Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

Abstract

Acute tissue inflammation after myocardial infarction influences healing and remodeling and has been identified as a target for novel therapies. Molecular imaging holds promise for guidance of such therapies. The amino acid 11C-methionine is a clinically approved agent which is thought to accumulate in macrophages, but not in healthy myocytes. We assessed the suitability of positron emission tomography (PET) with 11C-methionine for imaging post-MI inflammation, from cell to mouse to man. Uptake assays demonstrated 7-fold higher 11C-methionine uptake by polarized pro-inflammatory M1 macrophages over anti-inflammatory M2 subtypes (p<0.001). C57Bl/6 mice (n=27) underwent coronary artery ligation or no surgery. Serial 11C-methionine PET was performed 3, 5 and 7d later. MI mice exhibited a perfusion defect in 32-50% of the left ventricle (LV). PET detected increased 11C-methionine accumulation in the infarct territory at 3d (5.9±0.9%ID/g vs 4.7±0.9 in remote myocardium, and 2.6±0.5 in healthy mice; p<0.05 and <0.01 respectively), which declined by d7 post-MI (4.3±0.6 in infarct, 3.4±0.8 in remote; p=0.03 vs 3d, p=0.08 vs healthy). Increased 11C-methionine uptake was associated with macrophage infiltration of damaged myocardium. Treatment with anti-integrin antibodies (anti-CD11a, -CD11b, -CD49d; 100µg) lowered macrophage content by 56% and 11C-methionine uptake by 46% at 3d post-MI. A patient study at 3d after ST-elevation MI and early reperfusion confirmed elevated 11C-methionine uptake in the hypoperfused myocardial region. Targeting of elevated amino acid metabolism in pro-inflammatory M1 macrophages enables PET imaging-derived demarcation of tissue inflammation after MI. 11C-methionine-based molecular imaging may assist in the translation of novel image-guided, inflammation-targeted regenerative therapies.

Molecular Imaging to Monitor Left Ventricular Remodeling in Heart Failure

“…Inflammatory response after MI is another target that has been studied for predicting functional recovery after MI. Studies have shown increased myocardial uptake of metabolic markers 18F-FDG [118] and 11C-methionine [119] reflecting inflammatory activity after recent MI. Uptake of 18F-FDG early after an acute MI inversely correlated with the degree of functional recovery [119].…”

“…Studies have shown increased myocardial uptake of metabolic markers 18F-FDG [118] and 11C-methionine [119] reflecting inflammatory activity after recent MI. Uptake of 18F-FDG early after an acute MI inversely correlated with the degree of functional recovery [119]. Pentixafor is a novel 68Ga-labeled PET tracer that binds to CXCR4 chemokine receptor mediating leukocytes accumulation at the sites of inflammation [120][121][122].…”

Postconditioning Accelerates Myocardial Inflammatory Resolution Demonstrated by ¹⁴C-Methionine Imaging and Attenuates Ventricular Remodeling After Ischemia and Reperfusion

“…20 Another concern is post-infarction remote FDG uptake, which is difficult to differentiate as either inflammatory cell infiltration or increased metabolism in viable but compromised cardiomyocytes. 16,20 In this respect, 11 C-methionine PET has an advantage over 18 F-FDG PET as a clinical examination as 11 C-methionine PET does not require any special preparation, and no phenomenon such as increased remote myocardial uptake has been reported. The drawback of 11 C-methionine is its limited availability compared with 18 F-FDG.…”

Molecular Imaging in Ischemic Heart Disease

“…11 C-methionine is a well-characterized PET radiotracer commonly used for detection of brain tumors. Thackeray et al demonstrated in a murine model of MI that PET imaging with 11 C-methionine allows for detection of inflammation in the injured myocardium at the early stages post-MI and observed a signal decline over 7 days which was paralleled by a decrease of activated inflammatory cells [ 93 ] (Fig. 5 ).…”