strategy was
to incorporate different functional amino acid residues and flexible
linkers between the phenoxymethyl-biphenyl scaffold and the DOTA chelator.
Among the six radiotracers, [68Ga]Ga-PEG-PRO-ZB exhibited
high stability, strong binding affinity to PD-L1 (KD = 19.3 ± 0.6 nM), and low nonspecific uptake. Micro-PET/CT
imaging confirmed its ability to detect PD-L1 expression in multiple
tumor models. Notably, [68Ga]Ga-PEG-PRO-ZB also enabled
the dynamic monitoring of PD-L1 expression following immunotherapy.
These results demonstrate that [68Ga]Ga-PEG-PRO-ZB can
effectively visualize PD-L1 expression in vivo, offering valuable
insights into the rational design and optimization of small-molecule
based PD-L1 radiotracers.