Novel ACE2 PET imaging with 68Ga-cyc-DX600: a translational advancement for early detection and monitoring in heart failure and myocarditis

Abstract Background Angiotensin-converting enzyme 2 (ACE2), a pivotal regulator of the renin-angiotensin system (RAS), is upregulated in myocardial injury and linked to disease progression in heart failure (HF) and myocarditis. Current non-invasive imaging modalities lack specificity for ACE2 dysfunction, limiting early diagnosis and therapeutic monitoring. Molecular imaging targeting ACE2 may bridge this critical gap by enabling direct visualization of RAS dysregulation in cardiac pathology. Purpose This study aimed to evaluate the diagnostic feasibility of a novel ACE2-targeted PET tracer, 68Ga-cyc-DX600, in preclinical and clinical models of HF and myocarditis, and to compare its performance with the fibroblast activation marker 68Ga-FAPI-04. Methods ACE2-humanized murine models of HF (transverse aortic constriction TAC, n=8) underwent serial 68Ga-cyc-DX600 PET/CT at baseline, 5d, and 15d post-TAC. Yorkshire pigs were used for tracer biodistribution and dosimetry. Clinical validation included 10 patients (HF: n=3, myocarditis: n=1, controls: n=6). ACE2 expression was quantified via SUVmax and target-to-background ratio (TBR), validated by immunohistochemistry. Correlations with serum BNP and LVEF were analyzed. Results In TAC mice, 68Ga-cyc-DX600 PET demonstrated progressive myocardial ACE2 up-regulation (SUVmax: 1.8±0.3 vs. 0.9±0.2 in sham, p0.05 at day 15), correlating with histologic ACE2 density (p=0.01). Compared to 68Ga-FAPI-04, ACE2 imaging detected injury 5 days earlier with superior myocardial specificity (TBR 4.1 vs. 2.3, p=0.02). Clinical scans revealed distinct ACE2 uptake patterns in HF (SUVmax 2.6±0.4 vs. 1.1±0.2 in controls, p0.01) and myocarditis (focal SUVmax3.1±0.5). ACE2 tracer uptake inversely correlated with LVEF and positively with BNP. No significant off-target uptake was observed in major organs. Conclusions 68Ga-cyc-DX600 PET enables specific, non-invasive quantification of ACE2 dysregulation, demonstrating earlier detection of myocardial injury than fibroblast-targeted imaging. Its strong correlation with functional biomarkers and histopathology supports clinical utility for (1) early diagnosis of HF/myocarditis, (2) risk stratification, and (3) personalized RAS modulation therapies. This first-in-human validation establishes ACE2 PET as a transformative tool for precision cardiology.Novel ACE2 PET imaging with 68Ga-cyc-DX6