D Atherosclerotic inflammation imaging using 68ga-dotatate pet vs. 18f-fdg pet: a prospective clinical sudy with molecular and histological validation

Background Inflammation drives atherosclerotic plaque rupture underlying most clinical events. While inflammation can be measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), 18F-FDG lacks cell-specificity and is unreliable for coronary imaging owing to myocardial signal spillover. Up-regulation of somatostatin receptor-2 (SST2) occurs in activated macrophages offering a novel inflammation imaging target. Methods We comprehensively evaluated 68Ga-DOTATATE, a SST2 PET ligand, for imaging atherosclerosis. Target SSTR2 gene expression in macrophages and other immune cells were tested using population-based RNA-sequencing data. Patients with atherosclerosis (n=42) underwent 68Ga-DOTATATE PET imaging in a prospective head-to-head comparison with 18F-FDG. 68Ga-DOTATATE autoradiography, immunostaining and quantitative PCR were performed in macrophages and excised carotid specimens from patients who underwent PET imaging. Results Target SSTR2 expression occurred exclusively in “pro-inflammatory” M1 macrophages, and no other cell type studied in vitro . In clinical imaging, 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit vs. non-culprit arteries in patients with acute coronary syndrome (median difference 0.69 [IQR 0.22 to 1.15], p=0.008) and transient ischaemic attack or stroke (median difference 0.13 [IQR 0.07 to 0.32], p=0.003). 68Ga-DOTATATE mTBRmax accurately predicted stable non-culprit coronary lesions with high-risk CT features (ROC AUC 0.86 [95% CI 0.80 to 0.92], p in vivo 68Ga-DOTATATE PET signals measured from clinical images (r=0.89 [95% CI 0.28 to 0.99], p=0.02). Conclusion We provide gene, cell, plaque and patient-level data, demonstrating that SST2 PET imaging using 68Ga-DOTATATE represents a macrophage-specific marker of atherosclerotic inflammation that outperforms 18F-FDG in the coronary arteries. Future research will explore the utility of 68Ga-DOTATATE inflammation imaging to classify high-risk patients for aggressive therapeutic intervention.