Radiosynthesis and Evaluation of a Novel ⁶⁸Ga-Labeled Peptide for PD-L1-Targeted PET Imaging

Although programmed death-ligand 1 (PD-L1)-targeted immunotherapy has demonstrated favorable therapeutic effects, concern regarding a low response rate persists. Our study aimed to develop a novel peptide probe for PD-L1 targeting positron emission tomography (PET)/computed tomography (CT) imaging as an alternative for assessing PD-L1 expression and exploring its potential role in guiding PD-L1 immunotherapy <i>in vivo</i>. The probe targeting PD-L1 was obtained by modifying 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with the peptide CCC, followed by labeling with ⁶⁸Ga. Radiochemical purity, log <i>P</i>, pharmacokinetics, and stability of the probe were evaluated <i>in vitro</i> and <i>in vivo</i>. The systematic evaluation of the probe performance included microPET/CT imaging, biodistribution, biosafety, and an investigation of its use in immunotherapy monitoring. ⁶⁸Ga-DOTA-CCC was successfully synthesized with over 99% radiochemical purity, eliminating the need for purification. The probe exhibited good hydrophilicity and stability and was rapidly metabolized with a short blood clearance half-life of 16.1 ± 0.5 min. Additionally, the probe exhibited an excellent PD-L1 targeting ability, with tumor uptake positively correlating with PD-L1 expression levels in both cellular experiments and microPET/CT imaging. Moreover, the dynamic expression of PD-L1 was assessed using ⁶⁸Ga-DOTA-CCC during atezolizumab administration. ⁶⁸Ga-DOTA-CCC accurately reflects PD-L1 expression and holds promise for precisely guiding PD-L1-targeted immunotherapy.