The 68Ga-DOTA-ECL1i radiotracer specifically localized to sites of cardiac injury and bound to CCR2+ monocytes and macrophages in mouse models and human heart failure specimens.
Can 68Ga-DOTA-ECL1i noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in the injured heart?
The novel PET radiotracer 68Ga-DOTA-ECL1i can specifically and noninvasively visualize inflammatory CCR2+ monocyte and macrophage recruitment in the injured heart, offering potential for identifying patients for immunomodulatory therapy.
Rationale: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state conditions, the heart is largely populated by CCR2− (C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy. Objective: To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart. Methods and Results: We synthesized and tested the performance of a positron emission tomography radiotracer ( 68 Ga-DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i extracellular loop 1 inverso) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction). 68 Ga-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography. 68 Ga-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2 −/ − mice, demonstrating target specificity. Autoradiography demonstrated that 68 Ga-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance. Conclusions: These findings demonstrate the sensitivity and specificity of 68 Ga-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.
Heo et al. (Mon,) conducted a other in Cardiac injury and heart failure. 68Ga-DOTA-ECL1i radiotracer vs. Naive mice and CCR2-/- mice was evaluated on Myocardial tracer uptake and localization to sites of tissue injury. The 68Ga-DOTA-ECL1i radiotracer specifically localized to sites of cardiac injury and bound to CCR2+ monocytes and macrophages in mouse models and human heart failure specimens.