J Med Chem. 2026 Jun 8. doi: 10.1021/acs.jmedchem.6c00652. Online ahead of print.
ABSTRACT
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 68Ga-labeled small-molecule CXCR4 radiotracers ([68Ga]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, [68Ga]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, [68Ga]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 [68Ga]Ga-SDNUM11 as a promising CXCR4-targeted radiotracer for PET imaging of atherosclerotic plaque inflammation and cardiovascular risk stratification.
PMID:42258221 | DOI:10.1021/acs.jmedchem.6c00652