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.
[1]Shandong Univ, Key Lab Expt Teratol, Minist Educ, Jinan 250012, Shandong, Peoples R China.
[2]Shandong Univ, Res Ctr Expt Nucl Med, Sch Basic Med Sci, Jinan 250012, Shandong, Peoples R China.
[3]Shandong Univ, Qilu Hosp, Dept Radiat Oncol, Jinan 250012, Shandong, Peoples R China.
[4]Zibo Municipal Hosp, Dept Nucl Med, Zibo 255400, Shandong, Peoples R China.
[5]960Th Hosp PLA, Dept Nucl Med, Jinan 250033, Shandong, Peoples R China.
[6]Second Hosp Jilin Univ, Dept Nucl Med, Changchun 130041, Jilin, Peoples R China.
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