Rational Design, Synthesis, and Evaluation of a Novel PET Tracer Targeting Programmed Death-Ligand 1: From Bench to Bedside

Abstract Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint and an important PET/CT imaging target. Current PD-L1-targeted PET/CT tracers have the disadvantage of suboptimal pharmacokinetics and low tumor-to-background contrast. Based on the PD-L1-binding peptide RK-10, we rationally introduced different hydrophilic linkers containing aspartic acid and polyethylene glycol to design a series of novel precursors. Among them, NOTA-AP-PDL1p was selected with the best predicted binding affinity. [68Ga]Ga-AP-PDL1p was subsequently developed. The binding affinity, in vitro and in vivo properties, micro-PET/CT imaging, and first-in-human PET/CT imaging of [68Ga]Ga-AP-PDL1p were conducted. [68Ga]Ga-AP-PDL1p exhibited high affinity to human PD-L1, good in vitro and in vivo characteristics, as well as favorable in vivo pharmacokinetics. Moreover, [68Ga]Ga-AP-PDL1p administration also upregulates the PD-L1 expression in tumor xenografts. Pilot clinical studies showed good in vivo distribution of [68Ga]Ga-AP-PDL1p, and the uptake of [68Ga]Ga-AP-PDL1p in tumor lesions correlates with its PD-L1 expression. These promising results highlight the potential of [68Ga]Ga-AP-PDL1p as a novel tracer for PET imaging of the PD-L1 expression.