Synthesis and Preclinical Evaluation of Structurally Optimized ⁶⁸ Ga-Labeled CXCR4 Radiotracers for PET Imaging of Atherosclerotic Plaque Inflammation

Atherosclerosis is now widely recognized as a chronic inflammatory condition driven by the recruitment of leukocytes, with CXCR4 playing a critical role in plaque inflammation and disease progression. In this study, we report the development and initial assessment of five novel 68 Ga-labeled small-molecule CXCR4 radiotracers ([ 68 Ga]Ga-SDNUM08–12), engineered on an aniline-benzylamine scaffold with varying PEG linker lengths (PEG1 vs PEG2) and bridging amino acids (glutamic vs aspartic acid). Notably, [ 68 Ga]Ga-SDNUM11, incorporating dual PEG2 units and glutamic acid, exhibited optimal hydrophilicity, rapid blood clearance, excellent stability and high binding affinity. In a turpentine-induced sterile muscle inflammation mouse model, [ 68 Ga]Ga-SDNUM11 emerged as the lead radiotracer with optimal imaging efficacy. Subsequently, in a rat common carotid artery (CCA) atherosclerosis model, it exhibited focal uptake colocalizing with CXCR4-positive plaques. These findings establish [ 68 Ga]Ga-SDNUM11 as a promising CXCR4-targeted radiotracer for PET imaging of atherosclerotic plaque inflammation and cardiovascular risk stratification.